Ovarian cancer is the most frequent cause of death from gynaecological cancer and the fourth most frequent cause of cancer-related death in women in Europe and the United States [
Clinicopathological features known to be prognostic variables for ovarian cancer are surgical stage (FIGO stage), histological grade, lymph node involvement, residual tumour size after cytoreductive surgery, histological subtype, ascites, and age. According to the three-year analysis of the FIGO Annual Report on the Results of Treatment in Gynaecological Cancer, stage, grade, and residual tumour size have the greatest prognostic value [
It is well established that angiogenesis, the formation of new blood vessels, is necessary for the growth and metastatic spread of solid tumours [
Several studies have found VEGF levels to be significantly higher in the tissues and biological fluids of women with ovarian cancer compared with healthy controls [
Eligible studies in English and Italian were identified in MEDLINE (PubMed version) from VEGF discovery to October 2011 using the terms VEGF, “vascular endothelial growth factor” and synonyms, “ovarian cancer,” “ovary cancer,” and synonyms. We searched studies that used these terms in title and abstract and that was indexed by bibliographic database with the Mesh term “ovarian neoplasms.” We searched the database using these terms separately and also in combination.
Relevant papers were independently selected by two of the reviewers (E. Bandiera and R. Franceschini) based on the following inclusion criteria: studies that evaluated (i) sVEGF levels before any surgical and chemotherapeutic treatment; (ii) the association of sVEGF levels with the established clinicopathological prognostic factors (FIGO stage, tumour grade, residual tumour size, lymph node involvement, histological type, ascites, age); (iii) the value of sVEGF levels in predicting patients’ outcomes (overall survival (OS), disease-free survival (DFS), progression free survival (PFS)). Any disagreement in the inclusion of one study between two reviewers was solved by discussion.
Two of the reviewers (E. Bandiera and R. Franceschini) independently reviewed each study and abstracted data on first author, country of study, study characteristics (study design, followup duration, therapy), clinical and pathological variables, and study outcomes.
Our search strategy identified 758 journal abstracts. From these, we retrieved for further evaluation 15 full-text articles focused on the relationship between circulating preoperative VEGF and prognosis in ovarian cancer. Of these 15 articles, nine [
Six studies were excluded. The paper by Manenti et al. [
The nine selected studies were published between 1996 and 2010 and included 529 patients from seven countries. All but one [
All studies enrolled women with newly diagnosed and histopathologically confirmed ovarian cancer except the one by Cooper et al. [
Clinical and demographic characteristics of patients.
Author, year | ||||||||||
Tempfer | Gadducci | Chen | Oehler and Caffier, 2000 [ | Cooper | Li | Harloziňska | Hefler | Mahner | ||
Origin and Dates | 1990–1995 | 1990–1997 | 1992–1998 | Germany | 1995–2000 | 1999–2001 | 1997–2002 | 1990–2003 | 1996–2004 | |
Number of cases | 60 | 53 | 56 | 41 | 101$ | 50 | 86 | 314 | 37 | |
Age, mean or median* (range), years | 55.6* | 59* (23–81) | 52.5* (21–88) | 62 (32–83) | 64 | NA | NA | 59.9 | 58.61* | |
FlGO stage | I | 7 | 19 | 14 | 5 | 20 | 17 | 14 | 56 | 1 |
II | 12 | 1 | 6 | 2 | 9 | 27 | 1 | |||
III | 27 | 22 | 32 | 30 | 81 | 33 | 37 | 177 | 29 | |
IV | 14 | 11 | 4 | 4 | 26 | 46 | 6 | |||
Grade | G1 | 21 | 17 | 21 | NA | 39 | 13 | 19 | 60 | 0 |
G2 | 39 | 12 | 35 | NA | 41 | 88 | 9 | |||
G3 | 24 | NA | 61 | 30 | 26 | 150 | 27 | |||
Epithelial ovarian cancer | Serous | 28 | 33 | 30 | 32 | 81 | 15 | 49 | 166 | 31 |
Mucinous | 23 | 6 | 4 | 2 | 9 | 4 | 41 | 0 | ||
Undifferentiated | 3 | 6 | 8 | 0 | 19 | 13 | 15 | 4 | ||
Endometrioid | 3 | 7 | 10 | 7 | 0 | 20 | 39 | 1 | ||
Clear cell | 2 | 0 | 4 | 0 | 0 | 0 | 0 | 9 | 1 | |
Others | 1 | 1 | 0 | 0 | 0 | 0 | 0 | 44 | 0 | |
Nonepithelial ovarian cancer | 0 | 0 | 0 | 0 | 0 | 7 | 0 | 0 | 0 | |
Ascites | >500 mL/presence** | NA | 21** | NA | NA | 67** | 22 | 64** | NA | 21 |
<500 mL/absence** | NA | 12** | NA | NA | 34** | 28 | 22** | NA | 15 | |
Residual disease | <2 or 1*** cm | 38 | 9 | 40 | 11 | 68*** | 44 | 32 | 164*** | 22 |
>2 or 1*** cm | 22 | 24 | 16 | 30 | 33*** | 6 | 54 | 64*** | 14 | |
Lymph node involvement | yes | 23 | NA | NA | NA | NA | 12 | NA | 38 | 10 |
no | 37 | NA | NA | NA | NA | 38 | NA | 63 | 11 |
$: Cooper study contains a small group of peritoneal and fallopian tube malignant cancers; NA: not available data; *: Median values; **: Numbers of patients with presence/absence of ascites; ***: Numbers of patients with residual disease < or >1 cm.
Surgery for optimal tumour debulking included hysterectomy, bilateral salpingo-oophorectomy, omentectomy [
Surgery was followed by chemotherapy consisting of platinum analogues alone [
The sVEGF assay method was similar across studies. Venous blood was taken preoperatively from all patients. All sera were separated and stored at ≤20°C. Seven studies [
Data on the precision of sVEGF assays were reported in three studies [
The association between sVEGF concentrations and FIGO stage, tumour grade, residual tumour size, lymph node involvement, histological type, ascites, and age was analysed by 89%, 89%, 89%, 44%, 67%, 56%, and 78% of studies respectively (Table
Association between sVEGF and clinicopathological characteristics of patients.
Variable | Author, year | No. cases | Reported statistics for VEGF | Variable type | Statistical significance of association |
---|---|---|---|---|---|
Stage | Tempfer et al., 1998 [ | 60 | md | I/II versus III/IV | NO |
Gadducci et al., 1999 [ | 53 | md | I versus II and III versus IV | NO | |
Chen et al., 1999 [ | 56 | md | I/II versus III/IV | NO | |
Oehler and Caffier, 2000 [ | 41 | m | categorical | NO | |
Cooper et al., 2002 [ | 101 | md | I/II versus III/IV | NO | |
Li et al., 2004 [ | 50 | m | I/II versus III/IV | YES | |
Harloziňska | 86 | NA | I/II versus III/IV | NO | |
Hefler et al., 2006 [ | 314 | m | categorical | NO | |
Grade | Tempfer et al., 1998 [ | 60 | md | G1 versus G2/G3 | YES |
Gadducci et al., 1999 [ | 53 | md | G1-G2 versus G3 | NO | |
Chen et al., 1999 [ | 56 | md | G1 versus G2/G3 | YES | |
Cooper et al., 2002 [ | 101 | md | G1-G2 versus G3 | NO | |
Li et al., 2004 [ | 50 | m | G1-G2 versus G3 | YES | |
Harloziňska | 86 | NA | G1 versus G2/G3 | NO | |
Hefler et al., 2006 [ | 314 | m | categorical | NO | |
Mahner et al., 2010 [ | 37 | md | G2 versus G3 | NO | |
Residual tumour size (cm) | Tempfer et al., 1998 [ | 60 | md | ≥2 versus <2 | NO |
Gadducci et al., 1999 [ | 53 | md | ≥2 versus <2 | NO | |
Chen et al., 1999 [ | 56 | md | ≥2 versus <2 | NO | |
Oehler and Caffier, 2000 [ | 41 | m | ≥2 versus <2 | NO | |
Cooper et al., 2002 [ | 101 | md | ≥1 versus <1 | NO | |
Li et al., 2004 [ | 50 | m | ≥2 versus <2 | YES | |
Hefler et al., 2006 [ | 314 | m | ≥1 versus <1 | YES | |
Mahner et al., 2010 [ | 37 | md | ≥0 versus <0 | NO | |
Lymph node involvement | Tempfer et al., 1998 [ | 60 | md | yes versus no | NO |
Li et al., 2004 [ | 50 | m | yes versus no | YES | |
Hefler et al., 2006 [ | 314 | m | yes versus no | NO | |
Mahner et al., 2010 [ | 37 | md | yes versus no | NO | |
Histological type | Tempfer et al., 1998 [ | 60 | md | serous or mucinous versus others | NO |
Gadducci et al., 1999 [ | 53 | md | serous versus others | NO | |
Chen et al., 1999 [ | 56 | md | serous or mucinous versus others | NO | |
Oehler and Caffier, 2000 [ | 41 | m | categorical | NO | |
Li et al., 2004 [ | 50 | m | categorical | NO | |
Harloziňska | 86 | NA | categorical | NO | |
Ascites (mL) | Gadducci et al., 1999 [ | 53 | md | presence versus absence | YES |
Cooper et al., 2002 [ | 101 | md | presence versus absence | YES | |
Li et al., 2004 [ | 50 | m | ≥500 versus <500 | YES | |
Harloziňska | 86 | NA | presence versus absence | NO | |
Mahner et al., 2010 [ | 37 | md | ≥500 versus <500 | NO | |
Age (years) | Tempfer et al., 1998 [ | 60 | md | ≥50 versus <50 | NO |
Gadducci et al., 1999 [ | 53 | NA | NA | NO | |
Chen et al., 1999 [ | 56 | md | ≥50 versus <50 | NO | |
Oehler and Caffier, 2000 [ | 41 | m | ≥60 versus <60 | NO | |
Cooper et al., 2002 [ | 101 | md | ≥64 versus <64 | NO | |
Hefler et al., 2006 [ | 314 | m | continuous variable | NO | |
Mahner et al., 2010 [ | 37 | md | ≥61 versus <61 | NO |
Md: median, m: media, NA: not available data.
When the median (or mean) of sVEGF values was evaluated in relation to clinicopathological features, a statistically significant association between the level of sVEGF and FIGO stage, tumour grade, residual tumour size, lymph node involvement, and presence of ascites was found in at least one study. By contrast, no statistically significant association was found between sVEGF levels and histological type or age.
Tempfer et al. [
In evaluating its association with outcome variables, the levels of sVEGF were dichotomised using different cut-offs: 75th percentile [
In the univariate analyses, seven [
Univariate and multivariate analyses for survival were reported in Table
Univariate and multivariate analyses for overall survival.
Variable | Author, year | No. cases | Cut-off | Univariate analysis RR or HR, | Multivariate analysis RR or HR, |
VEGF (pg/mL) | Tempfer et al., 1998 [ | 60 | ≥826 versus <826 | ||
Gadducci et al., 1999 [ | 53 | NA | NA | ||
Chen et al., 1999 [ | 56 | NA | |||
Oehler and Caffier, 2000 [ | 41 | ≥440 versus <440 | |||
Cooper et al., 2002 [ | 101 | ≥380 versus <380 | |||
Li et al., 2004 [ | 50 | ≥100 versus <100 | |||
Harloziňska et al., 2004 [ | 86 | ≥750 versus <750 | |||
Hefler et al., 2006 [ | 314 | continuous variable | |||
Mahner et al., 2010 [ | 37 | 171 | NA | ||
Stage | Tempfer et al., 1998 [ | 60 | I/II versus III/IV | ||
Chen et al., 1999 [ | 56 | I/II versus III/IV | NA | ||
Oehler and Caffier, 2000 [ | 41 | I/II versus III/IV | |||
Cooper et al., 2002 [ | 101 | I/II versus III/IV | |||
Li et al., 2004 [ | 50 | NA | NA | ||
Harloziňska et al., 2004 [ | 86 | I/II versus III/IV | |||
Hefler et al., 2006 [ | 314 | NA | |||
Grade | Tempfer et al., 1998 [ | 60 | G1 versus G2/3 | ||
Chen et al., 1999 [ | 56 | G1 versus G2/3 | NA | ||
Cooper et al., 2002 [ | 101 | G1/2 versus G3 | |||
Li et al., 2004 [ | 50 | NA | NA | ||
Harloziňska et al., 2004 [ | 86 | G1 versus G2/3 | |||
Hefler et al., 2006 [ | 314 | NA | |||
Residual tumor size (cm) | Chen et al., 1999 [ | 56 | ≥2 versus <2 | NA | |
Oehler and Caffier, 2000 [ | 41 | 0 versus | |||
Cooper et al., 2002 [ | 101 | 0 versus | |||
Li et al., 2004 [ | 50 | NA | NA | ||
Harloziňska et al., 2004 [ | 86 | ≥2 versus <2 | |||
Hefler et al., 2006 [ | 314 | ≥1 versus <1 | |||
Lymph node involvement | Tempfer et al., 1998 [ | 60 | Yes versus No | ||
Li et al., 2004 [ | 50 | NA | NA | ||
Histological type | Chen et al., 1999 [ | 56 | serous/mucinous versus others | NA | |
Li et al., 2004 [ | 50 | NA | NA | ||
Harloziňska et al., 2004 [ | 86 | serous versus others | |||
Hefler et al., 2006 [ | 314 | serous versus others | |||
Ascites | Cooper et al., 2002 [ | 101 | presence versus absence | ||
Age (years) | Oehler and Caffier 2000 [ | 41 | ≥60 versus <60 | ||
Cooper et al., 2002 [ | 101 | NA | |||
Harloziňska et al., 2004 [ | 86 | ≥62 versus <62 | |||
Hefler et al., 2006 [ | 314 | continuous variable |
*:Subset of 40 patients with residual tumour size ≤2 cm; °:Subset of 56 patients with stage I; §:Subset of patients with stages I-II;
As expected, clinicopathological features known to be prognostic variables for EOC such as FIGO stage, tumour grade, residual tumour size after cytoreductive surgery, lymph node involvement, and age have been shown as independent prognostic factors in at least one study. Notably, sVEGF, in comparison with others prognostic variables, was reported as independent prognostic factors by the majority of studies.
Chen et al. [
Li et al. [
A planned subgroup analysis was performed for 56 patients with FIGO stage I in the study by Hefler et al. [
Only three [
Univariate and multivariate analyses for disease free survival.
Variable | Author, year | No. cases | Cut-off | Univariate analisys RR, | Multivariate analisys RR, |
---|---|---|---|---|---|
Tempfer et al., 1998 [ | 60 | ≥826 versus <826 | |||
VEGF (pg/mL) | Chen et al., 1999 [ | 56 | NA | ||
Harloziňska et al., 2004 [ | 314 | ≥750 versus <750 | |||
Stage | Tempfer et al., 1998 [ | 60 | I/II versus III/IV | ||
Chen et al., 1999 [ | 56 | I/II versus III/IV | NA | ||
Harloziňska et al., 2004 [ | 314 | I/II versus III/IV | |||
Grade | Tempfer et al., 1998 [ | 60 | G1 versus G2/G3 | ||
Chen et al., 1999 [ | 56 | G1 versus G2/G3 | NA | ||
Harloziňska et al., 2004 [ | 314 | G1 versus G2/G3 | |||
Residual tumour size | Chen et al., 1999 [ | 56 | ≥2 versus <2 | NA | |
Harloziňska et al., 2004 [ | 314 | ≥2 versus <2 | |||
Lymph node involvement | Tempfer et al., 1998 [ | 60 | Yes versus No | ||
Histological type | Chen et al., 1999 [ | 56 | serous/mucinous versus others | NA | |
Harloziňska et al., 2004 [ | 314 | serous versus others | |||
Age (years) | Harloziňska et al., 2004 [ | 314 | ≥62 versus <62 |
*:Subset of 40 patients with residual tumour size ≤2 cm; NA: not available data; NS: non-significant statistical analysis.
Chen et al. [
Finally, only Mahner et al. [
The management of patients with ovarian cancer is based on established prognostic factors such as tumour stage, histological grade, and residual tumour size after cytoreductive surgery. Recently, the concept of standard chemotherapeutic treatment with platinum/taxane combination, the necessity of adjuvant chemotherapy in early stages of disease, the use of neoadjuvant chemotherapy for patients expected not to be optimally debulked at primary cytoreductive surgery and the use of consolidation chemotherapy for patients at high risk of recurrence have all been questioned.
The need for additional prognostic data to calibrate therapeutic tools on an individual basis in women with ovarian cancer seems obvious. In contrast to other malignancies, no serological prognostic parameter other than CA125 has been shown to have clinical value in ovarian cancer, even though CA125 serum levels at diagnosis are not associated with OS and DFS [
From VEGF discovery till 2011, nine studies that directly correlated preoperative sVEGF with ovarian cancer outcome were published. Structured data extraction was performed on the articles to compare study populations, sVEGF assays, associations between sVEGF and clinicopathological characteristics, patient management, and outcome evaluation. Unfortunately, because of the heterogeneity of the studies and missing or incomplete information, it is not possible to pool data and to perform a meta-analysis in order to obtain univocal indications about sVEGF’s prognostic value.
The data reported in Tables
In order to find out how sVEGF influences ovarian cancer biology, all studies analysed the association between sVEGF and the clinicopathological characteristics of the patients. The results seem to confirm that VEGF plays an important biological role in the pathogenesis of ascites [
Interestingly, in our review of literature, sVEGF appears to be the best prognostic marker for OS in comparison with the established prognostic variables, since it stands out as an independent prognostic factor in most of the studies considered.
The scarcity of the data on the relationship between sVEGF levels and DFS makes it difficult to draw any firm conclusions in this regard. However, it is worth noting that sVEGF appears to be an independent prognostic factor for DFS in 2 out of 3 studies, as well as tumor stage and grade.
Chen et al. [
In conclusion, almost all of the studies analysed in the present review, including the largest one by Hefler et al. [
Thus, from analysis of the literature reported in this review, as well as from results reported by recent clinical trials, sVEGF appears to be a promising prognostic factor in ovarian cancer that could identify a subgroup of patients with poor survival and higher risk of death that could benefit of bevacizumab therapy to improve their outcome.
This work is supported by National Ministry of University and Research Project FIRB 2003 entitled “Nanosized cancer polymarker biochip,” CODE RBLA03S4SP, Rome, Italy, by grants from the Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN Project, prot2008AZJM9E), Rome, Italy, and by the Angelo Nocivelli Foundation, Brescia, Italy. This study was also supported by grants NIH R01 CA122728-01A2 to AS, by NIH Research Grant CA-16359 from the National Cancer Institute, and by grants 501/A3/3 and 0027557 from the Italian Institute of Health (ISS) to AS.