Abstract

Materials and Methods: We retrospectively analyzed 82 patients who were followed-up regularly and did not receive neoadjuvant or adjuvant chemotherapy. We classified patients as having Gleason scores ≥7 and <7, PSA values ≥10 ng/ml and <10, biochemical relapse positive or negative, T stages ≥T2 and Results: During 60-month follow-up, 66 (80.4%) patients had no relapse, while in 8 (9.8%) patients had early, and other 8 (9.8%) patients had a late biochemical relapse. There was no statistically significant difference between these 3 groups of patients according to their age, tPSA levels, and BMI parameters. We compared IGF-1 levels with tumor burden, tPSA levels, tumor grade, and Gleason scores without any significant difference between these parameters. When we accepted IGF-1 cut-off values as 60 ng/ml, we observed higher Gleason scores (≥ 7 and more) in these patients. There was a weak relationship between IGF-1 levels of non-relapse and early relapse patients (p:0.078). However, when we evaluated IGF-1 levels among patients with relapse, the early relapse group had significantly higher IGF-1 levels (p: 0.006). When the cut-off value of IGF-1 was accepted as 60 ng/ml, which was found to be significant for Gleason score, the early relapse group had significantly higher IGF-1 levels compared to the non-relapse group (p:0.023).

Conclusions: According to our study, the IGF-1 level has a predictive value for showing biochemical recurrence after surgery. Nevertheless, considering the number of patients, we need randomized controlled trials with a large number of patients.

Introduction

In carcinogenesis, inflammation, genetic, and multiple growth factors play an important role. Insulin is essential for both energy metabolism and glucose regulation. Also, it may have a role in PCa development because of its potent mitogenic and growth factor-like effects [2].

Insulin has a suppressive effect on insulin-like growth factor binding protein (IGFBP-1) secretion. Moreover, according to this relation, IGFBP-1 levels might be an essential factor for insulin activity on the target tissue [3]. Besides the effect of insulin on tissues, IGFBP-1 binds to insulin-like growth factor (IGF-1) with high affinity and decreases its level and effect [4]. In epidemiologic studies, low-risk PCas, are mostly related to high IGF-1 plasma levels. However, it is not definite whether IGF-1 and insulin interrelation causes PCa development or not [5].

Positive surgical margin (PSM) detected in pathology specimens after radical prostatectomy (RP) was accepted as a poor prognostic factor and has been reported as 10% in articles about RP. Both pathologic and biochemical findings have been investigated for estimation of biochemical recurrence in noninvasive cases after RP. According to recent studies, total tumor volumes and maximum tumor diameters are not enough to predict biochemical recurrence [6].

In this study, we aimed to find the contribution of IGF-1 levels in predicting biochemical relapse of RP patients with negative surgical margins (NSM).

Materials and Methods

PCa patients were classified as having Gleason scores ≥7 and <7, PSA values ≥10 ng/ml and <10, biochemical relapse positive or negative, T stages ≥T2 and Statistical Analysis
For statistical analyses, IBM SPSS version 22.0 (SPSS Inc, Chicago, IL) for Windows was used. Descriptive data were defined as number, percentage, mean ± standard deviation. Normal distribution of data was tested with the Kolmogorov-Smirnov test. Mann-Whitney U test was used for the analysis of quantitative data that did not show normal distribution. Kruskal- Wallis Test was used to analyze quantitative data of more than 2 groups that did not show normal distribution. For qualitative data, chi-square test, and when chi-square assumptions were not met, Fisher"s exact test was used. The ability of IGF-1 to predict the presence of relapse was evaluated by receiver operating characteristic (ROC) curve analysis and area under curve (AUC) values of the analysis were presented. Cut-off values were calculated according to Youden index. p<0.05 was considered statistically significant.

Results

Table 1: Distribution of age, PSA, BMI of all study patients

We compared IGF-1 levels with tumor burden, tPSA levels, tumor grade, Gleason scores detected in biopsy materials, and tumor specimens (GSs), without any significant difference between these parameters. When we accepted IGF-1 cut-off value as 60 ng/ml, we detected higher Gleason scores ( ≥ 7) (specimen GS p=0.011; biopsy GS p=0.017) in these patients (Table 2). There was statistically weak relationship between non-relapse and early relapse patients in terms of IGF-1 levels (p: 0.078) (Table 3).

Table 2: Distribution of IGF-1 values , tumor burden, stage, tPSA, and GS

Table 3: Comparison of patient groups according to IGF-1 levels

However, when we compared IGF-1 levels between the relapse groups, the early relapse group had higher IGF-1 levels significantly (p: 0.006) and also, this association had high sensitivity and specificity in ROC analysis (Figure 1).

Figure 1: Relationship between early, and late relapse groups as for IGF-1 levels

The non-relapse and relapse groups were compared again using a cut-off value of 60 ng/ml. IGF-1 levels of most of the patients in the early relapse group were more than 60 ng/ml (p: 0.023). We did not observe a significant difference between the late relapse and the non-relapse groups in terms of IGF-1 levels (p=0.12) (Table 3).

Finally, a statistically significant difference existed between early relapse and non-relapse groups in terms of IGF-1 levels with high degrees of sensitivity and specificity (Figure 2).

Figure 2: Relationship between early, and late relapse groups as for IGF-1 levels (cut-off for IGF-1 60 ng / ml)

Discussion

RP a curative treatment for localized PCa patients. Surgical technique has improved with the help of technologic developments during the last 10 years. But biochemical relapse still a problem in 27-53% of these patients [9]. Although biochemical relapse is mostly seen as local recurrence, it can also manifest as symptomatic or asymptomatic systemic disease. Increase in biochemical values indicate PCa recurrence but may not have an effect on quality of life and overall survival. The purpose of biochemical relapse control is to prevent development of metastatic disease and decrease metastasis-related morbidity and mortality rates. Also, we can avoid unnecessary adjuvant therapy in PCa patients with low risk of disease progression [10].

There are many reasons directly or indirectly related to PCa development [11]. IGF-1 and its binding proteins are produced in healthy and carcinomatous prostate tissues, and stimulate cellular proliferation with IGF-1 receptor activation [12]. While some studies report that IGF-1 levels are high in PCa patients [13], there are also studies that do not support this [14,15].

In a study investigating IGF-1 levels in PCa patients, the patients were grouped according to their specimen GSs. PCa patients with low-grade GSs (GS<7) had significantly higher IGF-1 levels than the control group, but any significant difference was not detected in terms of IGF-1 levels between PCa patients with low-, and high-grade GSs (GS≥7) PCa patients did not have a significant difference. Also, in localized PCa patients, IGF-1 levels were correlated with the disease grade. However any difference was not detected between locally advanced and metastatic PCa patients as for IGF-1 levels in this study [16].

When we did not specified the cut-off value for IGF-1 in our study, there was no significant correlation between IGF-1 levels and GSs of specimens or biopsy materials. However, if we specified the cut-off value as 60 ng/ml, both biopsy material and specimen GS's were significantly higher in patients with IGF-1 levels above 60 ng/ml (specimen GS p=0.011; biopsy material GS p=0.017).

Koliakos et al. investigated 147 patients with PCa and benign prostate hyperplasia (BPH) for the effect of IGF-1 levels on the early diagnosis of PCa patients. There was no difference between IGF-1 levels, but the free/total (f/t) PSA ratio was lower in the PCa group. They used this result for its correlation with PSA/IGF-1 level. PCa patients had significantly higher PSA/IGF-1 levels (p=0.002). But, for the BPH group, the correlation was weak (P=0.042). According to ROC analysis, as a screening test for PCa, PSA/IGF-1 level had higher sensitivity and specificity than PSA and f/t PSA ratio [17].

Nam et al. measured IGF-1 levels in precancerous prostatic patients. High-grade prostatic intraepithelial neoplasia (HGPIN) detected in biopsy materials was accepted as a precancerous pathology. Their IGF-1 levels were significantly higher than the control group (p=0.01) [18].

In our study, in addition to the effect of IGF-1 levels on the PSA relapse in cured PCa patients, we also calculated correlations of IGF-1 levels with T stage, total PSA levels, and tumor burden in specimens in the same group. As a result, IGF-1 values higher than 60 ng/ml had a weak correlation with increased tumor burden and high T stage. However, any statistically significant correlation with total PSA levels was not detected.

Many studies have investigated the relationship between pathogenesis of PCa, and IGF-1. However, there are few studies on biochemical relapse after RP and its relationship with IGF-1. Guidelines have determined the cut-off value of biochemical relapse after RP as 0.2 ng/ml. Times to early or late relapse have not been standardized in the literature. Various studies accept this period as 3 to 36 months [19].

Shahabi et al. have searched risk factors for biochemical relapse in 2262 RP patients. These patients had not received any neoadjuvant or adjuvant treatment (pT2-3N0M0) [20]. In this study, they accepted the first 35 months after RP as early relapse and more than 35 months as late relapse. They found an association between early relapse, GS≥7, PSM, and ≥pT3a stages. Besides, late relapse was associated with GS 7 (4 + 3), high preoperative PSA level, and ≥pT3a stage in the same study.

According to the literature, we accepted the relapse time classification limit as 18 months. IGF-1 levels in non-relapse and late relapse groups were not statistically different. There was a weak correlation between the early relapse and the non-relapse group. However, when the early and the late relapse groups were compared a significantly higher IGF-1 levels were found in the early relapse group (p=0.006).

Also, we investigated cut-off IGF-1 levels for biochemical relapse risk factors. When we accepted 60 ng/ml for a cut-off value for IGF-1 which was significant as for GSs, IGF-1 levels were higher in the early relapse group compared to the non-relapse group (p=0.023).

Our study also has limitations. First of all, our study was designed retrospectively. In addition, the small number of patients is one of the limitations.

Conclusion

Ethics Committee Approval: The study was approved by Turkey Yuksek Ihtisas Training and Research Hospital Education Plan and Coordination Board, Cankaya, Ankara, Turkey (Decision No: 03 July 2014/B.10.4.ISM.4.06.00.15).

Informed Consent: An informed consent was obtained from all the patients.

Publication: The results of the study were not published in full or in part in form of abstracts.

Peer-review: Externally peer-reviewed.

Authorship Contributions: Any contribution was not made by any individual not listed as an author. Concept – Y.K., E.U.; B.B.K, M.E.P.; Design – Y.K., E.U., B.B.K, M.E.P.; Supervision – Y.K., E.U., C.C., M.E.P.; Resources – Y.K., E.U., B.B.K, M.E.P.; Materials – Y.K., E.U., B.B.K, M.E.P.; Data Collection and/or Processing – Y.K., E.U., B.B.K, M.E.P.; Analysis and/or Interpretation – Y.K., E.U., B.B.K, S.T., C.C., M.E.P.; Literature Search – Y.K., E.U., B.B.K, M.E.P.; Writing – Y.K., E.U., B.B.K, S.T.; Critical Review – Y.K., S.T., C.C., M.E.P.

Conflict of Interest: The authors declare that they have no conflict of interest.

Financial Disclosure: The authors have declared that they did not receive any financial support for the realization of this study.

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