Comparison of Aggressiveness in Central Versus Peripheral T1a Clear-Cell Renal Cell Carcinoma - Beyond the Abstract

Surgical treatment of kidney cancer remains the gold standard for localized disease. It can also be successfully used to treat locally advanced disease. Over the last decades, partial nephrectomy has shown non-inferiority compared to radical surgery. All indications regarding the type of surgery are mainly based on the T-stage of the disease and the risk of potential complications according to nephrometry scoring.

However, there always exists a difference in the experience of surgeons: tumors that might seem complex for one surgeon can be a standard case for performing partial nephrectomy for another. Also, not all tumors are biologically equal, thus different treatment approaches might be needed, which looks quite important to consider before the treatment begins.

The current work is part of the scientific direction investigated between 2010 and 2022 at the National Cancer Institute of Ukraine. Material gathered during this period aimed to look at the problem of partial nephrectomy from another angle, determining unusual indicators that can influence the possibility of performing organ-sparing surgery. Primary research was mainly devoted to measuring remaining functioning parenchyma volume (RFPV), as an obvious parameter that predicts the part of the kidney to be left after resection of the tumor is done. A specially created formula to calculate this parameter using CT scans was developed. Initial findings indicate that surpassing 55% of healthy tissue with this criterion may result in the restored functioning of the remaining part, potentially regaining its previous level of activity after partial nephrectomy. Further multifactorial analysis of a large cohort of patients with RFPV data was conducted. To determine the relationship between the risk of radical or partial nephrectomy, the multivariate predictive modeling method containing 12 parameters was used. For polar and lateral tumor locations, the functioning parenchymal volumes of over 58 and 67%, respectively, served as partial nephrectomy indications. However, for medial lesions, the primary PN indication is a tumor size less than 38 mm. Based on the ROC curve comparison, there were no statistically significant differences between the AUCLin_12 and AUCMLP_3 (p = 0.12); thus, the reduced number of factor indicators from 12 to 3 did not worsen the model's predictive qualities (see Figure 1).

Figure 1: ROC curves of the neural network predictive models for RN: 1 – AUC lin 12, 2 – AUC lin 3, 3 – AUC MLP 3 RN, radical nephrectomy.

The mentioned approach was further implemented in practice in the department, showing quite high levels of sensitivity and specificity to detect candidates for organ-sparing surgery. It also prompted further investigations extending the role of partial nephrectomy. Whereas, 2 cycles of neoadjuvant targeted therapy (TT) were used to decrease the size of complex primary tumors and perform a kidney-preserving surgery. After two blocks of neoadjuvant TT in patients with localized RCC, the mean kidney tumor size reduction was 12.3 mm from (M ± SD (95% CI)) 60.8 ± 19.7 (55.7–66) to 48.5 ± 16.4 (44.2–52.8) mm (t-test; p < 0.001), which could have influenced surgical tumor complexity. The use of neoadjuvant TT in patients with localized RCC (Mann–Whitney U test; p < 0.001) increased the median (Me) RFPV by 21% from (Me [25%; 75%]) 62 (57; 77) mm to 83 (70; 90) mm. Neoadjuvant TT in patients with surgically complex localized RCC resulted in clinical tumor regression, providing a higher rate of conservative surgical treatment compared to similar patients without TT (see Figure 2).  
Figure 2: Percentage of regression of localized RCC after 2 cycles of neoadjuvant TT according to the results of spiral CT with bolus contrast enhancement, n = 58. Stable disease according to RE-CIST 1.1 (up to 30% regression) is shown as yellow, and partial regression according to RECIST 1.1 (30% regression to 100%), green. RCC, renal cell carcinoma; CT, computed tomography; TT, targeted therapy; RECIST, Response Evaluation Criteria in Solid Tumours.

The efficacy of cytoreductive partial nephrectomy was also evaluated in the metastatic setting. The influence of partial and radical nephrectomy on survival outcomes in patients with metastatic disease undergoing surgery was estimated. We found that partial nephrectomy was associated with a significantly lower mortality risk (HR = 0.62, 95% CI 0.48–0.82, p = 0.011). The 7-year overall survival rate was significantly higher in the partial nephrectomy group (23.9 ± 6.3) compared to the nephrectomy group (7.3 ± 3.9) (p = 0.011). Standardization based on the clinical complexity of the patient sample showed that cytoreductive partial nephrectomy decreased the risk of death compared to nephrectomy (HR = 0.62, 95%, CI 0.39–0.97, p = 0.037) (see Figure 3).
Figure 3. Survival curves of patients undergoing cytoreductive nephrectomy and cytoreductive partial nephrectomy after standardization by key parameters

Finally, personalized options for localized kidney cancer were investigated. The mi-RNA was shown to be a good prognostic and treatment response biomarker. A higher incidence of progression and cancer-specific death among patients with centrally-located tumors was marked in the investigational center during the last decade. Taking into account this data, it was decided to compare patients with T1a kidney tumors that had central and peripheral locations. Centrally located kidney cancer has shown in the present study a higher incidence of high ISUP grade, regional nodal involvement, and endophytic growth type (see Table 1).

Table 1. Comparison of Centrally versus Peripherally located tumors by major clinic-pathological findings

Endophytic growth type was associated with worse ISUP grading. The distribution of ISUP grade was not age-dependent, thus showing no difference by this criterion when comparing different age groups. A higher ISUP grade was strongly associated with the presence of distant metastases in T1a kidney tumors. This creates a potential knowledge gap, showing that even small renal masses tend to be more aggressive compared to peripheral ones and might require different treatment options, such as, for example, regional lymphadenectomy.

In our work, we have concentrated mainly on T1a kidney cancer, which is considered not aggressive and can be successfully managed even with active surveillance in elderly patients. However, the study revealed that even at cut-off at the time of surgery, centrally located small-renal masses behave differently compared to peripheral ones. Regarding the findings, it is also important to notice that current data should most probably apply to bigger tumors, where it is even more crucial to understand the potential treatment pathways of the patient, as new data about adjuvant treatment with checkpoint inhibitors is being dynamically received from clinical trials.

We strongly believe that the knowledge received during the discussed studies provides a good base to change existing standards of care. Results describe a potentially different view on the treatment approaches among patients with localized kidney cancer and its outcomes.

Acknowledgment: I am extremely grateful to Prof. Stakhovsky, whose generative mind has provided the basis for the further development of this scientific direction. I would also like to extend my deepest gratitude to the teams of the Department of Plastic and Reconstructive Onco-urology of the National Cancer Institute of Ukraine. In loving memory of P. Vukalovich, who supported science and preserved the traditions of the department until the last day of his life.

Written by: Sofiya Semko, Department of Oncological Urology, National Cancer Institute of Ukraine/Department of Urology, University Hospital of Cologne


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