Progress in cancer screening has led to an increase in the number of patients whose kidney cancer is detected at an early stage; however, synchronous metastases (Smts) are still detected in approximately 15% of patients at initial treatment. Twenty percent of patients have metachronous metastases (Mmts) during the dynamic follow-up after nephrectomy [1][2]. Therefore, Smts and Mmts cells have different genetic profiles, tumor cell activity, and tumor load, which can lead to different responses to systemic therapy [3-5]. Numerous prognostic models and nomograms have been developed for localized renal cell carcinoma (RCC) based on a combination of assessment of the tumor stage, degree, subtype, clinical signs, etc. However, there is insufficient evidence of their routine use. Heterogeneous characteristics of patients with metastatic RCC (mRCC) make it difficult to determine the prognosis, which requires the search for new prognostic factors or their combinations, depending on the characteristics of the metastatic disease itself.

The study aims to identify prognostic factors affecting survival rates in patients with mRCC suffering from Smts and Mmts.

A retrospective analysis was carried out; it was based on 934 mRCC patients who received treatment in the period from 2006 to 2020 at the Moscow City Oncological Hospital No. 62 and the St. Petersburg City Clinical Oncological Dispensary. The primary kidney neoplasm was removed in 862 (92.3%) patients at various times before the beginning of systemic therapy.

Systemic chemotherapy. Systemic chemotherapy was carried out by using five main groups of drugs – tyrosine kinase inhibitors (the most used group), mTOR inhibitors, immunotherapy (for 57 patients), cytokines, and PCT.

Nexavar (283 patients, 28.8%), Sutent (221 patients, 22.6%), and Pazopanib (160 patients, 16.3%) were prescribed more frequently to mRCC patients during first-line systemic therapy. First-line systemic therapy was carried out from 1 to 107 months. The overall response to treatment was 51.9%. Complete response was registered in only 1.0% of patients, partial regression – in 8.5%, stabilization – in 42.4%, and progression – in 39.8%.

Second-line systemic therapy was received by 667 patients; its duration ranged from 1 to 104 months. The most used drugs were Sutent (228 patients, 34.2%), Nexavar (167 patients, 25%), and Pazopanib (102 patients, 15.2%). During the second-line therapy, the overall response was achieved in 55.7% of patients. Therefore, complete response was recorded in 0.6% of cases, partial response – in 5.8%, stabilization – in 49.4%, progression – in 36.4%, and death – in 4.3%. Twenty-two (3.2%) patients were removed from the register.

Third-line systemic therapy was performed in 348 patients. The patients most frequently received Sutent (74 patients, 21.4%), Pazopanib (72 patients, 20.7%), and Everolimus (70 patients, 20.2%). The duration of third-line therapy ranged from 1 to 83 months. Complete response was recorded in 0.3% of patients, partial response – in 4.9%, stabilization – in 54.0%, progression – in 33.3%, and death – in 4.9%. Nine patients (2.6%) were removed from the register.

Fourth-line systemic therapy was performed in 138 patients. The three drugs prescribed most frequently were Everolimus (34 patients, 24.6%), Sutent, and Pazopanib (28 patients each, 20.3%). The duration of therapy ranged from 1 to 47 months. Partial response was noted in 7.2% of patients, stabilization – in 38.4%, progression – in 43.5%, and death occurred in 8% of cases. Four (2.9%) patients were removed from the registry.

Then, 49 patients received the fifth-line systemic therapy. Therefore, 12 (24.5%) patients received Pazopanib during the fifth-line therapy, nine (18.4%) patients received Everolimus, and 7 (14.4%) – Sutent. Therapy was carried out from 1 to 48 months. Partial response was observed in 6.1% of patients, stabilization — 40.8%, and progression — 51.0%. One (2.1%) patient was removed from the registry.

Then, 23 patients received the sixth-line systemic therapy; its duration ranged from 1 to 31 months. During the sixth-line therapy, six (26.1%) patients received Pazopanib, three (13.0%) patients received Everolimus, Temsirolimus, and Nexavar (each of them). Stabilization was noted in 56.5% of patients, progression – in 30.4%. One (4.4%) patient died; two (8.7%) patients were removed from the register.

Dynamic monitoring protocol. The protocol of dynamic medical follow-up included laboratory studies and methods of radiation diagnostics: general clinical and biochemical blood tests, coagulogram, urine tests, electrocardiography, fibrogastroduodenoscopy, ultrasound of the abdominal cavity, retroperitoneal space, and pelvis, bone scanning, as well as CT of the lungs and abdominal cavity. The prognostic factors studied were Heng prognosis and ECOG status (T and N categories), the degree of differentiation and histopathological type of tumor, the number of affected organs, as well as laboratory parameters.

Statistical analysis. Statistical analysis was performed using the Statistica 10.0 software package (StatSoft Inc., Tulsa, OK, USA). Indicators were checked for normality by the Shapiro-Wilk and Kolmogorov-Smirnov tests. Comparison of the lifetime of two groups of patients was performed by constructing Kaplan-Meier curves and survival tables. The construction of a mathematical survival model (proportional hazard (Cox) regression) was carried out to determine the prognosis of the survival function (time) of a certain group of patients and the degree of influence on it of signs (predictors) included in the model in the form of the odds ratio and its 95% confidence intervals (95% CI). The frequency of the event occurrence in the group was investigated by means of using the Pearson chi-square criterion. The significance level was assumed to be p < 0.05.

The characteristics of patients and their distribution by comparison groups are presented in Table 1.

Based on the presented Kaplan-Meyer curves (Fig. 1), the 3-year overall survival (OS) of patients with Smts and Mmts was 40.3 ± 1.7% and 82.5 ± 1.6%, the 5-year OS was 18.8 ± 1.8% and 64.3 ± 1.9%, respectively. Median OS at Smts was 25 months, at Mmts – 88 months (p < 0.001).

Therefore, 3-year and 5-year progression-free survival (PFS) in Mmts patients was 60.5 ± 1.6% and 55.7 ± 1.5%. In Smts patients, PFS was only 9 months, and the median PFS in patients with Mmts was 60 months (p < 0.001). Thus, there are significant differences in both OS and PFS depending on the time of occurrence of metastases.

Hemoglobin levels below normal and elevated erythrocyte sedimentation rate (ESR) were significantly more common in patients with Smts, while patients with Mmts were significantly more likely to have a normal number of platelets and alkaline phosphatase. In addition, Smts patients were significantly more likely to have an unfavorable prognosis for Heng and ECOG status, a higher stage T, a low degree of tumor differentiation, histologically non-light cell carcinoma variants, the presence of lymphogenic metastases, and a greater number of organs affected by hematogenous metastases, that is, from the point of view of generally accepted prognostic factors in oncology, they had a poorer status (Table 2).

The results of single- and multi-factor analyses of proportional risks (according to Cox) for OS are summarized in Table 3. In single- and multivariate analyses, only anemia and an unfavorable prognosis according to Heng were statistically significant prognostic factors for the S of patients with Smts and Mmts. A single-factor analysis found that an increase in ESR, platelets, and alkaline phosphatase was a statistically significant unfavorable prognostic factor of the OS and SM group (p < 0.001).

Prognostic assessments are necessary for the development of individual protocols for dynamic patients monitoring and, possibly, for the choice of adjuvant therapy in the future. Due to the active development of systemic therapy capabilities in mRCC, the use of molecular markers makes it possible to increase the accuracy of established prognostic models, but often does not have independent external validation [6].

In this study, patients with Smts had a worse prognosis and a lower OS compared to Mmts patients, according to a combination of factors, which was noted in other studies [1][3][7]. The classification of metastases by the time of occurrence logically explains the best OS in patients with Mmts: the patient is initially burdened only with the primary tumor, which the clinicians' forces are directed at, which allows the adaptive and compensatory reactions of the body to rebuild the metabolism to the needs of the tumor.

Differences in the biological potential of Smts and Mmts were studied using immunohistochemical markers [2], and patients in these groups should initially be treated as two different prognostic groups.

Thus, Kim et al. (2019) studied prognostic factors in patients with Smts and Mmts and showed that patients with Smts and a poor prognosis according to Heng have the lowest survival rates, which are affected by systemic therapy and improves PFS in patients with Mmts of intermediate prognosis. While the single-factor analysis of cancer-specific survival, statistically significant prognostic factors were the type of metastasis, hypercalcemia, neutrophilia, increased LDH and thrombocytopenia, in multifactorial analysis – hypercalcemia, neutrophilia, increased LDH, and thrombocytopenia as well. The authors also noted in their study that the differences in OS for Smts and Mmts became statistically insignificant when comparing patients with a poor prognosis according to Heng [8]. Naito et al. (2020) based on the analysis of five independent prognostic factors (stage T, stage N, the presence of brain metastases, serum calcium level, neutrophils and lymphocytes ratio) demonstrated that none of them affected OS in the presence of Mmts, and risk factors were different for Smts and Mmts [9]. Anemia and neutrophilia are also considered factors affecting OS, together with the type of metastases (Smts or Mmts) without division into groups [7].

Prognostic assessments for patients with metastatic RCC receiving systemic therapy are used regularly but have limited accuracy. In this study, prognostic factors that affect survival rates were identified in mPCC patients with Smts and Mmts. The search for new prognostic factors and their combinations with an emphasis on the features of the metastatic disease itself will improve the predictivity of outcomes and optimize the results of systemic therapy.