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Renal Cell Carcinoma- Prognosis via Albumin Levels
Metastatic renal cell carcinoma (mRCC) – An Introduction
Renal cell carcinoma (RCC) constitutes approximately 90% of all urologic malignancies. Approximately 30% of patients with RCC present with metastatic disease, and amongst those with localized disease, a substantial proportion will recur. Before 2005, immunotherapy with interleukin-2 (IL-2) and interferon-α (IFN-α) represented the mainstay of therapy for metastatic renal cell carcinoma (mRCC). Over the past decade, mRCC therapy has been revolutionized through the introduction of targeted therapies using rapamycin (mTOR) inhibitors and tyrosine kinase inhibitors (TKI).
Among the first TKIs developed were gefitinib and erlotinib, which specifically inhibit EGFR tyrosine kinase. Later on, a further group of TKIs with multiple kinase targets was developed. Notable among them in RCC treatment was sorafenib, which targets VEGFR-2 and -3, platelet-derived growth factor receptor (PDGFR), B-RAF, C-RAF, c-kit, and Flt-3. Also relevant to RCC are sunitinib and Sutent, which targets VEGFR-2, PDGFR, c-kit, and Flt-3; imatinib, which targets c-kit and PDGFR. Other therapeutically important TKLs for mRCC are, pazopanib, axitinib, and cabozantinib, all of which have been described in phase III studies and found effective in treating metastatic renal cell carcinoma.
Predicting the outcome of mRCC patients
According to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), the most important prognostic parameters to predict the outcome of mRCC patients include hemoglobin count, platelet count, corrected calcium levels, neutrophil count, Karnofsky performance status, and the time from the first diagnosis to treatment. However, the concordance index of the studies assessing the performance of these models was only between 0.53 to 0.70 indicating the need for novel biochemical prognostic parameters.
In recent years, numerous studies highlighted a close correlation between pretreatment serum albumin and tumor prognosis; specifically, the lower the concentration of pretreatment serum albumin, the worse the prognosis of cancer patients. Some of these studies have also elaborated on the relationship between pretreatment serum albumin and the prognosis of renal cell carcinoma patients. Furthermore, some single-centered studies have even identified
the significance of hypoalbuminemia as a poor prognostic factor for advanced/metastatic renal cell carcinoma.
The current study aims to evaluate the prognostic significance of albumin in metastatic renal cell carcinoma patients receiving TKI-targeted therapy in the era of targeted therapies.
Review of Literature
PubMed, Embase, and Cochrane Library were searched. Potentially eligible randomized clinical trials (RCT), cohort studies, and case-control studies were identified using keywords. “Carcinoma, Renal Cell, Sunitinib, Sorafenib, Axitinib, clinical trials as a topic, random allocation, cohort studies, case-control studies, or risk factors” – [Mesh]. “Secondary, mortality”[MeSH Subheading]. “Protein-tyrosine kinases” [MeSH Terms. “Pazopanib, Cabozantinib” [Supplementary Concept].
Study selection and data extraction
Two reviewers independently screened the title, abstract, and full text to identify eligible studies. All screening disagreements were discussed.
The data extracted from each study included: first author’s surname, published year, albumin levels (cut-off point), HR and 95% CI of survival outcome, study design, analysis type, number of patients, race, age, gender, histology, follow-up period, TKI agents, prior treatment and metastasis status.
Population, intervention, comparisons, outcomes, and study design (PICOS) criteria were considered to evaluate study eligibility. The study evaluated the population and intervention as a/mRCC patients treated with TKIs. Pre-treatment serum albumin levels were compared; overall survival (OS) and progression-free survival (PFS) were used as primary endpoints.
Exclusion criteria were as follows: (i) non-English or non-human studies; (ii) Duplicate literature and subject data; (iii) No eligible original data; (iv) Patients treated with TKIs and other therapies simultaneously.
Studies that provided hazard ratio (HR) and 95% confidence interval (CI) of either OS or PFS according to pretreatment albumin levels of a/mRCC patients treated with TKIs were included.
Newcastle-Ottawa Scale (NOS) was used to evaluate the quality of the study.
- The effect of albumin levels on OS or PFS was assessed using a Hazard ratio (HR) extracted or calculated from the original literature. HR > 1 = poor outcome. Two-sided P-value < 0.05 = statistically different value.
- Cochran Q test and I2 testing were used to assess inter-study variance. I2 > 50% indicated moderate-to-high heterogeneity; meta-regression, subgroup, or sensitivity analyses were performed to identify sources of heterogeneity.
- The random-effects model was used to assess pooled data.
- A funnel plot with Begg’s and Egger’s tests was used to evaluate publication bias. A P-value of < 0.1 was considered statistically significant.
- All statistical analyses were performed with Stata (version 12.0).
Literature search and study selection
After removing duplicate records and screening titles and abstracts, 781 full-text articles were assessed for eligibility. Of the 16 eligible studies, 2 had no adequate data for quantitative synthesis hence excluded; the remaining 14 studies with adequate survival data (N = 2,863 participants) were included in quantitative synthesis (meta-analysis). All 14 studies were conducted from 2002 to 2019 and had 45 to 557 subjects.
Characteristics and quality of eligible studies
- Based on clinical and statistical parameters, the eligible studies were categorized by variable types of albumin levels; 9 studies defined albumin as a dichotomous variable and in 5 studies albumin was the continuous variable. Some studies (n=10) analyzed both OS and PFS while others (n=4) provided either.
- Patient ages ranged from 18 to 88 and 73.2% of them were male. About 93.9% of participants were histologically diagnosed as ccRCC and 84.7% received a nephrectomy.
- The TKIs used in these studies were sunitinib, pazopanib, axitinib, and sorafenib.
- All non-randomized studies had scores ≥ 7 (NOS scale).
Impact of pre-treatment albumin levels on OS and PFS
Of 14 studies included, OS and PFS outcomes were available in 13 and 11 studies, respectively. In Kosuke and other eight studies that used dichotomous albumin data, lower pretreatment albumin levels had poorer OS (n = 9, HR = 2.01, 95% CI: 1.64-2.46, P < 0.001; I2 = 28.8%, P = 0.188) and poorer PFS (n = 6, HR = 1.45, 95% CI: 1.04-2.01, P = 0.029; I2 = 57.4%, P = 0.039). Similarly, in Bulent usand other four studies using continuous albumin data, lower pretreatment albumin levels also indicated poorer OS (n = 4, HR = 0.93, 95% CI: 0.86-1.00, P = 0.040;
I2 = 67.5%, P = 0.026) and poorer PFS (n = 5, HR = 0.89, 95% CI: 0.80-0.98, P = 0.023; I2 = 93.3%, P < 0.001)
These results indicate a 101% increased risk of poor OS and a 45% increased risk of poor PFS in mRCC patients with lower pre-treatment albumin levels when compared to those with normal albumin levels before TKI therapy.
The two studies which had inadequate survival outcome data were also reviewed. Yildiz et al. reported hypoalbuminemia as an adverse prognostic factor for OS and PFS (Univariate analyses, P = 0.016 and 0.05). Yasuda et al. confirmed that albumin levels were not a significant prognostic factor based on multivariate analysis (dichotomous: P = 0.77, continuous: P = 0.48) of OS in patients with mRCC treated with TKIs.
Meta-regression and sensitivity analysis
Meta-regression analysis reported 98.3% of the heterogeneity in each subgroup except for OS in the continuous albumin group. However, sensitivity analysis showed no significant change of pooled HR when any
a single research study was eliminated.
The funnel plot was symmetric for the dichotomous albumin group while the other three subgroups had insufficient data for the funnel plot. Begg’s (z = 0.52, P = 0.602) and Egger’s (t = 0.55, P = 0.598) tests indicated that there was no significant publication bias of OS in the dichotomous albumin group.
Numerous studies reported that the systematic inflammatory response in cancer patients also alters serum albumin levels. Under inflammatory conditions, activated proinflammatory cytokines, including tumor necrosis factor, and interleukin −1, −6, and −8, inhibit liver cells from generating albumin. A systematic review published in Nutrition Journal reported that the TNF generated by cancer cells increases the permeability of capillaries, which results in the direct loss of albumin from the circulation. Furthermore, the development of micrometastases in the liver impairs liver function and albumin synthesis. However, since most retrospective studies were limited in terms of sample size, and standard of intervention, further prospective multicenter studies should be carried out to confirm the prognostic value of albumin to guide mRCC patient management.
This systematic review and meta-analysis showed that hypoalbuminemia is an adverse prognostic factor of OS and PFS in mRCC patients treated with TKIs. Motzer et al. excluded albumin from multivariate analysis of the MSKCC model even though it had a negative regression coefficient (-0.798, P = 0.0001) and a risk ratio (RR) of 2.12 (95% CI:
1.80-2.50). A 2014 study reported that mRCC and hypoalbuminemia patients undergoing cytoreductive nephrectomy (CN) have decreased OS and CSS.
Serum albumin as a prognostic indicator in RCC patients does have some limitations. For example, in the overhydrated state or with liver diseases, serum albumin may not indicate the true nutritional status, so its prognostic value in mRCC patients can be questioned. Meanwhile, serum albumin concentration is a blood index, which may be slightly affected by diet and other noncancerous factors. Nevertheless, without these interferences, pretreatment serum albumin is of great prognostic value in a/mRCC patients.
- The literature was restricted to the English language and most of the eligible studies were retrospective.
- Since albumin is an accessible marker liver, hematologic or immunologic diseases might affect the results of original literature.
- Missing or lack of original data and methodological differences also impacted the results.
- Lack of RCTs studying the specific impact of albumin levels.
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