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In developed countries RCC is the tenth greatest cancer-related cause of death, with an estimated 60 920 new cases expected in the USA in 2011 and 46 151 new cases in the European Union in 2008 [1,2]. Generally, 30% of new cases are diagnosed at an advanced stage and 20% become metastatic during follow-up [3,4].
Although the prognosis of patients with metastatic RCC (mRCC) has been dramatically improved since targeted therapies have been introduced into the clinical armamentarium, the median overall survival (OS) is still limited, with very few patients reaching cure and around 20% getting no benefit from available therapies [5,6].
Prognostic models have been described to help to stratify the patient risk of cancer progression or death. These prognostic models are very useful for the selection of patients for clinical trials to avoid selection bias and erroneous interpretation of results. Ideally, they should also help to better select which patients will benefit from a given treatment and which drug to use in an individual patient.
During the last 10 years, several classifications have been proposed to assess the prognosis of mRCC. The most commonly used has been the Memorial Sloan Kettering Cancer Centre (MSKCC) classification , which has been used to stratify patients in the majority of the registration trials. This model stratifies patients using biological variables, such as haemoglobin, corrected calcium and lactate dehydrogenase, rather than using nephrectomy and performance status. Other models, such as the French classification, have been further developed in the cytokine era and then validated in patients treated with target agents .
Recently, a new model has been built for patients receiving target agents. In this new model, baseline values of neutrophils and platelets count have been added to MSKCC variables .
So far, tumour burden (TB) has not been considered in any of these models as a possible prognostic factor. Although the number of metastatic sites, reported as an independent prognostic factor by Mekhail et al. , may be considered a surrogate of TB, this is limited by the major differences in TB that could be present in the same metastatic site of different patients.
The aim of the present study was to investigate the possible prognostic role of baseline TB in a homogeneous group of patients treated with anti-angiogenic drugs within clinical trials.
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- MATERIALS AND METHODS
- CONFLICT OF INTEREST
Tumour burden has been shown to be a prognostic factor in several tumour types; in diffuse large cell lymphoma, the independent predictive role for survival and for achievement of remission as well as relapse-free survival was reported over 25 years ago . In Hodgkin lymphomas, the initial TB was predictive for response to two different chemotherapy regimens  and increases the half life of rituximab in treated patients . The negative impact of high tumour volume at baseline on response to treatment was also reported in neoadjuvant treatment for breast cancer . Recently, the metabolic volume assessed by postitron emission tomography has also been reported to have a prognostic role in lymphoma , such as in advanced solid tumours .
With regard to mRCC, few studies have evaluated the role of TB, even though it has been considered to be an important factor in localized disease. For example, the risk of malignancy and the tumour grade increase with tumour's size in patients with suspected renal lesions [20,21]. It was calculated that each 1-cm increase in tumour size, leads to an increase of 16% in the odds of malignancy .
In localized RCC, the UCLA Integrated Staging System divides patients into three prognostic groups based on Fuhrman grade, ECOG performance status and tumour size. Among patients with high-risk non-metastatic disease, the study found a shorter survival in those with the greatest primary lesions (T4N0M0) . The prognostic relevance of primary tumour extension was confirmed by the Mayo Clinic SSIGN algorithm that reported, in univariate analysis, a direct relationship between the tumour size and the risk of death. These data were confirmed in multivariate analysis showing a doubled risk of death when tumour was >5 cm (risk ratio: 1.99; 95% CI: 1.47–2.70; P < 0.001) .
In metastatic patients, three studies have retrospectively analysed the impact on survival of baseline TB. Stein et al.  described the role of TB in 89 patients with mRCC, treated with ixabepilone in two prospective trials [25,26]. As with the present study, TB was defined as the sum of the longest diameter of all measurable lesions (>1.0 cm), although limited to five lesions. The study reported a median TB value of 21.7 cm and showed a negative correlation between TB and survival (Pearson r=−0.49; P < 0.001) as well as with the tumour growth rate .
In patients with mRCC treated with targeted agents, two retrospective studies analysed the role of TB as a prognostic factor. In the first study, Basappa et al.  reviewed 69 patients treated with sunitinib after failure of different therapies with cytokine or other antiangiogenic agents. In their analysis, the median value of baseline TB (14.0 cm; range 3.0–42.2 cm) was used as the threshold for assessing the impact on PFS and OS; other variables were also analysed, such as soft tissue TB present above and below the diaphragm and their ratio, the number of metastatic sites involved and the total number of metastases . Among variables related to tumour extension, a TB < 13 cm and a TB above the diaphragm ≤6.5 cm were prognostic factors for both PFS and OS in univariate analysis. In multivariate analysis, a TB above the diaphragm ≤6.5 cm, in addition to <10 metastases and the Cleveland Clinic Foundation risk classification were found to be independent prognostic factors .
The second retrospective study investigated the prognostic role of TB in 42 patients enrolled in the RECORD-1 and REACT expanded access programmes, testing everolimus after sorafenib, sunitinib or both. The results of the univariate analysis confirmed that patients with a TB below the median value (15.5 cm) have a longer OS (25.2 vs 11.8 months; P= 0.01) but not better PFS compared with patients with greater TB; whether this is an independent prognostic factor in multivariate analysis is not reported .
In the present series, we found a direct relationship between the absolute baseline value of TB and OS, and we report for the first time, its prognostic role in multivariate analysis independently of the site of metastases (above or below the diaphragm) and the MSKCC risk score. Notably, we have used the modified MSKCC score, which already accounts for the number of metastatic sites, for the present analysis. We believe that this information could be translated in clinical practice, by concluding that patients with the same MSKCC risk group may have a different survival based on initial tumour extension. In clinical practice, a greater TB may be associated with a symptomatic disease, a worse ECOG performance status and a worse prognostic score; however, it remains controversial whether active treatment can be delayed in asymptomatic patients.
The present data might be useful in patient's treatment decision-making to schedule the beginning of an active treatment with anti-angiogenic drugs. The evidence from randomized phase III trials comparing sorafenib or everolimus with placebo suggest that patients who received active drugs after placebo have no difference in PFS, explaining the lack of difference in OS in both studies [29,30]; however, the present data suggest that there may be a threshold when active treatment should be started. This hypothesis needs to be confirmed in future prospective trials.
Limited results are available in the literature regarding the role of TB in predicting the efficacy of anti-angiogenic drugs. In patients with mRCC treated with sunitinib and sorafenib, Yuasa et al.  reported greater tumour shrinkage in smaller tumours (<2.4 cm), but this tumour shrinkage did not correlate with survival. Furthermore, in patients with mRCC who receive sunitinib before undergoing nephrectomy, a tumour shrinkage >10% has been found able to determine an improvement of 2 years in OS (78.8 vs 27.3%; P= 0.01) . The same threshold of tumour shrinkage has been reported in metastatic disease as sufficient to determine a statistically significant improvement from 5.6 to 11.1 month in terms of PFS , and from 15.8 to 32.5 months in terms of OS . Although these studies report a relationship between the TB and response to therapy and between response and prognosis, they fail to report a direct relationship between baseline TB and OS.
The present study better analyses this aspect, relating the tumour extension to PFS and OS and showing that a smaller TB leads to a better OS, and adding predictive information to traditional risk classification to increase the possibility of identifying patients who may have a greater benefit from a treatment with targeted agents. The major limits of the present study are its retrospective nature and the timing of treatment, with targeted agents used after previous cytokine treatment. In fact, even if cytokines are still recommended for selected cases by current guidelines , they do not represent current clinical practice. Despite this, in the present series of patients, the relevance of the prognostic role of baseline TB may be only marginally influenced by previous treatment, considering the low response rate to interferon and interleukin reported in the medical literature . Furthermore, this analysis includes all patients treated in the two trials with targeted agents at our institution without selection for previous tumour response to cytokines.
To our knowledge, the present study includes the largest and most homogeneous population in which the prognostic role of baseline TB has been reported. It may be considered as a solid background to explore these data prospectively in patients with untreated mRCC.
In conclusion, TB is easy to calculate from standard CT and significantly relates to PFS and strongly relates to OS in patients with clear-cell mRCC treated with anti-angiogenic agents after cytokines. Prospective studies are needed to determine whether there is a well-defined threshold for TB, which could help to determine when to start treatment in asymptomatic patients.