Treatment alternatives and clinical guidelines for SRM

Current clinical guidelines recommend PN as the preferred management of SRM, if technically feasible based on primary tumor size and location. Although RN has been the historical gold standard for SRM, several observational studies have demonstrated that PN can provide equivalent long-term cancer-specific survival when compared with RN while also reducing the risks of adverse functional renal outcome, cardiovascular events, and all-cause mortality. For example, Lau and colleagues were among the first to report a matched analysis of patients surgically treated with RN and PN for unilateral RCC at the Mayo Clinic, where the long-term outcomes at 15 years were similar for local (99% vs 95%, P = .18) and distant recurrence-free survival (99% vs 95%, P = .18) and cancer-specific survival (96% vs 91%, P = .71). Likewise, Zini and colleagues used a multi-institutional historical cohort to similarly demonstrate that PN and RN achieved equally low cancer-specific mortality at 5 years (2.1% vs 1.0, P = non-significant).

Although it is generally accepted that both PN and RN confer durable cancer control for T1a and T1b renal tumors, several observational studies have recently indicated that the benefits of PN in comparison with RN may be attributable to the lower risks of chronic kidney disease and, as a result, lower risks of associated cardiovascular disease and all-cause mortality. In 2006, Memorial Sloan-Kettering Cancer Center reported the incidence of new-onset chronic kidney disease from its retrospective cohort of 662 patients with T1a renal tumors who underwent surgical extirpation from 1989 to 2005. In comparison with PN, patients who underwent RN for SRMs were 3.82 times more likely to develop new-onset moderate to severe chronic kidney disease after surgery ( P <.001). Population-based cohorts from Surveillance, Epidemiology and End Results (SEER)-Medicare also demonstrated the benefits of PN in observing a 26% reduction in adverse renal outcomes (hazard ratio [HR], 0.74; P <.001). These observational studies support the findings that PN, with its lower risks of adverse functional renal outcome, also correlated with improved overall survival. Indeed, we previously reported that RN was significantly associated with a 2-fold higher risk of all-cause mortality than PN in a subset of patients younger than 65 years (HR, 2.16; P = .02). Another SEER-Medicare population-based study from 1995 to 2002 confirmed these findings in that RN resulted in a higher incidence of cardiovascular disease (HR, 1.4; P <.05) and all-cause mortality (HR, 1.38; P <.01). The results of these observational studies have served as the basis for the recent changes to the clinical guidelines in recommending PN for SRM. Consequently, PN remains the treatment of choice for those patients having SRMs amenable to resection based on location and tumor size and who are healthy enough to tolerate surgery.

Ablative therapy with cryoablation or radiofrequency ablation is an alternative treatment option for SRM. Although the indications and outcomes of thermal ablation are discussed in greater detail in another article by Cadeddu and Faddegon in the same issue, it does warrant some discussion here because thermal ablation represents an acceptable treatment alternative for SRM. At present, clinical guidelines recognize cryoablation and radiofrequency ablation as treatment options only in the setting of patients who are poor surgical candidates due to limited life expectancy and multiple comorbidities, among others. Although ablative therapy allows for a greater use of minimally invasive percutaneous approaches, the existing evidence is characterized by studies with small sample sizes and insufficient long-term follow-up that limit the ability to fully ascertain whether this form of therapy is as effective for durable cancer control.

A recent systematic review on the treatment of SRMs also underscores that patient populations from single-institution historical cohort studies examining cryoablation include older patients (65.7 vs 61.6 years, P <.001) having smaller renal tumors (2.56 vs 3.40 cm, P <.001) compared with studies examining nephrectomy. Despite the smaller mean renal tumor size observed in these studies, Kunkle and colleagues also reported a statistically higher risk of local recurrence for cryoablation (relative risk [RR], 7.45; P <.05) and radiofrequency ablation (RR, 18.21; P <.05) compared with surgery, although the heterogeneity in defining local recurrence as an outcome represents an important obstacle in ascertaining the comparative effectiveness of this treatment modality. We also submit that further observations are needed before determining if one form of ablation (ie, cryoablation) is superior to the other. Another important consideration in evaluating the relative effectiveness of ablative therapy for SRM is that there is a paucity of randomized clinical trials or multi-institutional prospective studies critically assessing the ability of either form of ablative therapy to achieve long-term oncologic control and investigating the potential harms associated with treatment and recurrence.

Active surveillance is another emerging treatment strategy for SRM that has become increasingly relevant for patients and urologists because of the evolving demographics of the US population and the slow growth rate, on average, of SRM. Although the mean age at the time of diagnosis of stage I RCC is currently 60.8 years, the aging of the US population profoundly alters the typical presentation of SRM such that it has been estimated that 69% of patients with newly diagnosed SRM will be 65 years or older by 2030. In this context, there is an ongoing clinical debate about whether patients with limited life expectancy would derive a survival benefit from primary treatment of localized RCC while being exposed to the potential harms from surgery associated with older age and comorbidity.

Although a study using SEER-Medicare data suggested more aggressive primary treatment with PN conferring superior survival compared with RN for octogenarians with SRM, a historical cohort study from the Cleveland Clinic found similar 5-year cancer-specific mortality with RN, nephron-sparing intervention, and active surveillance (9.3% vs 4.0% vs 5.8%, P = .33). Hollingsworth and colleagues performed a competing risk analysis from SEER-Medicare in which all patients underwent nephrectomy for RCC to elucidate the relationships of age and primary renal tumor size with cancer-specific versus other-cause mortality after nephrectomy was performed. The competing risk analysis revealed that patients with advanced age were far more likely to die from other causes than from RCC after nephrectomy was performed. Taken together, these data suggest advanced age, limited life expectancy, and comorbidity are critically important aspects that should be taken into consideration in identifying the appropriate patients for primary treatment of SRM.

Although it is becoming increasingly acknowledged that poor functional status, extensive comorbidities, and limited life expectancy may compromise the benefits of primary treatment, the relatively slow growth of SRM and low risk of progression to metastatic disease also underscore the potential clinical value of active surveillance in appropriately selected patients. Several observational studies of patients with advanced age or who are medically unfit for surgery have documented that most SRMs have relatively static renal tumor growth on serial radiographic surveillance imaging. For example, the Cleveland Clinic initially described their cohort of patients with advanced age (>75 years) who underwent active surveillance. Among the 110 patients placed on active surveillance, the mean growth rate was 0.26 cm per year at a median follow-up of 2 years. Although there were no cancer-related deaths, only 2 (1.8%) patients subsequently developed distant metastasis.

In a systematic review and meta-analysis of 9 retrospective single-institution studies on the natural history of SRM, the pooled mean growth rate was also 0.28 cm per year, while only 1% of patients progressed to metastatic disease and none of the patients died from RCC. A recent update of the evidence by systematic review further supported the static growth rate of renal tumors and low rates of progression to metastatic disease while on active surveillance. Although previous studies indicate that tumor growth kinetics and initial primary tumor size may not be reliable predictors of progression, the findings from this recent meta-analysis contribute to the understanding of the risk of progression by suggesting that the linear and volumetric growth rates are significantly higher in those in whom the condition subsequently progresses. In the only prospective phase 2 clinical trial of active surveillance of 178 older and infirmed patients, the condition progressed locally in 25 patients (14%), as defined by either a growth of 4 cm or more or an annual doubling time, and 2 (1.1%) patients went onto to develop metastatic disease. Approximately a third of patients’ renal tumors, however, were observed to have minimal growth on radiographic imaging. Furthermore, in an era of rising health care costs and increased attention to comparative effectiveness research, active surveillance has been put forth as the most cost-effective treatment strategy for SRM compared with immediate nephrectomy.

Although these findings are encouraging in considering active surveillance as an acceptable treatment strategy, these observational studies are subject to selection bias and are underpowered to accurately predict the risk of cancer-related deaths. Furthermore, although a validated protocol on the intensity of computed tomographic surveillance imaging for active surveillance has yet to be established, radiation exposure is becoming an increasingly recognized public health concern for associated secondary malignancies. Therefore, active surveillance should not be considered in younger patients who can tolerate nephrectomy, given the lack of high-quality evidence comparing the different treatment options, significant heterogeneity across studies, and the cumulative radiation exposure due to cross-sectional imaging from active surveillance.

Predictive models for SRM s

Treatment decisions for SRM on whether to intervene surgically with PN, RN, and thermal ablation or to use active surveillance require careful deliberation based on the individualized patient and tumor characteristics. For patients to make informed medical decisions on how to treat the SRM, it is essential for physicians to accurately communicate the benefits and risks associated with each treatment modality and active surveillance. In response, prediction models have been developed from surgical cohorts to ascertain the risks of various oncologic end points. These prognostic models can help patients diagnosed with SRM and urologic surgeons to have deliberate discussions on the risks SRM pose for recurrence, metastasis, cancer-specific survival, and overall survival. In addition, using these prediction models in the clinical setting represents one of the first steps in objectively discussing the risks and benefits of each treatment alternative, thereby minimizing subjective assessments that are likely prone to bias and contribute to variations in the use of PN and RN.

Several prediction tools and models using only clinical variables available in the preoperative setting have been proposed to facilitate a quantitative assessment in determining the risks of recurrence, progression, and survival ( Table 1 ). For example, Cindolo and colleagues developed a prognostic model for recurrence-free survival using multi-institutional retrospective data from 660 patients who underwent PN or RN for nonmetastatic RCC. From the multivariate model, the candidate variables identified as significantly associated with the primary outcome included clinical presentation (asymptomatic vs symptomatic) and primary tumor size, which were then aggregated into a model for good and poor prognostic groups. Patients in the poor-risk group achieved only a 5-year recurrence-free survival of 68%, whereas the good-risk group had a 5-year recurrence-free survival of 93% ( P <.001). Likewise, investigators using retrospective institutional data from Johns Hopkins also developed a similar predictive model for recurrence-free survival from 296 patients who underwent open RN for localized RCC. The investigators also similarly dichotomized the risk groups into low and high risk by a recurrence risk score. Limitations of both models include the lack of an external validation cohort and a modest predictive accuracy (65%–67%) of recurrence-free survival.

Table 1

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