The choice of treatment options for small kidney cancer has been endlessly debated, and in recent years, two main camps have gradually emerged, one supporting surgical treatment and the other supporting active surveillance. Who is stronger or weaker?
Active surveillance
With the continuous development and use of 3D imaging technology, the detection rate of renal cell carcinoma has been increasing. Coupled with the relatively low mortality rate of renal cell carcinoma, people are becoming concerned about the overtreatment of renal cell carcinoma. Active surveillance for renal cell carcinoma is also becoming accepted and a reality. Outgrowing renal cancers smaller than 3 cm are well suited for minimally invasive surgery or ablative therapy, which are the usual treatment options chosen by clinicians and patients, but are these treatments really necessary?
In the literature of familial retinal and central nervous system angiomatosis (VHL), 3 cm is a meaningful threshold for renal cell carcinoma. The high incidence of potential metastases in tumors of this size implies the need for surgical intervention. Considering the inherent problems between hereditary and sporadic renal cancers, it is clear that this criterion does not apply to all typical small-volume renal cancers. Although one study showed that approximately 16% of the 20,000 kidney cancer patients with tumors less than 3 cm had a nuclear grade of 3 or higher, this percentage was only 3% higher than that of patients with tumors less than 2 cm, and increased by only 2% and 4% in patients with tumors less than 4 cm and 5 cm.
Another study examined the relationship between kidney cancer size and mortality and found a very low 5-year specific mortality rate for 2-3 cm tumors (3.8%) and a slight increase in 5-year mortality for tumors between 3-4 cm in size (4.1%). Although these observational studies explain the natural history of small-volume renal cancers, they also suggest that 3 cm is not an absolute threshold for renal cell carcinoma and that invasive treatment of these tumors may not be necessary.
Based on several reviews and meta-analyses, it is now generally accepted that active surveillance of small renal masses (SRMs) is safe, which may be more beneficial in some specific clinical situations. A prospective multi-institutional trial of 178 patients with 209 SRMs (mean maximum diameter of 2.1 cm) who were followed for a mean of 28 months was reported in 2011.
Of the 151 patients followed for more than 12 months, 72 underwent biopsy. Thirty-three percent of them were not kidney cancer patients, and only 2 patients had metastases. Interestingly, one-third of the SRMs were either non-tumor or tumor non-growing, and the biopsies demonstrated that the kidney cancer lesions grew at the same rate as other benign tumors.
Despite the inconclusive results and the lack of uniform biopsy evidence and longer follow-up, this Level 1 level of evidence again suggests that growth and metastasis of small-volume renal cancers are uncommon and points to active surveillance as a safe option for such renal cancers.
It is difficult to conclude whether kidney unit-preserving surgery is needed in the strongest patients with good functional status. Conversely, we would not hesitate to monitor older, poorly functioning patients with SRM who have a short life expectancy because kidney cancer will not be the ultimate cause of their death. However, this different clinical scenario does not reflect the real situation of most patients facing such a scenario.
For different medical and psychosocial reasons, a healthy individual may wish to delay eventual treatment, while a less healthy patient on active surveillance would be at risk of progression. crispen et al. concluded that deferral of treatment for SRM patients on active surveillance is effective. They followed 82 patients with SRMs with masses less than 4 cm or smaller for a mean of 14 months.
Sixty of the subjects had treatment deferred for 12 months, and 29 had treatment deferred for 24 months or longer. 73 of the 87 masses were kidney cancer, and 76% of the patients with kidney cancer underwent kidney unit-sparing surgery. Only 2 patients developed pT1b stage kidney cancer without tumor metastasis or tumor-related death.
In this study, renal mass biopsies (RMB) were performed in patients with renal cancers smaller than 3 cm. Therefore, there is a need to determine the value of RMB in patients with SRM who are actively monitored. Patients with aggressive histopathology require immediate treatment, while those with low-grade malignancy can be monitored aggressively first. In fact, for renal cancers with masses smaller than 2 cm, more than 90% of Fuhrman grades are 1-2.
Although the sensitivity of biopsy is limited, the use of biopsy for small renal masses is increasing. An international organization recently recommended that RMB should be performed in patients who are actively monitored and whose histopathologic findings may alter the treatment strategy.
Overall, for patients with renal cancer with masses less than 3 cm, active surveillance coupled with deferred treatment, combined with RMB results to determine treatment options, is a reasonable option given the unknown clinical, anatomic, and psychosocial issues.
Surgery
The diagnosis of small renal masses has increased with the increased use of cross-sectional imaging, which has led to staged metastases in renal cell carcinoma without a corresponding decrease in mortality from renal cancer. Due to the slow progressive nature of SRMs, various protocols for active surveillance are gradually being recommended and used. Several retrospective studies have supported active surveillance for kidney cancer, suggesting that SRMs have a low chance of progressing to metastatic disease.
Indeed, this approach is more appropriate for those patients who are older or in poor health, as they may have a higher incidence of death from other causes than kidney cancer-related deaths. However, most patients diagnosed with SRMs are relatively healthy and able to tolerate the risk of tumor migration over time, so they can benefit from the procedure.
A Canadian trial analyzed 178 patients with kidney cancer who did not undergo surgery and were actively monitored for other comorbidities, age, and their own wishes. Overall, 25 patients had tumors that grew to 4 cm or more in size or doubled in size in less than 12 months. Two additional patients developed metastatic disease within 1 year of the start of surveillance.
In particular, the authors note that growth rate alone is not a sufficient indicator of all features of SRM. Other cohort studies of active surveillance have revealed that SRMs have a 2.1% cumulative risk of developing localized or metastatic kidney cancer during surveillance.
The relatively low growth and metastasis rates of SRMs may sound good, but for a younger and healthier population, this is an unacceptable risk and immediate treatment is clearly necessary. Risk is stratified based on observations of SRM growth or biopsy results. Personalized therapy determined by the aggressive tumor phenotype would be the ideal treatment modality. Unfortunately, there is no effective strategy to consistently identify the aggressive nature of SRMs.
A combination of preoperative imaging features such as size, outward growth, and adjacent collecting system could predict the benignity of the tumor, while allowing for grading of renal cancer. However, further external examination is needed for this model, and none of the current models can predict the likelihood of progression of SRMs to metastatic disease or actively monitor the cohort for kidney cancer-specific mortality. Even if linear growth is not demonstrated on serial imaging, malignancy cannot be ruled out. This suggests the limitations of imaging tools in characterizing the biological behavior of renal masses.
What about the effectiveness of biopsy? In recent years, the accuracy of biopsy in diagnosing renal cancer has reached over 90%, but the ability to correctly assess tumor grading is still very poor. In addition, studies of pathological specimens of kidney cancer have shown a great heterogeneity at the grading and molecular levels, which limits the accuracy of biopsy in detecting tumor aggressiveness.
The use of molecular techniques or radiographic imaging in biopsies could improve the ability to predict the phenotype of aggressive kidney cancer, thereby limiting the population requiring surgical treatment. Unless these techniques are further developed and matured, surgery will continue to be the treatment modality for most small exophytic renal cancers.
Preservation of the renal unit surgery has largely replaced radical nephrectomy as the mainstay of treatment measures for SRMs, reducing the risk of developing chronic kidney disease over time. Minimally invasive partial nephrectomy is an ideal option for exophytic SRMs, which also reduces treatment-related mortality. Thus, the relative safety of SRMs as a therapeutic measure provides a further argument for avoiding the oncologic risk of surveillance occurring.
Furthermore, in patients initially monitored, tumor progression may lead to tumor growth, resulting in increased difficulty or even inability to perform surgery. When patients are incidentally found to have localized SRMs, they are not only in the most curable period, but also in the best position to tolerate surgery. Suitability for surgery does not improve with age, and given that most renal masses continue to grow over time, deferred surgery with active monitoring is unlikely to improve clinical outcomes.
As always, patient selection is the key. For those patients who do not have a long life expectancy because of age and other comorbidities, active surveillance may be a wise choice. However, for most patients with small volume renal cancer, we have the ability to eliminate the risk of metastasis and death from renal cancer at minimal cost, while reducing the risks associated with treatment.
The American and European Societies of Urology unanimously recommend that partial nephrectomy remains the standard of care for stage cT1a kidney cancer unless those with accurate diagnostic techniques can confirm that patients with SRMs will not experience disease progression and will not require invasive treatment.