Early 21st Century renal cell carcinoma

A “paradigm shift”

Authors

  • Massimo Lazzeri MD, PhD,

    Corresponding author
    1. Department of Urology, Vita-Salute University, San Raffaele Hospital, Turro, Milan, Italy
    • Department of Urology, San Raffaele Hospital, Vita-Salute University, San Raffaele Turro, Via Stamira D'Ancona 20, 20127 Milan, Italy
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  • Giorgio Guazzoni MD

    1. Department of Urology, Vita-Salute University, San Raffaele Hospital, Turro, Milan, Italy
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  • We thank Amy Sussman for the linguistic revision of the article.

  • See referenced original articles on pages 3119-26 and 3135-42, this issue.

Abstract

Individuals involved in the management of patients with small renal masses should acknowledge the role and the importance of active surveillance in older populations (aged >75 years) and minimally invasive ablative therapies. These new therapeutic strategies should be inculcated during medical training and practice so that they may become just as embedded as the emphasis on the oncologic outcome of standard treatment.

In 1962, the philosopher Thomas Kuhn (1922-1996) wrote and published his book The Structure of Scientific Revolution, which introduced the concept of “paradigm shift.” Kuhn argued that scientific advancement results from a succession of peaceful intervals punctuated by intellectually violent revolution and that 1 world view often is replaced by another. In other words, a paradigm shift changes the way we think about a topic: it is a transformation or a sort of metamorphosis. This may be what will happen with our approach to managing renal cell carcinoma (RCC).

It has been estimated that, in 2008, approximately 55,000 new renal tumors were diagnosed in the United States, resulting in 13,000 deaths, and similar figures are expected throughout the world.1, 2 Renal parenchymal tumors, generally referred to as RCC, represent 2% of all adult cancers and are regarded as highly lethal urologic cancers, and approximately 35% of patients die from this disease after 5 years.3 RCC incidence rates have risen steadily each year during the last 3 decades in most of the world, with an average increase of 2% to 3% per year.4 In the last 2 decades, the widespread use of modern imaging techniques, such as abdominal ultrasound (US), cross-sectional computed tomography (CT), and magnetic resonance imaging (MRI), have produced a continual increase in the detection rate of small renal masses (SRMs).5, 6 Thus, more and more renal tumors are detected today in asymptomatic patients, and approximately 50% are observed in aging patients.7 These “incidental” tumors typically are smaller, of lower stage, of lower histologic grade, and have better survival rates than symptomatic tumors, although, in a non-negligible percentage of patients, these incidental tumors have high-grade histology and indicate a poor prognosis.8 Many of us realize that the incidental finding of an SRM (generally <4 cm in asymptomatic patients) poses a therapeutic dilemma: surveillance versus operative option.

In this issue of Cancer, 2 articles attempt to address this dilemma and advance a “paradigm shift” in the management of SRMs.9, 10 Lane et al9 report on the overall and cause-specific survival of patients with renal tumors in the aging population (aged ≥75 years) with a localized tumors ≤7 cm and specifically cast doubt whether surgical intervention improves survival compared with active surveillance. They observed that active treatment was not associated with improved overall survival relative to active surveillance in a heterogeneous population of patients aged ≥75 years who had clinically localized renal cancer after adjusting for potential confounder bias. They suggest/argue that localized renal tumors are being over treated. Active surveillance is a reasonable strategy yet is greatly underused in the elderly population. Although their study design has several limitations, which specifically are addressed and discussed in the article, their study should be diffused widely among urologists, surgeons, oncologists, and all physicians involved in the management of patients with renal carcinoma. Since the end of World War II, there has been a remarkable increase in life expectancy in Japan and in the Western world, especially in European countries like Spain and Italy. According to the Human Mortality Database, most babies born after the Year 2000 in countries with long-living residents will celebrate their 100th birthday if the current yearly growth in life expectancy continues throughout the 21st Century.11 We all realize that this scenario is just an estimate, but we do not have to look to the future for the challenges of an aging population. Over the past 2 decades, the population aged >75 years has been the most rapidly expanding segment of the Western population. In accordance with the suggestions of Lane et al,9 active treatment for SRMs might impact the general health of elderly people and, thus, may have a fundamental effect on the sustainability of modern healthcare systems. Very long lives are not a privilege of the next generations but are the probable destiny of most individuals who are alive now in developed countries. The increase prevalence of a very old population poses major challenges for national healthcare systems. Physicians involved in the management of kidney cancer should do their part in sparing renal parenchyma, not only allowing patients to live longer but also allowing them to live longer with fewer disabilities and fewer functional limitations.

Several minimally invasive nephron-sparing surgery (NSS) techniques that aim to achieve parenchyma preservation, low morbidity, and reliable oncologic results have been advocated recently for selected patients with an SRM.12 These include open or laparoscopic partial nephrectomy (PN) as well as laparoscopic or percutaneous probe-guided ablative procedures. Laparoscopic PN is technically challenging, requires advanced laparoscopic dexterity, and is time-sensitive to intracorporeal suturing.13 Ablative techniques have gained in interest, mainly because of decreased morbidity, short hospital stays, preservation of renal function, and the ability to treat patients who otherwise would be at surgical risk.14 They include cryoablation (CA), radiofrequency ablation (RFA), high-intensity focused US, microwave thermotherapy, laser interstitial thermotherapy, chemoablation with or without radiofrequency, and radiosurgery. Percutaneous or laparoscopic CA and RFA are the most commonly used ablation techniques and clinically investigated procedures.

Tracy et al10 report their experience with RFA of SRMs performed by a laparoscopic or percutaneous approach in 1 of the largest series of patients in the literature—>208 patients with 243 tumors. They reported 5-year metastasis-free and cancer-specific survival rates in patients with proven malignancy (179 of 243 patients; 79%) of 95% and 99%, respectively. Of the patients in their current cohort, 7 patients had a primary treatment failure, and the initial success rate was 97%. All 7 of those patients underwent a biopsy: Six patients had biopsy-proven, persistent RCC, and 1 patient had an indeterminate pathology. Nine patients developed a disease recurrence (histologically proven RCC) ≤3 years after follow-up, yielding 3-year and 5-year recurrence-free rates of 90% when exclusively considering biopsy-proven RCC lesions. The authors concluded that RFA provides successful treatment of SRMs with a low rate of recurrence and prolonged metastasis-free and cancer-specific survival rates. Nevertheless, the mean follow-up in their series remains short (27 months), and longer term follow-up will be required to determine late recurrences, although the results reported by Tracy et al indicate no evidence of disease recurrence in patients who have >3 years follow-up.10

Over the past years, several articles have been published detailing RFA and CA for SRMs. Most series have been relatively small with limited follow-up. For this reason, the data reported by Tracy et al may represent an evidence-based contribution to a “paradigm shift” in the management of SRMs.

Unfortunately, several issues remain open, such as the role of preoperative biopsy to prove malignity before active treatment is delivered, the ideal thermal ablative energy (ie, RFA vs CA), the percutaneous or laparoscopic approach, and follow-up modality and extension. Percutaneous renal biopsy or fine-needle aspiration traditionally has served a limited role in the evaluation of renal masses before treatment because of a high false-negative rate and potential complications associated with renal mass biopsy.15 However, in recent years, the potential role of biopsy for localized renal tumors has been revisited, in part driven by the recognition that 20% of clinical stage T1 renal masses may represent benign disease and cannot be considered aggressive. Given the significant heterogeneity in the biologic aggressiveness of SRMs and the wide range of treatment options currently available for different populations, renal mass biopsy should be used increasingly for patient counseling and clinical decision making (surgery vs observation) and for patients who are unwilling to accept the uncertainty associated with minimally invasive thermal ablative procedures.

RFA and CA, as opposed to extirpative surgery, which allows for the assessment of the entire pathologic specimen, rely on imaging techniques to determine treatment success and outcome. Nonenhancement of the central portion of the ablated lesion was considered the primary CT/MRI hallmark of radiologic success. Generally speaking, persistent lesion enhancement on radiologic imaging after 3 months, nodular enhancement, or the lack of a decrease in size of the thermal ablated lesion should be considered suspicious for locally persistent/recurrent disease. Since publication of the landmark article by Gill et al,16 several studies have appeared in the literature on this topic. Lawatsch et al observed 2 recurrence at a mean follow-up of 25.2 months (median, 26.8 months) that were identified by residual enhancement of the cryolesion on contrast-enhanced imaging studies and confirmed by definitive histology on nephrectomy.17 Similar results were reported by Schwartz et al, who reported that 2 of 85 patients (3.6%) had radiologic enhancement after CA and postablative positive biopsies.18 Although urologists and radiologists generally have used MRI or CT imaging accuracy in measuring the adequacy of tumor destruction and recurrence after ablative therapies, radiographic success remains largely an extrapolation of data accumulated in an extirpative surgical series. Weight et al reported the largest experience available on the correlation of radiographic findings and pathology results after ablative procedures.19 Those authors demonstrated a high correlation rate between radiographic and pathologic findings in the setting of the postcryotherapy, but not after radiofrequency. For cryoablation, the sensitivity of central nodular contrast enhancement on a 6-month follow-up CT or MRI to predict a positive biopsy in the post-CA cohort was 77.8% with 95.1% specificity, 63.4% positive predictive value (PPV), and 97.7% negative predictive value (NPV). Conversely, the sensitivity of central nodular enhancement on a 6-month follow-up CT or MRI to detect a positive biopsy after RFA was only 38.4% with 91.3% specificity, 71.4% PPV, and 72.4% NPV.

Kutikov et al completed a meta-analysis comparing outcomes after excision (PN), thermal ablation procedures (RFA and CA), and surveillance in patients with SRMs.20 The local recurrence rates were 2.6%, 4.6%, and 11.7% for PN, CA, and RFA, respectively; and, despite different modalities in the outcome evaluation and short follow-up, a statistically significant high risk of developing recurrent disease was observed for CA (relative risk [RR], 7.45) and for RFA (RR, 18.23) in a multivariate analysis. However, the cancer-specific survival rates were very high and were similar, without any statistical significant difference, across all modalities of treatment. Those authors concluded that PN remains the standard of care for SRM, but cancer-specific metrics for ablative treatments appear promising, suggesting that CA is superior to RFA, although this result may be a function of the application of the technology rather than the technology itself. Very recently Guazzoni et al reported a cancer-specific survival rate of 100% and an overall survival rate of 93.2% in 44 patients who underwent laparoscopic cryotherapy for SRMs in the setting of RCC with a mean follow-up (±standard deviation) of 61.3 months (±13.76 months). This result seems to confirm the robust and extended long-term oncologic results for CA.21

Everyone involved in the management of patients with SRMs should acknowledge the role and the importance of the achievements of Lane et al9 and Tracy et al10 and bring these results into practice. We are aware that this process may require time, longer follow-up, and more studies under more controlled conditions. The high-quality data reported by Lane et al and Tracy et al should be inculcated during medical training and practice so that it may become just as embedded as the emphasis on the oncologic outcome of standard treatment. We must be ready to look after the “paradigm shift” of the 21st Century in the management of SRMs, redefining ourselves as an innovative group to cope with the challenges of the future: aging population, minimally invasive procedures, and organ-sparing surgeries. We believe that oncology continues to attract the interest of both the public and patients, and the challenge is to make room for a “new science” that puts our results and expertise to the best public use. We maintain that our approach to the treatment of SRMs is flexible, promptly considers innovations, and supports surgical development under rigorous guidelines.

CONFLICT OF INTEREST DISCLOSURES

The authors made no disclosures.

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