Advanced Kidney Cancer

Tumor biology

Pathology

Histologic subgroups

Clinical presentation of RCC

Screening for RCC

Staging of RCC

1. Clinical characteristics:
   1. Performance status
   2. Systemic symptoms
   3. Symptomatic (vs. incidental) presentation
   4. Anemia
   5. Thrombocytosis
   6. Hypercalcemia
   7. Elevated lactate dehydrogenase
   8. Elevated erythrocyte sedimentation rate
   9. Elevated C-reactive protein
   10. Elevated alkaline phosphatase
2. Tumor anatomic characteristics:
   1. Tumor size
   2. Venous extension
   3. Contiguous invasion of adjacent organs (i.e. T4 stage)
   4. Adrenal involvement (i.e. T4 or M1 stage)
   5. Lymph node metastasis (i.e. N1 stage)
   6. Presence and burden of metastatic disease (i.e. M1 stage)
3. Tumor histologic characteristics:
   1. Histologic subtype
   2. Presence of sarcomatoid differentiation
   3. Nuclear grade
   4. Presence of histologic necrosis
   5. Vascular invasion
   6. Invasion of perinephric or sinus fat
   7. Invasion of collecting system
   8. (post-operative) surgical margin status

Treatment of RCC (localized)

The rapid spread of Coronavirus Disease 2019 (COVID-19), caused by the betacoronavirus SARS-CoV-2, has had dramatic effects throughout the world on healthcare systems with impacts far beyond the patients actually infected with COVID-19.

Patients who manifest severe forms of COVID-19 requiring respiratory support typically require this for prolonged durations, with a mean of 13 days of respiratory support reported by the China Medical Treatment Expert Group for COVID-19.¹ This lengthy requirement for ventilator support and ICU resources, exacerbated by relatively little excess health system capacity to accommodate epidemics, means that healthcare systems can (and have in the case of many hospitals in Italy) become overwhelmed relatively quickly. In an effort to conserve hospital resources, on March 13^th the American College of Surgeons recommended that health systems, hospitals, and surgeons should attempt to minimize, postpone, or outright cancel electively scheduled operations.² This was done with the primary goal to immediately decrease the use of items essential for the care of patients with COVID-19 including ICU beds, ventilators, personal protective equipment, and terminal cleaning supplies. On March 17^th, the American College of Surgeon then provided further guidance on the triage of non-emergent surgeries, including an aggregate assessment of the risk incurred from surgical delays of six to eight weeks or more as compared to the risk (both to the patient and the healthcare system) of proceeding with the operation.³ In the UK, all non-urgent elective surgical procedures have been put on hold for three months to use all of those clinical resources to care for patients with COVID-19.

Most bodies, including the American College of Surgeons, have recommended proceeding with most cancer surgeries. Thus, clinicians and patients must carefully weigh the benefit of proceeding with cancer treatment as scheduled, the risks of COVID-19 to the individual patient, to healthcare workers caring for patients potentially infected with COVID-19, and the need to conserve health care resources. A severe SARS-CoV-2 phenotype is seen more commonly in men and older, more comorbid patients.⁴ Baseline characteristics among 1,591 patients admitted to the ICU in the Lombardy Region, Italy, showed that the median age was 63 years (IQR 56-70), 82% were male, 68% had ≥1 comorbidity, 88% required ventilator support, and the mortality rate was 26%, with a large proportion requiring ongoing ICU level care at the time of data cut-off.⁵ Work from China demonstrated that patients with cancer had a higher incidence of COVID-19 infection than expected in the general population and had a more severe manifestation of the disease with a significantly higher proportion requiring invasive ventilation in the ICU or death.⁶ Patients at increased risk of COVID-19 are comparable to the kidney cancer population, namely more likely male, hypertensive, and with more than one comorbidity.⁵


Thus, considering the differences in the natural history of different cancers may meaningfully change this balance of risks and benefits. Kidney cancer has a wide range of phenotypic presentations ranging from very indolent, incidentally diagnosed small renal masses to large, symptomatic tumors with vascular or adjacent organ invasion and de novo metastatic disease. Previous articles in the UroToday Kidney Cancer Today Center of Excellence have discussed the Epidemiology and Etiology of Kidney Cancer and particular nuances of staging and management for Malignant Renal Tumors. The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread, and 16% had evidence of distant, metastatic disease.⁷

While the effect of delays in surgical intervention has been most thoroughly explored in muscle-invasive bladder cancer and prostate cancer in the urologic literature, both data and inference may help guide the management of patients with kidney cancer at this time. A single previous narrative review has assessed this question,⁸ however, conclusions from this study are limited. In the absence of data, the guidance of care relies on expert opinion, including a collaborative review pre-published in European Urology (Wallis et al.). This article will discuss the impact of potential delays among patients with kidney cancer, providing recommendations as to who can safely defer treatment until after the pandemic is over versus those that should be treated without delay.

While there are no randomized data, numerous institutional studies have demonstrated both the safety and feasibility of active surveillance (AS) with delayed intervention in patients with small renal masses (SRMs).^9,10

Among 457 patients treated at Fox Chase Cancer Center, McIntosh et al. found that rates of delayed intervention were 9%, 22%, 29%, 35%, and 42% at one-, two-, three-, four-, and five-years following diagnosis.¹¹ Importantly, delayed intervention was not associated with overall survival (OS) (hazard ratio [HR] 1.34, 95% confidence interval [CI] 0.79-2.29), and of the 99 patients on AS without delayed intervention for more than five years, only one patient metastasized. Interestingly, they found a median initial linear growth rate was 1.9 mm/year (IQR 0-7) which was not associated with OS.

Data from the University of Michigan has also assessed the effect of delayed resection (at least six months from presentation) after initial surveillance for patients with SRMs.¹² In this study, there were 401 patients that underwent early resection and 94 patients (19%) that underwent delayed resection. The median time to resection was 84 days (IQR 59-121) in the early intervention group and 386 days (IQR 272-702) in the delayed intervention group. Importantly, there was no difference in adverse final pathology (grade 3-4, papillary type 2, sarcomatoid histology, angiomyolipoma with epithelioid features, or stage ≥ pT3) comparing those that underwent early vs late intervention.

Among 497 patients in the DISSRM registry, 223 (43%) chose AS and 274 (57%) chose primary intervention with 21 (9%) eventually undergoing delayed intervention after a period of AS. There was no difference in cancer-specific survival (CSS) at five-years between the groups (primary intervention: 99%; AS 100%, p=0.3) though patients choosing surveillance had lower five-year OS (75% vs 92%), likely attributable to comorbidity which drove their initial selection of surveillance.

Taken together, there is robust data supporting AS for masses < 4cm, even up to five years after the initial diagnosis, without age restriction.^13,14 Thus, delays in the diagnosis and management of these patients during the COVID-19 pandemic is unlikely to meaningfully affect their outcomes.

Although the data is less robust, several studies have assessed the impact of a surgical delay for larger localized kidney tumors (≥pT1b). An institutional cohort from Memorial Sloan Kettering Cancer Center examined 1,278 patients who underwent radical or partial nephrectomy with renal masses > 4 cm between 1995 and 2013. The authors tested the association between surgical wait time and disease upstaging at the time of surgery, as well as two- and five-year recurrence rates.¹⁵ Among these patients, 267 (21%) had a surgical wait time of more than three months, including 82 patients (6%) with a wait time of more than six months. On multivariable analysis, the surgical wait time was not associated with disease upstaging, recurrence or CSS, but longer wait time was associated with worse OS (HR 1.17, 95% CI 1.08-1.27), potentially reflecting comorbidity which necessitated the initial delays.

Similarly, an institutional cohort from the Fox Chase Cancer Center of patients with cT1b/cT2 renal masses assessed the safety of active surveillance.¹⁶ Twenty-three patients (34%) underwent delayed intervention. Over a median follow-up of 32 months (range 6-119), no patients progressed to metastatic disease or died of kidney cancer. The median linear growth rate was 0.34 cm/year (range 0-1.48) suggesting that delays of months to years are unlikely to affect the resectability of these tumors.

Finally, a retrospective review of 722 patients undergoing partial or radical nephrectomy for relatively large kidney tumors (mean tumor size of 6.4 +/- 4.4cm; 64.7% ≥pT1b and 49.0% ≥pT2) from Stec et al. assessed the effect of delays to surgery on survival.¹⁷ They found that the mean time from initial visit to surgery was 1.2 months (range 0-30 months) and that 64.1% of patients underwent surgery within 30 days of initial visit and 94.3% within three months. The authors found no difference in OS for patients receiving early vs. late surgery, whether using a threshold of one month (p=0.87), two months (p=0.46), three months (p=0.71), or six months (p=0.75). However, T-stage was a significant predictor of recurrence-free survival (RFS), independent of time to surgery.

There are essentially no available data on the effect of delays in treating patients with locally advanced kidney cancer. However, several large institutional studies have described timing of preoperative imaging for assessing renal vein/inferior vena cava (IVC) thrombus, which may guide the urgency of surgical timing. While Woodruff et al. recommended the longest interval between imaging (CT/MRI) and surgery being no longer than 30 days,¹⁸ studies from the Mayo Clinic and Berlin, Germany report a median interval from imaging to resection of 4 and 16 days, respectively.^19,20 As a result, the collaborative review pre-published in European Urology suggested that these patients should be prioritized for intervention given the locally advanced nature of their disease, unknown risk of delayed resection, and potential for significant symptomatic complications including bleeding and IVC occlusion.

In contrast, in patients with known metastatic kidney cancer, cytoreductive nephrectomy during the ongoing pandemic was not recommended in this collaborative review on account of the evidence from the CARMENA trial which failed to demonstrate a survival benefit to the addition of cytoreductive to systemic therapy with sunitinib.²¹ Additionally, the SURTIME trial found that upfront systemic therapy followed by cytoreductive nephrectomy was associated with longer survival than patients who received upfront cytoreduction followed by systemic therapy.²²

The question of when to initiate systemic therapy in patients with metastatic kidney cancer is also pertinent during this pandemic and depends on symptoms, patient comorbidities, and tumor risk stratification. In treatment-naïve patients with favorable and intermediate-risk disease who are asymptomatic or minimally symptomatic with limited disease burden, a number of studies, including two narrative reviews^23,24 and two prospective trials,^25,26 have assessed the safety and feasibility of delaying the initiation of systemic therapy. In the largest prospective study of surveillance in patients with metastatic kidney cancer, Rini et al. enrolled fifty-two asymptomatic patients in a Phase II trial.²⁶ All but one patient had favorable (23%) or intermediate (75%) risk disease according to IMDC criteria with the vast majority (80%) of patients having only one or two organ sites with metastases. The median time on surveillance was 14.9 months and 37 of 43 patients experiencing RECIST-defined disease progression started systemic treatment. The median PFS and OS from the start of surveillance was 9.4 and 44.5 months, respectively. In a smaller study of 15 patients who received CN followed by observation until progression, Wong et al. found a median time to progression of eight weeks and a median OS of 25 months.²⁵ Neither of these studies have compared outcomes with patients who started systemic therapy upfront. However, this has been assessed in two large retrospective studies. Among a European cohort of patients ineligible for active surveillance, Iacovelli and colleagues found that a delay of more than six weeks in the initiation of systemic therapy did not significantly affect the cancer-specific outcomes.²⁷ Further, delayed treatment initiation was not independently associated with worse OS in an analysis based on the National Cancer Database utilizing multivariable logistic regression analyses.²⁸

There is no evidence to guide the choice of systemic therapy during the COVID-19 pandemic and thus, standard guideline recommendations should prevail. However, at least theoretically, the risk of severe adverse reactions associated with immunotherapy using checkpoint inhibitors, as well as the requirement for infusion, may preferentially support the use of VEGF-targeted therapy with the convenience of oral administration.

Written by: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Atlanta, Georgia

Published Date: April 2020

The History of Cytoreductive Nephrectomy

Cytoreductive Nephrectomy in the Targeted Therapy Era

Early years: cytokine therapy

A new standard: molecularly targeted agents

What’s old is new: immunotherapy for RCC

The next frontier: combinations of targeted therapy and immunotherapy

Dead-ends

Integration of treatment options for patients with metastatic ccRCC

What about surgery?

Kidney cancer is a broad, encompassing term that borders on colloquial. While most physicians are referring to renal cell carcinoma when they say “kidney cancer”, a number of other benign and malignant lesions may similarly manifest as a renal mass. Considering only the malignant causes, kidney cancers may include renal cell carcinoma, urothelium-based cancers (including urothelial carcinoma, squamous cell carcinoma, and adenocarcinoma), sarcomas, Wilms tumor, primitive neuroectodermal tumors, carcinoid tumors, hematologic cancers (including lymphoma and leukemia), and secondary cancers (i.e. metastases from other solid organ cancers).

Epidemiology

In the United States, cancers of the kidney and renal pelvis comprise the 6th most common newly diagnosed tumors in men and 10th most common in women.¹ In 2018, an estimated 65,340 people will be newly diagnosed with cancers of the kidney and renal pelvis in the United States. In men, this comprises 42,680 estimated new cases in 2018 representing 5% of all newly diagnosed cancers. In women, 22,660 new cases are anticipated in 2018 representing 3% of all newly diagnosed cancers. Additionally, 14,970 people are expected to die of kidney and renal pelvis cancers in 2018 in the United States, with this being the 10^th most common cause of oncologic death among men.

In Europe, results are similar. In 2018, the incidence of kidney cancer is estimated at 136,500 new cases representing 3.5% of all new cancer diagnoses.² This corresponds to an estimated age standardized rate (ASR) of 13.3 cases per 100,000 population. As in the United States, the incidence of kidney and renal pelvis cancers is higher among men (incidence 84,9000, 4.1% of all cancers, ASR 18.6 per 100,000) than women (incidence 51,600, 2.8% of all cancers, ASR 9.0 per 100,000). Correspondingly, 54,700 people were estimated to die of kidney and renal pelvis cancers in Europe in 2018, accounting for 2.8% of all oncologic deaths. The age standardized mortality rate was 4.7 deaths per 100,000 population. Again, death from kidney and renal pelvis cancer was more common among men (mortality 35,100, 3.3% of oncologic deaths, ASR 7.1 per 100,000) than among women (mortality 19,600, 2.3% of oncologic deaths, ASR 2.7 per 100,000). Interestingly, within Europe, there is considerable variation in the incidence and mortality of kidney and renal pelvis cancer between countries.²

While the aforementioned data have already demonstrated that gender is strongly associated with the risk of both diagnosis of and death from kidney and renal pelvis cancers, age also importantly moderates this risk. Among patients in the United States, the probability of developing kidney and renal pelvis cancer rises nearly ten fold from age <50 to age >70 years.¹


Thus, kidney cancer is predominantly a disease of older adults, with the typical presentation being between 50 and 70 years of age. However, over time, rates of diagnosis of kidney cancer have increased fastest among patients aged less than 40 years old.³

In the United States, kidney cancers are more common among African Americans, American Indians, and Alaska Native populations while rates are lower among Asian Americans.⁴ Worldwide, the highest rates are found in European nations while low rates are seen in African and Asian countries.⁴

The vast majority of patients have localized disease at the time of presentation. According to Siegel et al., 65% of all patients diagnosed with kidney and renal pelvis tumors between 2007 and 2013 had localized disease at the time of presentation while 16% had regional spread and 16% had evidence of distant, metastatic disease.¹ This is in large part due to incidental diagnosis due to the increased use of ultrasonography and computed tomography in patients presenting with abdominal distress. In fact, 13 to 27% of abdominal imaging studies demonstrate incidental renal lesions unrelated to the reason for the study⁵ and approximately 80% of these masses are malignant.⁶ Dr. Welch and colleagues demonstrated elegantly that the use of computed tomography is strongly related to the likelihood of undergoing nephrectomy, likely due to detection of renal masses. Thus, with the increasing utilization of abdominal imaging, the incidence of kidney cancer has increased by approximately 3 to 4% per year since the 1970s.

Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common kidney cancer. A number of histological subtypes have been recognized including conventional clear cell RCC (ccRCC), papillary RCC, chromophobe RCC, collecting duct carcinoma, renal medullary carcinoma, unclassified RCC, RCC associated with Xp11.2 translocations/TFE3 gene fusions, post-neuroblastoma RCC, and mucinous tubular and spindle cell carcinoma. Conventional ccRCC comprises approximately 70-80% of all RCCs while papillary RCC comprises 10-15%, chromophobe 3-5%, collecting duct carcinoma <1%, unclassified RCC 1-3%, and the remainder are very uncommon.

Histologically, most of these tumors are believed to arise from the cells of the proximal convoluted tubule given their ultrastructural similarities. Renal medullary carcinoma and collecting duct carcinoma, relatively uncommon and aggressive subtypes of RCC, are believed to arise more distally in the nephron.

Familial RCC Syndromes

While the vast majority of newly diagnosed RCCs are sporadic, hereditary RCCs account for approximately 4% of all RCCs. Due in large part to the work of Dr. Linehan and others, the understanding of the underlying molecular genetics of RCC have progressed significantly since the early 1990s. These insights have led to a better understanding of both familial and sporadic RCCs.

Von Hippel-Lindau disease is the most common cause of hereditary RCC. Due to defects in the VHL tumor suppressor gene (located at 3p25-26), this syndrome is characterized by multiple, bilateral clear cell RCCs, retinal angiomas, central nervous system hemangioblastomas, pheochromocytomas, renal and pancreatic cysts, inner ear tumors, and cystadenomas of the epididymis. RCC develops in approximately 50% of individuals with VHL disease. These tumors are characterized by an early age at the time of diagnosis, bilaterality, and multifocality. Due in large part to improved management of the CNS disorders in VHL disease, RCC is the most common cause of death in patients with VHL.

Hereditary papillary RCC (HPRCC) is, as one would expect from the name, associated with multiple, bilateral papillary RCCs. Due to an underlying constitutive activation of the c-Met proto-oncogene (located at 7q31), these tumors also present at a relatively early age. However, overall, these tumors appear in general to be less aggressive than corresponding sporadic malignancies.

In contrast, tumors arising in hereditary/familial leiomyomatosis and RCC (HLRCC), due to a defect in the fumarate hydratase (1q42-43) tumor suppressor gene, are typically unilateral, solitary, and aggressive. Histologically, these are typically type 2 papillary RCC, which has a more aggressive phenotype, or collecting duct carcinomas. Extra-renal manifestations include leiomyomas of the skin and uterus and uterine leiomyosarcomas which contribute to the name of this sydrome.

Birt-Hogg-Dube, due to defect in the tumor suppressor folliculin (17p11), is associated with multiple chromophobe RCCs, hybrid oncocytic tumors (with characteristics of both chromophobe RCC and oncocytoma), oncocytoma. Less commonly, patients with Birt-Hogg-Dube may develop clear cell RCC or papillary RCC. Non-renal manifestations include facial fibrofolliculomas, lung cysts, and the development of spontaneous pneumothorax.

Tuberous sclerosis, due to defects in TSC1 (located at 9q34) or TSC2 (16p13), may lead to clear cell RCC. More commonly, it is associated with multiple benign renal angiomyolipomas, renal cystic disease, cutaneous angiofibromas, and pulmonary lymphangiomyomatosis.

Succinate dehydrogenase RCC, due to defects in the SDHB (1p36.1-35) or SDHD (11q23) subunits of the succinate dyhydrogenase complex, may lead to a variety of RCC subtypes including chromophobe RCC, clear cell RCC, and type 2 papillary RCC. Extra-renal manifestations including benign and malignant paragangliomas and papillary thyroid carcinoma. In general, these tumors exhibit aggressive behaviour and wide surgical excision is recommended.

Finally, Cowden syndrome, due to defects in PTEN (10q23) may lead to papillary or other RCCs in addition to benign and malignant breast tumors and epithelial thyroid cancers.

Etiologic Risk Factors in Sporadic RCC

While numerous hereditary RCC syndromes exist, they account for only 4% of all RCCs. However, many sporadic RCCs share similar underlying genetic changes including VHL defects in ccRCC and c-Met activation in papillary RCC. A number of modifiable risk factors associated with RCC have been described.⁴

The foremost risk factor for the development of RCC is cigarette smoking. According to both the US Surgeon General and the International Agency for Research on Cancer, observational evidence is sufficient to conclude there is a causal relationship between tobacco smoking and RCC. A comprehensive meta-analysis of western populations demonstrated an overall relative risk for the development of RCC of 1.38 (95% confidence interval 1.27 to 1.50) for ever smokers compared to lifetime never smokers.⁷ Interestingly, this effect was larger for men (RR 1.54, 95% CI 1.42-1.68) than for women (RR 1.22, 95% CI 1.09-1.36). Additionally, there was a strong dose response relationship: compared to never smokers, men who smoked 1-9 cigarettes per day had a 1.6x risk, those who smoked 10-20 per days had a 1.83x risk, and those who smoked more than 21 per day had a 2.03x risk. A similar trend was seen among women. Notably, the risk of RCC declined with increasing durations of abstinence of smoking. Smoking appears to be preferentially associated with the development of clear cell and papillary RCC.⁸ In addition to being associated with increased RCC incidence, smoking is associated with more aggressive forms of RCC, manifest with higher pathological stage and an increased propensity for lymph node involvement and metastasis at presentation.⁹ As a result, smokers have worse cancer-specific and overall survival.⁹

Second, obesity is associated with an increased risk of RCC. While this risk was historically felt to be higher among women, a more recent review demonstrated no such effect modification according to sex.¹⁰ In a meta-analysis of 22 studies, Bergstrom et al. estimated that each unit increase of BMI was associated with a 7% increase in the relative risk of RCC diagnosis.

Third, hypertension has been associated with an increased risk of RCC diagnosis, with a hazard ratio of 1.70 (95%CI 1.30-2.22) in the VITAL study.¹¹ Interestingly, in an American multiethnic cohort, this effect appeared to be larger among women (RR 1.58, 95% CI 1.09-2.28) than in men (RR 1.42, 95% CI 1.07-1.87).¹² Again, as with obesity, there appears to be a dose-effect relationship between severity of hypertension and the risk of RCC diagnosis.¹³

Fourth, acquired cystic kidney disease (ACKD) appears to be associated with a nearly 50x increase risk of RCC diagnosis.¹⁴ ACKD occurs in patients with end-stage renal disease on dialysis. These changes are common among patients who have been on dialysis for at least 3 years.¹⁴ Interestingly, the risk of RCC appears to decrease following renal transplantation.

Finally, a number of other putative risk factors have been described. These lack the voracity of data that the aforementioned four have. Such risk factors include alcohol, analgesics, diabetes, and diet habits.⁴

Published Date: November 20th, 2018

Adjuvant targeted therapy

Tyrosine kinase inhibitors (TKIs) quickly became standard of care for patients with metastatic renal cell carcinoma following their introduction in the early 2000s. They have subsequently been investigated as adjuvant therapy in 4 published randomized trials to our knowledge. In addition, the SORCE trial was presented at ESMO 2019 at the end of September 2019.

As has been highlighted in the accompanying article on the Epidemiology and Etiology of Kidney Cancer, cancers of the kidney and renal pelvis comprise the 6^th most common newly diagnosed tumors in men and 10th most common in women.¹ With the increasing use of abdominal imaging, a growing number of small renal masses are being detected. In fact, 13 to 27% of abdominal imaging studies demonstrate incidental renal lesions unrelated to the reason for the study² and approximately 80% of these masses are malignant.³Thus, a large number of small, incidentally-detected renal masses are now being diagnosed. Due to the increase in diagnosis of small renal masses and the general predilection for diagnosis of renal tumors in older adults (typically diagnosed between age 50 and 70 years), the paradigm for treatment of renal tumors has focused on minimally invasive approaches and nephron sparing in the past few years.

According to the American Urological Association guidelines on the management of stage 1 renal tumors, nephron sparing surgery (partial nephrectomy) is recommended.⁴ However, renal mass ablation is considered an alternative, particularly among the elderly and comorbid.⁴ Renal ablation may be undertaken by percutaneous approaches (nonsurgical) or through laparoscopic or open approaches.

Rationale for Focal Therapy

As with any tumor site, focal ablative therapies offer several potential advantages to traditional surgical approaches. First, focal ablative therapies are less physiologically demanding on the patient than extirpative surgery. As a result, these may often be performed as ambulatory day surgical procedures with a much shorter convalescence and fewer complications when compared to laparoscopic partial nephrectomy.⁵ Second, renal mass ablation is associated with comparable post-operative renal function when compared to partial nephrectomy.^5,6 Third, while laparoscopic partial nephrectomy is a technically challenging operation, requiring advanced laparoscopic skills for tumour resection and renal reconstruction,⁷ focal ablation (either via laparoscopic or percutaneous approach) allows minimally-invasive treatment of renal tumors with relative technical simplicity.⁵ Finally, renal mass ablation may be accomplished by a variety of approaches including open, laparoscopic, and percutaneous approaches.

While long-term data are lacking, intermediate term data (with a median follow-up of approximately 3.5 years) suggest that cancer control is similar between renal tumor ablation (using laparoscopic cryotherapy) and minimally-invasive partial nephrectomy.⁶

Indications for Focal Therapy of Renal Tumors

Treatment choice in the management of small renal masses depends on a complex interplay of patient preference, tumor characteristics, host (patient) factors including age and comorbidity, and the expertise/ability of the treating physician. A number of indications have been well-recognized for the use of renal tumor ablation. Ablation is indicated for patients with small renal tumors who are: poor surgical candidates or at high risk of renal insufficiency. Patients may be at risk of renal insufficiency due to underlying nephron-threatening conditions such as diabetes or hypertension, due to a solitary kidney (either congenital or due to prior nephrectomy), or due to oncologic factors such as bilateral tumors or hereditary syndromes which predispose to recurrent, multifocal tumors.

However, given the good outcomes of renal mass ablation in the treatment of small renal masses among these patients, a number of authors have now advocated the use of renal mass ablation in otherwise healthy patients.⁸

Approaches to Focal Therapy

Non-surgical focal therapy refers to a therapeutic strategy, rather than a specific treatment modality. A number of different focal therapy modalities have been employed in the treatment of small renal masses. Foremost among these are cryoablation and radiofrequency ablation (RFA).

Prior to ablation, the American Urologic Association guidelines recommend biopsy of the renal mass either prior to ablation or at the time of treatment.⁹

Cryotherapy

Cryoablation, also known as cryotherapy, is the therapeutic use of extremely cold temperature. While first employed in the treatment of breast, cervical, and skin cancers, cryoablation has subsequently been used in the treatment of a variety of benign and malignant conditions. Initially, liquified air was used, then solidified carbon dioxide, liquid oxygen, liquid nitrogen, and finally argon gas. Today, the majority of commercially available systems rely on argon gas.

It wasn’t until Onik et al. identified that the cryogenic ice-tissue interface was highly echogenic on ultrasound that an accurate, controlled treatment of intra-abdominal malignancies could be undertaken.¹⁰ Today, cryotherapy of renal tumors is undertaken under real-time imaging.

Ablation during cryoablation occurs during both the freezing and thawing phases of the treatment cycle. During freezing, the rapid decrease in temperature immediately adjacent to the probe causes the formation of intracellular ice crystals which lead to mechanical trauma to plasma membranes and organelles and subsequent cell death through ischemia and apoptosis.¹¹ More distal to the probe, a slower freezing process occurs in which extracellular ice crystals form, causing depletion of extracellular water and inducing an osmotic gradient which causes intracellular dehydration. During the thaw cycle, extracellular ice crystals melt leading to an influx of water back into the cells, resulting in cellular edema. In addition to these cellular effects, the freezing cycle results in injury to the blood vessel endothelium resulting in platelet activation, vascular thrombosis and tissue ischemia. The result of these process is coagulative necrosis, cellular apoptosis, fibrosis and scar formation. Due to evidence that multiple freeze-thaw cycles led to larger areas of necrosis, the current treatment paradox suggests a double freeze-thaw cycle.

For optimal cellular death, the preferred target temperature for cryotherapy is at or below -40o C. As temperatures at the edge of the ice ball are 0o C, most authors suggest that the ice ball extends at least 5 or 10mm beyond the edge of the target lesion. In some cases, this will require the use of multiple probes.

Radiofrequency Ablation

In contrast to cryotherapy which utilizes freeze-thaw cycles to induce cellular damage, radiofrequency ablation (RFA) relies upon radiofrequency energy to heat tissue until cellular death. Using monopolar alternating electrical current at a frequency of 450 to 1200 kHz, RFA induces vibrations of ions within the tissue which leads to molecular friction and heat production. The resulting increased intracellular temperature leads to cellular protein denaturation and cell membrane disintegration. The success of RFA treatment depends on the power delivered, the resulting maximal temperature achieved, and the duration of ablation.

A number of variations in RFA delivery have been described: temperature- or impedance-based guidance, single or multiple tines, “wet” vs “dry” ablation, and mono- or bi-polar electrodes.

Unlike cryoablation which relies upon real-time imaging guidance, RFA may be guided by either temperature-based or impedance-based monitoring. Systems which rely on temperature-based guidance measure temperature at the tip of the electrode. However, they do not measure temperature within the surrounding tissue. Systems which rely on impedance-based guidance measure the resistance to alternating current (the impedance). These systems are calibrated to achieve a predetermined impedance level. There is no data to support the superiority of either of these approaches. For temperature-based systems, the target is 105o C with a minimum of 70o C during the heating cycle. For impedance-based systems, the target is 200 to 500 ohms, which is achieved by progressively increasing the power beginning from 40-80W to 130-200W at a rate of 10W/minute.

A number of studies have demonstrated that multi-tine electrodes are associated with more complete tissue necrosis and improved treatment outcomes.¹²

In addition to the guidance approach and number of tines, RFA technology may be stratified according to “wet” vs. “dry” approach. Through the tissue ablation process, tissue desiccation leads to charring which can increase impedance. This in turn increases the resistance to the current emanating from the electrode and limits the size of the ablation field. A “dry” approach functions within these limitations and cannot treat more than 4cm with a single electrode. In contrast, a “wet” approach continuously infuses saline through the probe tip. This cools the tissue and prevents the tissue charring. As a result, larger ablation zones are possible.

Finally, energy delivery may be either through monopolar or bipolar electrodes. The benefit of bipolar electrodes is both increased temperature generation¹³ and a larger treatment field.¹⁴

The efficacy of RFA is affected not only by the characteristics of the tissue being treated but also by the surrounding tissues. For example, large vessels may dissipate heat and result in relative undertreatment of adjacent tissues.

Monitoring following Focal Therapy

The definition of treatment success following renal mass focal ablation has been controversial. Currently, radiographic assessment utilizing computed tomography or magnetic resonance imaging is considered an accepted measure of treatment effect.¹⁵ Typically, this is performed 4-12 weeks following treatment. However, some rely on post-ablation biopsy to confirm treatment success though this is not well accepted.

The most reliable radiographic marker of successful ablation is the lack of contrast enhancement, corresponding to complete tissue destruction.¹⁶ Persistent enhancement is considered incomplete treatment and re-treatment or an alternative treatment strategy may be warranted. Alternatively, subsequent enhancement on surveillance imaging in an area with prior loss of enhancement suggests local recurrence.¹⁷ Many tumors following cryoablation have a significant reduction in tumor size while this is uncommon following RFA.

The AUA guidelines recommend contrast enhanced CT or MUI at 3 and 6 months following treatment and then each year for the following 5 years.⁹

Oncologic Outcomes

Long-term outcomes are lacking for renal ablation techniques. The summary data from the AUA guidelines panel suggests local recurrence free rates of approximately 90% for patients undergoing cryoablation and 87% for patients undergoing RFA.⁴ Outcomes between cryoablation and RFA appear to be comparable. Compared to partial nephrectomy, the available data suggest higher rates of local recurrence despite shorter follow-up. However, metastasis-free survival and cancer-specific survival appear to be comparable.

Complications

Major complications following renal mass ablation are uncommon. Further, percutaneous, nonsurgical ablation has lower complication rates than other approaches.¹⁸ As with oncologic outcomes, complication rates are comparable between RFA and cryoablation. Major urologic complications occurred in 3.3-8.2% of patients undergoing ablation while non-urologic complications occurred in 3.2-7.2%. These rates are lower than extirpative approaches including open or laparoscopic nephrectomy.

The most common complication is pain or paresthesia at the percutaneous access site.¹⁹ The most concerning complications relate to inadvertent injury to intra-abdominal organs. A variety of tumor characteristics including anterior location, proximity to collecting system and those without easy percutaneous access increase the risk of complications when percutaneous ablation is undertaken. Permanent urologic damage including injury to calyces, the ureteropelvic junction, or the ureter is uncommon.²⁰

Hemorrhage is the most common serious complication of cryoablation. This is less common with RFA. Bleeding is more common when multiple probes are used to treat large tumors.²¹

Published Date: November 20th, 2018

Prospective cohort studies

Retrospective cohort studies

Patient selection

Treatment recommendations

Conclusions