Renal cell carcinoma

Table V.

Treatment Status	Clear Cell RCC	Non-clear Cell RCC
Treatment Naive	Favorable Risk	No Groups Defined
	Intermediate Risk
	Poor Risk
Treatment Refractory	Cytokine Refractory	No Groups Defined
	TKI Refractory – duration previous therapy
	mTOR Inhibitor Refractory
Co-morbid Conditions	Recent Cardiovascular Event	Recent Cardiovascular Event
	Impaired Renal Function	Impaired Renal Function
	Impaired Hepatic Function	Impaired Hepatic Function
Unique Categories	Sarcomatoid Differentiation	Sarcomatoid Differentiation
	CNS metastases	CNS metastases
	Osseous Metastases	Xp11.2 Translocation
	Elderly Patients	Collecting duct, medullary RCC

Metastatic clear cell carcinoma

The histologic diagnosis of clear cell carcinoma is important to assist in determining therapy. If there is uncertainty, the likelihood exists the underlying histologic pattern represents clear cell carcinoma, and therapy can be administered for this presumed diagnosis.

Treatment naïve, metastatic clear cell carcinoma

These individuals have not received previous systemic therapy. Most individuals will fall into this category.

Treatment naïve, favorable risk metastatic clear cell carcinoma

Patients in this category should have no poor risk factors (10 to 20% of patients). They generally have low volume metastatic disease, predominantly pulmonary metastases, are asymptomatic, and may have long disease-free intervals.

The therapy recommended in this group would include:

• a TKI such as sunitinib or pazopanib,

• or the combination of bevacizumab plus IFN-a.

All of these options are associated with clinical toxicity; therefore, risk-benefit assessment may be helpful when estimating the potential utility of starting treatment. There are patients in this category where therapy can be delayed, the rate of disease progression observed, and therapy initiated at a later time. Recently, the COMPARZ (phase 3) and PISCES (phase 2) trials have compared pazopanib and sunitinib as first line therapeutic options. Pazopanib was found to be non-inferior to sunitinib, but importantly patient tolerance and preference favoured pazapanib. Everolimus has been shown to be inferior to TK1 therapy in the first line (RECORD-3 trial).

No published criteria are available that define this group; however, it probably includes the patient with low-volume disease, small but stable lung metastases, and a long disease-free interval. Not all patients with newly diagnosed metastatic RCC should receive immediate systemic therapy. Active surveillance, as in the case of small renal masses is a viable option.

An alternate therapeutic option in this category is cytokine therapy with high dose IL-2. This approach requires hospitalization, is associated with toxicity from the capillary leak syndrome, and a low rate of treatment associated mortality. It is generally utilized only in centers with significant expertise in administering high dose IL-2, and in patients who can tolerate this type of aggressive treatment.

Treatment naïve, intermediate risk metastatic clear cell carcinoma

This group contains the largest number of patients (60 to 70%). They are minimally symptomatic, most have had a prior nephrectomy, and have few, if any, laboratory abnormalities.

Therapy for this group should consist of:

• A TKI, or

• Combined bevacizumab and IFN-a.

Selection of the specific agent or regimen will depend on the presumed risk benefit of each approach in patients; however, all of the options are acceptable. No comparative trials have been published that define differences or similarities between these treatments.

Occasionally, patients in this group will have disease compromising vital organ function, e.g. mediastinal lymph nodes producing respiratory compromise, hematuria secondary to a primary tumor. In this setting, rapid tumor response is desirable. The agent with the highest likelihood of response may be the best alternative.

As with the favorable group, high dose IL-2 therapy is an option to be discussed with these patients dependent upon their age and cardiovascular status. The issues discussed in the favorable group are applicable in these patients.

Treatment naïve, poor risk metastatic clear cell carcinoma

This group of patients has the largest tumor burden, are symptomatic, may have their primary tumors in place (10 to 15% of patients).

Treatment generally consists of:

• The mTOR inhibitor temsirolimus.

This is the only treatment that has been examined in a phase 3 trial in these patients. This agent was well tolerated by poor-risk patients, without excessive toxicity noted. In view of these level 1 data, therapy with weekly intravenous temsirolimus is recommended for poor-risk patients. Use of sunitinib in this group is poorly defined; however, a phase 3 trial comparing sunitinib to IFN-a suggested selected poor risk patients may benefit. The role of other first-line treatment options such as pazopanib or bevacizumab plus IFN-a remains poorly defined.

Treatment refractory, metastatic clear cell carcinoma

The majority of patients receiving a targeted agent will have partial responses or stable disease, and will ultimately progress. The mechanisms responsible for the development of resistance are unclear, and therapeutic decisions require knowledge of previous therapy, as well as response or clinical benefit related to front-line treatment. Therapy for refractory patients is best defined by considering the type of initial treatment, and whether the resistance is acquired or intrinsic.

Cytokine refractory, metastatic clear cell carcinoma

Use of cytokines as initial therapy is currently limited, but some of the earlier clinical trials have defined treatment of this patient population. The TKIs sorafenib, sunitinib, pazopanib, or axitinib can be utilized. The data for sorafenib and axitinib are from randomized trials. Axitinib proved superior in prolonging progression-free survival (PFS), and is generally considered as the first choice for these patients. Sunitinib and pazopanib represent alternatives. Response rates to sunitinib or pazopanib are 30 to 40%, and PFS between 7 and 8 months. The recent data for axitinib suggest a similar response rate and PFS.

The available data in cytokine refractory patients suggest initial therapy with the TKI axitinib should be considered based on the trial size and design. Alternatively, either sorafenib, sunitinib, or pazopanib can be utilized based on available data.

TKI Refractory, metastatic clear cell carcinoma

Although targeted therapies have become the new cornerstone of systemic RCC therapy, eventual treatment-emergent resistance has become a major impediment to long-term success with these new agents.

To address this issue the mTOR inhibitor everolimus was tested in patients progressing after sorafenib and/or sunitinib. Patients receiving everolimus compared to placebo showed prolongation of PFS with acceptable side effects. These data supported the use of this agent as second-line therapy in patients failing initial treatment with a TKI. One rationale for this sequence is the use of an agent with an alternate mechanism of action.

Subsequent trials of other TKIs such as axitinib, cabozantinib (a multikinase inhibitor with activity against VEGF, MET, and AXL), Lenvatinib and everolimus, and the immune checkpoint inhibitor nivolumab (discussed below) have used everolimus as a benchmark, and all demonstrated superiority. As a consequence, single-agent everolimus is no longer commonly used as a second-line therapy. Lenvatinib, another anti-VEFG TKI given with everolimus, has been shown to prolong progression-free survival over everolimus alone and the combination is approved for use after progression on a prior anti-angiogenic therapy.

The standard of care in TKI refractory patients continues to evolve as new data become available. Based on phase 3 data demonstrating their superiority to everolimus, nivolumab and cabozantinib are the current preferred agents following progression on a prior TKI, although axitinib or the combination of everolimus and lenvatinib are supported by similar data and are reasonable options. The optimal agent or sequence of agents is not yet established.

Another approach in these refractory patients is re-challenge with the same agent, or another TKI. The concept of sequential utilization of several TKI’s has been proposed. Evidence demonstrating efficacy comes from phase 2 trials and a recent phase 3 trial comparing axitinib to sorafenib. In the setting of sunitinib failure, second responses to the same drug have been described.

Immune Checkpoint Inhibitors in TKI refractory, clear cell carcinoma

The immune checkpoint inhibitor nivolumab is approved for treatment of clear-cell renal cell carcinoma for patients progressing with prior anti-angiogenic therapy (TKI or VEGF inhibitor). Clinical trials are ongoing to study combined therapy with the anti-cytotoxic T lymphocyte antigen 4 (CTLA4) antibody ipilimumab in combination with nivolumab, a monoclonal antibody targeting programmed death receptor 1 (PD1). Trials with pembrolizumab (another PD1 antibody), or atezolizumab (a PD-L1 antibody) are also ongoing. Immune checkpoint inhibitors are not currently approved for non-clear cell cancers.

A phase 3 study (Checkmate 025) comparing everolimus with nivolumab after progression on one or two prior anti-angiogenic therapies demonstrated an improvement in overall survival (25 vs. 19.6 months), and objective response rate (25% vs. 5%) for patients receiving nivolumab. This was only the second trial to demonstrate an improvement in overall survival among the newer targeted agents, the first being temsirolimus.

Unlike with other malignancies (e.g., lung, melanoma) programmed death ligand 1 (PDL1) expression on tumor cells was not a reliable predictor of response, and in fact patients with <1% expression had slightly better overall survival on nivolumab than patients with >1% expression. It has previously been reported that increased PDL1 expression is a poor prognostic marker in clear cell carcinoma.

The most common adverse events of immune checkpoint inhibitors are fatigue, low-grade nausea, and anorexia. No standard premedication is given.

Autoimmune toxicities affecting specific organs occur in a minority of patients. Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis, and others have been observed. Their management is addressed under the “What if scenarios” below. As a consequence of these toxicities, immune checkpoint inhibitors should be avoided in patients with pre-existing autoimmune disease or patients requiring chronic high-dose steroids.

mTOR inhibitor refractory, clear cell carcinoma

The group of patients who fail first-line therapy with an agent such as temsirolimus generally represent poor-risk patients who had initially responded or had disease stability. The numbers of patients in this group represent approximately 35% of those treated in first-line. Data to assist treatment decisions in this group is lacking currently; however, a second line TKI is a reasonable alternative. For dosing, schedule, and toxicity of targeted agents, see Table VI.

Table VI.

Co-morbid conditions, metastatic clear cell carcinoma:

Recent cardiovascular event

Cardiovascular toxicity in the form of hypertension appears to represent a class effect of the VEGF/VEGF receptor (VEGFR) inhibitors. Treatment-induced hypertension also appears to correlate with clinical outcomes in RCC. This has been shown retrospectively for therapy utilizing sunitinib, axitinib, or bevacizumab.

These analyses have utilized several definitions of hypertension such as grade of toxicity or specific systolic and/or diastolic blood pressure levels. Correlations with objective response, PFS, and overall survival have been consistently found in patients who develop treatment-induced hypertension. This finding is being investigated prospectively, and the mechanisms underlying this phenomenon are unclear. Pre-existing hypertension should not therefore be considered a contraindication to the use of TKI’s or bevacizumab.

Cardiac dysfunction in the form of left ventricular dysfunction has been reported with the TKI’s sunitinib and sorefenib (>10%). A history of congestive heart failure or a decreased LVEF is a relative contraindication to the use of these agents. Studies with pazopanib suggest cardiac dysfunction is not seen with this TKI. In view of this, pazopanib appears to represent an alternative for this patient group, as well as individuals with a recent (<6 months) acute cardiovascular episode such as a myocardial infarction.

Impaired renal function

Abnormal renal function is frequently noted in patients with advanced RCC. The safety and efficacy of VEGF-targeted agents in patients with renal insufficiency is therefore relevant. Pharmacokinetic studies of various TKIs have demonstrated renal elimination is a minor component of drug metabolism. Hepatic metabolism is the major pathway. Therefore, it was assumed that the TKIs can be safely given to patients with renal insufficiency.

Retrospective reviews have shown that sunitinib and sorafenib can be administered to patients with impaired renal function. Monitoring of renal function is recommended, since TKI administration may produce serum creatinine elevations. Patients with worsening renal function may require dose modifications. Recent data from the CALGB has suggested that sorafenib dose can be maintained with a creatinine clearance above 40 mL/min, but below this level, dose reductions are required.

Patients with metastatic RCC on hemodialysis represent a distinct population. Information is largely anecdotal in this group, and two recent retrospective reports suggest administration of sunitinib is possible with acceptable toxicity. Dose levels have varied, with patients receiving either 50, 37.5 or 25 mg PO daily utilizing the 4 weeks on/2 weeks off schedule.

Impaired hepatic function

Hepatotoxicity is a recognized class toxicity of the TKIs, irrespective of the targets inhibited. Metabolism of these agents is primarily by the liver, and administration to patients with impaired liver function has not been studied adequately. However, some information is available in this patient group.

Preliminary data from a dose escalation study with pazopanib demonstrated that drug clearance is decreased by 50% in patients with moderate hepatic impairment when compared to individuals with normal hepatic function. The maximum tolerated dose in patients with moderate impairment of hepatic function is 200 mg PO daily. No data is available for patients with severe hepatic impairment, and pazopanib is not recommended in this setting.

Hepatic toxicity with sunitinib has also been reported. Comparison of data from the phase 3 pivotal trials suggests grade 3 toxicity may be more common with pazopanib. The safety of sunitinib in patients with hepatic enzyme elevation over 2.5 times normal or, if due to liver metastases, above 5.0 times normal, has not been established, and it is not recommended in these individuals

The use of sorafenib in patients with hepatic impairment has been more adequately characterized. Pharmacokinetic studies of sorafenib have been conducted in patients with hepatocellular carcinoma. Hepatic impairment may reduce plasma concentrations of sorafenib, and comparison suggests sorafenib levels may be lower in these patients than in non-hepatocellular patients (without hepatic impairment).

The area under the time-concentration curve (AUC) of sorafenib is similar in patients with mild (Child-Pugh A) and moderate (Child-Pugh B) hepatic impairment who have hepatomas. No dose adjustment is necessary in patients with Child-Pugh A and B hepatic impairment. Sorafenib has not been studied in patients with severe (Child-Pugh C) hepatic impairment.

The mTOR inhibitors everolimus and temsirolimus require dose modification in patients with hepatic impairment. For temsirolimus, the recommended starting dose in patients with mild hepatic impairment (bilirubin > 1.0 to 1.5 x normal, or AST > normal with normal bilirubin) is 15 mg IV weekly. Similarly, a dose reduction of everolimus to 5mg daily is recommended in patients with Child-Pugh class B. These agents have not been adequately studied in patients with severe hepatic impairment.

Finally, bevacizumab can be utilized in RCC patients with impaired hepatic function. Although no formal evaluation in this patient population is available, hepatic toxicity is not a prominent feature of this agent.

Because of the limited information available for RCC patients with hepatic impairment, liver function tests (ALT, AST, bilirubin) should be monitored before initiation of treatment, during each treatment cycle, and as clinically indicated.

Unique patient categories, clear cell carcinoma

Sarcomatoid differentiation, metastatic clear cell carcinoma

Sarcomatoid differentiation in RCC occurs when the malignant cells acquire a higher grade, have a spindle cell appearance, and evidence of epithelial and mesenchymal differentiation. The reported incidence of RCC sarcomatoid differentiation is estimated between 1% and 23% of cases.

Patients whose pathology report notes “sarcomatoid change” appear to have a worse prognosis with a median survival less than one year. There is no uniform definition of sarcomatoid RCC such as the percentage of sarcomatoid differentiation required for the diagnosis. Chemotherapy with doxorubicin-containing combinations has been evaluated in these patients, and occasional tumor shrinkage is seen.

Targeted agents have also been evaluated in this patient group. In these reports, tumor shrinkage has been reported, but the data are retrospective for the most part. Several important points are noted:

• The prognosis of patients with sarcomatoid tumors is poor.

• Pathologic criteria for a diagnosis are variable.

• The underlying histologic pattern may be crucial for determining therapy.

• Currently, the data does not support one particular option, however, responses to sunitinib in clear cell carcinoma with sarcomatoid elements have been reported.

• Chemotherapy with agents such as fluorouracil and/or cisplatin has also been reported to produce tumor regressions in selected patients, but the overall results with this group of agents is poorly characterized.

CNS metastases, metastatic clear cell carcinoma

Patients with brain metastases are generally not eligible for clinical trials, and therefore prospective data are limited. Therapy for patients with newly diagnosed CNS metastases will generally require radiation (whole brain and/or stereotactic) or surgical removal, dependent upon the location, size and number of lesions.

Previously, patients with CNS metastases secondary to RCC received only supportive therapy, but aggressive approaches in selected patients will often permit additional systemic therapy to be considered. The effects of systemic therapy in this patient population are not entirely clear. A retrospective subgroup analysis of patients receiving sorafenib suggested a decreased incidence of CNS metastases in patients treated with sorafenib compared to placebo (3% vs. 12%, P<0.05). This data has not been confirmed.

In the sunitinib expanded access study, 7% of patients (n=321) had treated brain metastases and received open label sunitinib. The median PFS of this group was 5.6 months, and median survival was 9.2 months. No differences in toxicity were seen when patients with CNS metastases and the overall population were compared.

The overall incidence of treatment-related adverse events was 92%, regardless whether CNS metastases were present or not. These results suggest that it is possible to utilize agents such as sunitinib in RCC patients with treated CNS metastases. Toxicity is acceptable, and control of systemic disease may be seen. The best systemic therapy for patients with CNS metastases remains unclear, but if considered, a TKI is a reasonable option.

Osseous metastases, clear cell carcinoma

Bone is a common site of metastasis in RCC patients, with a frequency of solitary or multiple osseous metastases ranging from 24% to 51%. Complications associated with bone metastases include decreased performance status, pain, pathologic fracture, spinal cord compression and hypercalcemia. Management of this patient group depends upon patient status, presence of co-morbid factors, and whether the osseous metastases are solitary or multiple sites are involved.

Supportive measures include:

• radiation therapy

• surgical removal and/or fixation

• pain control

• bisphosphonates or denosumab

Patients should receive supportive measures as previously described, the indicated systemic therapy for their disease, and treatment with a bisphosphonate such as zoledronic acid based on the results of a randomized placebo controlled trial (zoledronic acid versus placebo) in solid tumor patients with bone metastases.

RCC patients receiving zoledronic acid have reduced numbers of skeletal related events (SREs), delayed the time to the first SRE, and interestingly prolonged time to disease progression versus a placebo. Of interest are several reports suggesting a rapid improvement in metastatic bone lesions and patient symptoms after receiving zoledronic acid in combination with sunitinib.

Although there are no trials of bisphosphonates specifically in an RCC population, the available data suggests therapy with zoledronic acid and a TKI such as sunitinib has acceptable toxicity, and use of bisphosphonates delays the complications of bone metastases.

Recently, denosumab, a monoclonal antibody that binds and neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) was investigated in patients with solid tumors. A phase 3 trial comparing the effects of denosumab to zoledronic acid was conducted. Patients with RCC and osseous metastases were eligible; however, the report does not provide subset data on this population of patients. The results demonstrated the non-inferiority of denosumab in delaying skeletal complications. It is likely this agent has effects in RCC patients with bone metastases equivalent to zoledronic acid, but data are not yet available to confirm this.

Elderly patients, clear cell carcinoma

It has been suggested that older individuals may not benefit from treatment with the currently available targeted agents, and will develop an increased frequency of adverse events. Despite these concerns, age has not emerged as a poor-risk factor in recent analyses of prognostic factors. These issues have been examined in several of the recently reported trials with sunitinib, sorafenib, and bevacizumab + IFN.

Overall, data from these clinical trials and meta-analyses demonstrate elderly patients aged greater than 65 or 70 years can be treated in a fashion similar to their younger counterparts. They appear to have similar degrees of benefit, and tolerate TKI or bevacizumab plus IFN-a therapy in a manner similar to younger patients.

Metastatic non-clear cell carcinoma

RCC is a heterogeneous disease, comprised of several different histological types with distinct genetic alterations, varying clinical course, and variable responsiveness to systemic therapy.

The main histopathological RCC subtypes based on tumor morphology, immunohistochemistry, cytogenetics and molecular studies include:

• clear cell carcinoma (60-70%)

• papillary (7-14%)

• chromophobe (6-11%)

• collecting duct carcinoma (0.3%)

• Xp11 translocation carcinomas (<1%)

• renal cell carcinoma unclassifiable (4-5%).

In earlier studies, RCC was considered a single disease classification. Currently these subtypes are categorized as either clear cell or collectively non-clear cell. Clinical studies have suggested chromophobe and papillary RCC have a better prognosis following nephrectomy for localized disease compared to clear cell RCC. The reverse appears true for patients with metastatic disease.

A recent retrospective analysis demonstrated metastatic non-clear cell RCC is resistant to systemic therapy and is associated with poor survival. It also was noted that patients with chromophobe RCC may have longer survival than those with papillary RCC. The treatment of patients with metastatic non-clear cell carcinoma remains an area that is poorly defined. Clinical trials for these tumors have been limited, and the available data is largely retrospective and/or analysis of patient subsets.

Treatment naïve, metastatic non-clear cell carcinoma

Temsirolimus, an mTOR inhibitor, was evaluated in an international prospectively randomized phase 3 trial which included 626 patients with metastatic RCC. The entry criteria only specified metastatic renal cell carcinoma. Therefore, approximately 20% (n=124) of patients entered had non-clear cell histology. In a retrospective subgroup analysis, the histologic subtypes included as non-clear cell carcinoma were: papillary carcinoma (n=55), chromophobe carcinoma (n=12), collecting duct, other, and indeterminate (n=57).

The subset analysis noted an overall survival improvement for patients treated with temsirolimus versus IFN-a (11.6 vs 4.3 months). Based on this exploratory analysis, temsirolimus appears to be efficacious in patients regardless of the underlying tumor histology, and importantly may be a useful drug for the treatment of patients with non-clear cell histology.

Retrospective analyses of patients with non-clear cell RCC receiving TKI’s suggest sunitinib may have a low level of activity, but its overall efficacy remains unclear.

Treatment refractory, non-clear cell carcinoma

Unlike clear cell carcinoma, minimal information is available on the therapy of patients failing initial therapy. Presumably, an agent such as temsirolimus may be utilized as front-line treatment. At disease progression, it is likely a TKI may be utilized. There is no standard of care for this patient group. Patient functional status, co-morbid factors, and type of initial treatment will influence the choice for second-line therapy.

Co-morbid conditions, non-clear cell carcinoma

As in the patient with metastatic clear cell carcinoma, the various co-morbid conditions may influence therapy. The reader is referred to that section for a discussion of cardiovascular, renal, and hepatic factors that may modify or influence treatment.

Unique categories, non-clear cell carcinoma

Sarcomatoid differentiation, metastatic non-clear cell carcinoma

The influence of sarcomatoid elements in the various non-clear cell histologic groups on treatment outcomes for patients with metastatic disease is poorly defined. The role of chemotherapy versus the targeted agents such as the TKIs has not been adequately defined. Metastatic sarcomatoid RCC is associated with a poor response to systemic therapy. Studies to characterize the underlying tumor biology, to assess outcome to targeted agents, and to develop novel treatment strategies are needed.

CNS metastases, metastatic non-clear cell carcinoma

Data on frequency of CNS metastases in patients with the various non-clear cell histologies are not available. Therapy for these patients is similar to that described for clear cell carcinoma.

Xp11.2 translocation, metastatic non-clear cell carcinoma

RCC associated with Xp11.2 translocations (TFE3 gene fusions) are rare tumors predominantly in the pediatric age group; however, a small number of adult Xp11.2 translocation RCC cases have been described.

Histologically, this tumor can resemble either the clear cell or papillary carcinoma, and may contain elements of both. Given the degree to which these tumors overlap morphologically with clear cell and/or papillary RCC, many adult Xp11.2 translocation RCC may be misclassified. Optimal therapy is not defined for this patient group, but recognition is important since this type of tumor may not benefit from currently available targeted agents, although prolonged responses to a TKI such as sunitinib have been reported.

Collecting duct, medullary carcinoma

Collecting duct carcinoma (CDC) also referred to as “Bellini duct carcinoma,” is an uncommon, aggressive form of renal cell carcinoma, accounting for less than 2% of kidney cancers. CDC arises from the epithelium of the distal collecting system in the renal medullary pyramids. Prospective reports suggest chemotherapy may be useful, and data with TKIs such as sunitinib suggest no benefit. Current recommendations are to treat this histologic variant with chemotherapy utilizing a platinum based regimen.

Renal medullary carcinoma is also a rare tumor that is most common in young black men with sickle cell disease or trait. This entity is often confused with CDC or poorly differentiated transitional cell carcinoma. In the majority of experiences reported, this rare subtype is characterized as a highly aggressive disease. Recent reports suggest chemotherapy has anti-tumor activity in this variant.

Regimens utilized for the treatment of urothelial carcinoma include:

• MVAC (methotrexate, vinblastine, doxorubicin, and cisplatin) or

• Combination of cisplatin, paclitaxel, and gemcitabine.

Additional studies are needed to define the overall activity of platinum based chemotherapy in medullary RCC, but the anecdotal data available suggest this non-clear variant should be approached as a urothelial neoplasm.

What other therapies are helpful for reducing complications?

Supportive therapies that may be of value in the management of patients with metastatic RCC include those utilized to decrease the complications of osseous metastases:

• Bisphosphonates: zoledronic acid

• RANK ligand inhibitor: denosumab

What should you tell the patient and the family about prognosis?

Since treatment of metastatic RCC rarely produces complete responses, and cure is unlikely, current therapy is focused on control of disease progression. The median overall survival of these patients was in the range of 14 to 16 months during the cytokine era, and recently, median survivals of 23 to 26 months have been reported with various targeted agents.

The prognosis for patients with advanced metastatic disease can be estimated by utilizing the MSKCC criteria. They can be classified as having favorable, intermediate, or poor-risk disease, with median survivals of 28.0, 13.6 and 4.6 months. This data is from the cytokine era; recent reports indicate that with utilization of the current treatment paradigm, median survivals of 20.7 and 5.3 months in the intermediate and poor-risk groups respectively. In favorable-risk patients, median survival is now approaching 3 years.

The goal of therapy in metastatic RCC patients is to maximize therapeutic benefit, delay the development of a disease burden that becomes life threatening, and maximize a patient’s quality of life and convenience. This translates into selection of therapy with the optimal risk/benefit ratio for an individual patient. Unfortunately, only limited clinical criteria are available that predict efficacy, and ultimately multiple sequential treatments with available agents is utilized.

What if scenarios.

Recognition of histologic RCC subtypes is a frequent issue, and as pathologists become more familiar with current classification schemes, this will be less of an issue. Major issues in the field currently relate to the following questions:

1) What is the best therapy or standard of care in treatment naïve mRCC?

This will require comparative trials, several of which are underway. The phase 3 COMPARZ trial in which pazopanib was compared to sunitinib in this patient population has recently been reported. The study endpoints included PFS and survival, and utilized a non-inferiority design. Pazopanib was found not inferior to sunitinib. Additional phase 3 studies comparing various immune checkpoint inhibitors such as nivolumab + ipilumumab, TKI’s plus a checkpoint inhibitor (Lenvatinib + pembrolizumab, axitinib + pembrolizumab), Lenvatinib + everolimus, or bevacizumab + atezolizumab with sunitinib are underway. These will provide important information on the optimal therapy for untreated mRCC patients.

2) Is the use of the MSKCC scheme mandatory?

In the absence of biomarkers, this classification should be utilized to assist with treatment decisions. The IMDC classification represents an alternative approach, and can be employed.

3) What is the definition of refractory?

No pre-specified criteria are available, except as listed when utilizing RECIST criteria. In some patients, RECIST disease progression may be documented, but the patient is asymptomatic or minimally symptomatic. In this setting, continuation of current therapy is justified, until definitive evidence of new sites of disease is found, especially in patients with small volume metastases.

4) How should the adverse events associated with targeted therapy be managed?

This will vary with the agent and the adverse event type. A complete discussion of toxicity management for each agent is beyond the scope of this review, but several more common class effects are relevant to discuss:

a) Dose and schedule:

Lower doses may be employed if there are significant concerns about potential side effects; however, the results reported in the various phase 3 pivotal studies utilized a standard dose and schedule. In the case of sunitinib, a significant relationship between sunitinib exposure and efficacy/toxicity has been identified.

Patients with the highest exposure not only displayed a higher probability of a response and tumor shrinkage, but also longer time to progression and, most importantly, longer overall survival. This emphasizes the importance of maintaining patients at 50 mg dose of sunitinib and striving to avoid any unnecessary dose reductions during treatment.

Continuous dosing versus the intermittent schedule have been compared in a phase 2 randomized trial. No differences in adverse events were found, and the traditional intermittent schedule appeared superior.

Recently, use of sunitinib in alternate schedules has been studied. Two weeks of therapy followed by one week of rest has been suggested to be better tolerated than the traditional “4/2 schedule.” The “2/1schedule,” however, has not been compared directly to the original sunitinib schedule.

b) How should patient fatigue related to TKI therapy be managed?

Potential alternative causes for fatigue such as underlying dehydration, hypothyroidism, hypercalcemia, anemia or depression should be excluded. All patients should have thyroid function tests prior to and during TKI treatment (every 8 to 12 weeks) and be treated according to standard medical practice.

Thyroid hormone replacement is recommended in mRCC patients with overt hypothyroidism (defined as an elevated serum thyroid-stimulating hormone (TSH) level and a low T4 level) and possible hypothyroidism-related symptoms. Blood transfusions may be used at the discretion of the treating physician to correct anemia.

Depression, a frequent finding in metastatic cancer patients, is known to impact upon the severity of fatigue. Fatigue improves in some patients who have received antidepressants. Finally, patient education about fatigue and its occurrence is very important. On occasion drug holidays may be helpful, and if severe fatigue is a recurrent problem, dose reduction may be appropriate.

Currently, there are no evidence-based interventions to treat fatigue, and therefore when it interferes with quality of life, management by changes in dose would be appropriate.

c) How can the hand-foot syndrome be managed?

The frequency of this cutaneous complication varies dependent upon the TKI utilized. The lowest frequency is seen with pazopanib, and the highest with sorafenib. Hand–foot changes may present as painful symmetrical erythematous areas on the palms and soles. Patients may experience paraesthesias, tingling or numbness.

Desquamation can occur in severe cases. Painful hyperkeratotic areas in pressure regions surrounded by rings of erythema as well as bullous lesions and/or blisters may be noted. These are seen in areas of pressure, and pre-existing hyperkeratotic areas seem predisposed to development of these changes. When functional consequences develop, patients may refuse to continue therapy.

Palliative interventions include:

• moisturizers

• foot and hand care products (e.g. gel pad inserts, cotton gloves)

• medication for pain management

• instructing patients to decrease pressure on the areas affected, by staying off their feet if possible and avoiding pressure on their hands.

Treatment for grade 2 hand-foot syndrome usually involves these measures, as well as dose interruptions, and if necessary dose reductions. Dose interruptions for 5 to 7 days are generally sufficient to permit resolution of most severe skin changes. Anecdotal reports suggest steroid creams can be helpful, but well designed prospective studies are lacking. This complication is not an inflammatory response, but steroid creams may prevent secondary inflammatory changes.

When patients with hand-foot changes does not respond to dose interruption or reduction, other diagnoses should be considered such as fungal infection, allergic contact dermatitis, and irritant dermatitis. At this time referral to a dermatologic consultant would be appropriate. Finally, recent analysis of the sunitinib phase 3 trials suggests the development of hand-foot syndrome may correlate with efficacy.

d) How should diarrhea be managed?

Diarrhea occurs frequently, and over 50% of patients may experience this toxicity. Grade 3 and 4 diarrhea is uncommon. Some degree of diarrhea often remains when other common side effects have been controlled with dose/schedule changes.

In contrast to chemotherapy-induced diarrhea, which is usually continuous, TKI-induced diarrhea may be irregular. Dose reductions are rarely necessary for grade 1 and 2 diarrhea, which can be managed by oral anti-diarrheal agents as needed, such as loperamide. Treatment should be interrupted for grade 3 diarrhea until it has decreased to grade 1 or has returned to baseline. Patients should temporarily discontinue use of stool softeners and fiber supplements.

e) How should the hematologic toxicity secondary to the TKIs be managed?

Severe hematologic toxicity is infrequent in patients receiving either pazopanib or sorafenib, and most common in sunitinib-treated patients. Only 5 to 8% of sunitinib-treated patients develop grade 3/4 neutropenia or thrombocytopenia and few cases of neutropenic fever have been reported.

Blood counts usually recover quickly within the 2-week treatment break. Due to the usually rapid recovery of blood counts during the 2-week treatment break, hematologic growth factors are not routinely recommended.

Dose modification for grade 4 neutropenia or grade 3 thrombocytopenia may be required. Severe anemia usually does not require dose modification. Of interest are the macrocytic indices that frequently develop in sunitinib treated patients. These are related to therapy, and do not have an underlying nutritional cause. Due to recent data concerning potential risks and toxicities, the use of erythropoietin-stimulating agents should be utilized only when necessary.

f) How should hypertension induced by TKI therapy be managed?

Hypertension is a class effect of VEGF/VEGFR inhibitors, and can be seen in 30-50% of patients receiving these agents. Hypertension is therefore commonly observed event during treatment, and is generally manageable with use of standard antihypertensive agents. An interesting association between hypertension and clinical efficacy appears to exist with TKI therapy.

In a retrospective analysis the occurrence of hypertension was associated with increased PFS and survival. This data suggests that in patients with mRCC, hypertension may not only be an adverse event, but also a potential prognostic biomarker. Pre-existing hypertension is not a contraindication to therapy, and worsening hypertension (grade 3) generally should be manageable with a change in antihypertensive medications, with dose reductions or interruption reserved for uncontrolled elevations of blood pressure.

g) How should pneumonitis secondary to administration of mTOR inhibitors be managed?

Non-infectious pneumonitis is a potentially serious adverse event associated with rapamycin and rapamycin derivative therapy. Clinically, it can present as a typical radiographic appearance of interstitial pneumonitis with or without signs and symptoms (pleural effusion, hypoxia, cough, dyspnea, malaise). It is defined as the radiographic lung change irrespective of signs or symptoms, in the absence of a non-drug cause.

Administration of both everolimus and temsirolimus has been reported to produce pulmonary toxicity. In the RECORD 1 trial, 8% of patients receiving everolimus developed pneumonitis, and 8 (3%) were grade 3. Of the 8 patients with grade 3 pneumonitis, six discontinued everolimus, four resolved completely, and three improved to grade 2 or less.

Recommendations for management depend upon the severity of the pneumonitis. Patients should be instructed to report any new or changing respiratory symptoms. In asymptomatic patients, with radiographic changes only, everolimus can be continued, and patients observed closely.

In patients with moderate symptoms, therapy should be held, and restarted when symptoms improve with a dose reduction of everolimus to 5mg daily. In patients with severe pneumonitis (grade 3), everolimus should be discontinued. The role of corticosteroids in improving the interstitial pneumonitis is unclear, but they can be utilized in this group.

The development of pneumonitis secondary to temsirolimus was investigated retrospectively in the phase 3 pivotal trial (ARCC) utilizing blinded radiology review. 29% of the evaluable patients receiving temsirolimus developed radiographic evidence of drug-related pneumonitis, compared to 6% of patient receiving IFN-a.

In contrast, the investigators reported the incidence of temsirolimus-related pneumonitis as 2%. 16/52 patients with pneumonitis developed symptoms (31%), which developed during the first 8 weeks of therapy in 60% of patients. Patients with radiographic changes of pneumonitis who are asymptomatic should continue treatment and be monitored closely for respiratory symptoms. Patients who develop symptoms and radiographic changes should have treatment held. Treatment with temsirolimus may be resumed, with or without dose reduction (15mg weekly), depending on the patient’s clinical course.

An important concept in the evaluation of the pneumonitis related to mTOR inhibitors involves further assessment with pulmonary function tests and bronchoscopy to exclude other causes, e.g. infection. Empiric therapy with corticosteroids and antibiotics may be initiated if clinically warranted. Continuation of these agents in patients who are benefiting from treatment involves the availability of other treatment options, and the overall risk/benefit assessment.

h) Management of complications of immune checkpoint inhibitor therapy.

Clinical syndromes include pneumonitis, thyroiditis, colitis, hepatitis, dermatitis, nephritis, hypophysitis, endophthalmitis have been reported. Frequency of events varies by agent and class, although generally the incidence of grade 3-4 autoimmune toxicities is less than 5%.

Depending on the severity of the toxicity, treatment is either withheld or permanently discontinued. There are no dose reductions. The mainstay of management is corticosteroids. A typical approach might be prednisone 1 mg/kg equivalent daily. Once toxicity has improved to grade 1 in severity, a 4-6 week taper is initiated. Oral budesonide has also been used for treatment of colitis. Only if symptoms remain improved after taper completion is the immunotherapeutic agent re-initiated. In some instances, other immune-modulating agents such as TNF inhibitors may be warranted. Consultation with appropriate medical services (endocrinology, pulmonary medicine, gastroenterology, nephrology) for assistance with diagnosis and treatment may be considered. For patients with treatment-related hypothyroidism and adrenal insufficiency, replacement with levothyroxine and hydrocortisone is given.

Follow-up surveillance and therapy/management of recurrences.

Recommendations for follow-up and surveillance will vary depending upon the stage, type of surveillance and whether active therapy is ongoing. These individual situations are discussed in the following paragraphs.

Patient with recent nephrectomy, partial nephrectomy, or thermal ablative procedure and stage 1A, 1B, II, or III renal cell carcinoma

Every 6 months for 2 years, then annually for total of 5 years:

• History and physical examination.

• Chest and abdominal CT with contrast.

At 4 to 6 months then as indicated:

• Complete blood count.

• Metabolic panel.

These recommendations are based on the NCCN treatment guidelines for localized RCC. The possibility that more prolonged observation for selected patients should be considered has been suggested.

Patients with small renal mass (<4.0 cm) being considered for active surveillance

In this setting determination of the characteristics of the renal mass and the growth rate are important. No accepted guidelines exist; however, the NCCN guidelines for follow-up of patients following therapy for a localized renal tumor are applicable. These can be individualized depending upon the patient and tumor characteristics.

Patients with metastatic renal cell carcinoma

a) Receiving systemic therapy including TKIs, mTOR inhibitors, and bevacizumab plus IFN-a. Standardized guidelines do not exist, however, the following should be considered during active therapy, until disease progression.

Every 4 to 6 weeks, dependent upon type of therapy and treatment schedule:

• Complete blood count.

• Metabolic panel.

• Urinalysis.

• Fasting blood sugar, triglycerides, cholesterol (for patients receiving an mTOR inhibitor).

• Thyroid function studies: TSH, T4 levels (for patients receiving a TKI).

Every 12 weeks:

• History and physical examination.

• CT scan: chest, abdomen, pelvis.

• Chest x-ray (for patients receiving an mTOR inhibitor).

• Bone scan – if positive at baseline.

• Radionuclide LVEF if at baseline this was abnormal, or the patient has a history of cardiovascular disease.

Annually: CT scan or MRI of brain

These recommendations will vary depending upon the patient, type of tumor, and type of systemic therapy. The guidelines for follow-up of patients with metastatic RCC reflect the type of follow-up obtained during the clinical trials of the approved agents for treating RCC, as well as the natural history of mRCC.

b) Patients with metastatic RCC, under observation and not receiving active therapy. The recommendations reflect the underlying metastatic RCC, no standard accepted guidelines are available.

Every 3 months:

• History and physical examination.

• CT scans: chest, abdomen, pelvis.

• Complete blood count, metabolic profile.

Annually:

• CT or MRI of brain.

• Bone scan.

Pathophysiology

The molecular characteristics of RCC have been intensively studied during the past 20 years. Approximately 2 to 3% of RCC tumors are familial. Several autosomal dominant syndromes have now been described, each having a distinct genetic basis and phenotype. The von Hippel-Lindau (VHL) syndrome is the most common.

These patients develop vascular tumors including clear cell RCC, hemangioblastomas, and pheochromocytomas. The VHL tumor suppressor gene is located on chromosome 3 (3p25-26). In patients with the VHL syndrome, a defect on one VHL gene allele is inherited, and a second in the remaining allele is then acquired.

Studies in the 1990s demonstrated most patients (>80%) with sporadic clear cell RCC acquire defects of both VHL gene alleles, producing dysfunction of the VHL protein. This functions as a tumor suppressor, and is responsible for proteasome degradation of hypoxia-inducible factor (HIF), a regulator of the hypoxic response. When VHL protein is absent or non-functioning, HIF-1-alpha accumulates, and activates transcription of hypoxia-inducible genes, such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF).

Clear cell cancers are characterized by high vascular content, secondary to enhanced tumor associated angiogenesis. The loss of VHL gene function results in constitutive expression of HIF, over secretion of VEGF, PDGF, and produces the vascular phenotype characteristic of clear cell RCC.

Cytogenetics and gene expression profiling studies have also clarified the molecular characteristics of RCC non-clear cell histologic subtypes. Morphologically, papillary RCC is divided into type 1 and type 2, but genetic patterns in the inherited papillary RCC syndromes may also differentiate the two. Chromophobe carcinomas and oncytomas are uncommon non-clear cell variants. Chromophobe tumors may present as extremely large abdominal masses, are generally locally advanced tumors, and are slow growing. Oncocytomas are generally considered benign tumors, grow very slowly, and may be multifocal.

Collecting duct carcinomas (CDC) and medullary cancers of the kidney are related to transitional cell carcinomas, based on histology and gene expression profiles. They arise in the collecting ducts and medullary systems of the kidney. Collecting duct carcinoma, also referred to as “Bellini duct carcinoma,” is an uncommon, aggressive form of RCC, and accounts for less than 2% of renal tumors. It arises from the epithelium of the distal collecting system in the renal medullary pyramids. CDC is associated with a poor prognosis in patients with advanced disease.

Renal medullary carcinoma (RMC) is also a rare tumor which typically affects younger individuals with sickle cell disease or trait. It is a highly aggressive malignancy and most often produces locally advanced and metastatic disease at diagnosis. Increased levels of topoisomerase II have been recently described along with deregulation of DNA remodeling and repair. As with CDC, this RCC variant resembles more the patterns described in urothelial rather than epithelial cancers.

Translocation carcinomas of the kidney, which were first described in children, were considered as aggressive tumors. These Xp11.2 translocations RCC now constitute a well-recognized entity. In children, these tumors comprise at least one third of RCC tumors reported, but in adults, they remain a rare entity. In view of the fact these tumors overlap morphologically with clear cell and/or papillary RCC, many adult Xp11.2 translocation RCC may be misclassified as clear cell or papillary RCC.

The histologic variant of high-grade RCC referred to as sarcomatoid carcinoma refers to the spindled morphology of a dedifferentiated subset of RCC tumor cells. Approximately 4% of RCC tumors will have a sarcomatoid component. Renal cell carcinoma with sarcomatoid features is a variant of other RCC subtypes, not a separate entity. At present, the diagnosis rests on demonstration of conventional histopathologic features, assessment of the percentage of sarcomatoid dedifferentiation, and immunohistochemical stains confirming epithelial rather than mesenchymal lineage.

Finally, the category of unclassified RCC is utilized for tumors that cannot be placed in one of the previous histologic subtypes. Unclassified RCC represents a category assigned when a tumor does not fit into the other RCC histological subtypes, based on pathological and/or genetic analyses. It is a rare variant and accounts for 3–5% of RCC cases. A recent study indicated that unclassified RCC presents with a higher stage and grade, and has a higher mortality than clear cell carcinoma.

What other clinical manifestations may help me to diagnose renal cell carcinoma?

The majority of renal tumors are now discovered incidentally during an imaging procedure, and patients are asymptomatic. The classic presentation that included the triad of hematuria, flank pain and a palpable mass are seldom seen currently.

Past medical history and smoking history are important, as well as a work and environmental exposure history. Patients with suspected RCC should be examined carefully to document any evidence of metastatic or advanced disease. This includes a careful system review focusing on the skeletal, genitourinary and systemic systems.

In young patients (<40 years) with RCC, a family history is relevant, and any manifestations of the various inherited RCC syndromes should be determined.

What other additional laboratory studies may be ordered?

In patients with advanced or metastatic RCC, routine hematologic and biochemical studies are recommended. Hemoglobin levels, calcium and serum albumin, and serum LDH should be obtained to allow MSKCC classification of the untreated newly diagnosed RCC patient. There are no biomarkers or other specialized laboratory studies that are helpful during the initial evaluation. In the future, SNP analyses and tumor genetic studies may be helpful in this regard.