Renal Cell Carcinoma

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]

The AKT inhibitor MK-2206 was not superior to everolimus (Afinitor) for patients with metastatic renal cell carcinoma refractory to vascular endothelial growth factor inhibitors, according to a phase II trial from the University of Texas MD Anderson Cancer Center, Houston.

Median progression-free survival was 3.68 months in the 29 patients randomized to MK-2206, versus 5.98 months in the 14 randomized to everolimus, leading to closure of the study, reported Eric Jonasch, MD, of the department of genitourinary medical oncology at MD Anderson, and his associates.

However, dichotomous response rate profiles were seen in the MK-2206 arm with one complete response and three partial responses in the MK-2206 arm versus none in the everolimus arm.

“Whereas patients treated with everolimus for the large part had minimal changes in tumor size, MK-2206 induced a fairly dichotomous response dynamic, with [a few] patients demonstrating profound response, [but] a number of patients exhibiting rapid growth,” Dr. Jonasch and associates said (Ann Oncol. 2017 Jan 3. pii: mdw676. doi: 10.1093/annonc/mdw676).

Several studies have shown that upregulation of the PI3K/AKT pathway is associated with poor prognosis in renal cell carcinoma (RCC), making the pathway an attractive target for therapeutic intervention. The trial “results indicate that potential exists for effective blockade of the PI3K pathway in patients with RCC, but considerable work is required to better understand the nuances of this pathway before we can consistently modulate it to benefit patients with RCC,” the investigators said.

Molecular analysis failed to find a biomarker for response, but did demonstrate that deleterious tumor protein 53 or ataxia telangiectasia mutations or deletions were associated with poor prognosis. Among patients who progressed, 57.1% had TP53 or ATM aberrations; TP53 and ATM defects were absent in patients who did not progress.

Malfunction of DNA repair driven by TP53 and ATM gene modifications, the group said, “are associated with early disease progression, indicating that dysregulation of DNA repair is associated with a more aggressive tumor phenotype in RCC ... This subcategory of patients clearly needs new approaches based on our emerging understanding of the significance of TP53 mutations in RCC biology.”

MK-2206 induced significantly more rash and pruritus than did everolimus, with dose reduction in 37.9% of MK-2206 versus 21.4% of everolimus patients.

Subjects were a median of 63.5 years old in the everolimus group and 59 years in the MK-2206 group. The majority of patients were white men. More than 65% of the patients had performance status 1 and around 60% were in the Memorial Sloan Kettering Cancer Center intermediate risk group. The majority of patients in both treatment arms had clear cell histology; 57.1% (8) in the everolimus group and 82.8% (24) in the MK-2206 group had lung metastasis; half of the everolimus and 59% (17) of MK-2206 subjects were previously treated with sunitinib (Sutent).

The National Institutes of Health funded the work. The authors reported no conflicts of interest.

[email protected]

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common malignancy arising in the kidney, comprising 90% of all renal tumors.¹ Approximately 55,000 new RCC cases are diagnosed each year.² Patients with RCC are often asymptomatic, and most cases are discovered as incidental findings on abdominal imaging performed during evaluation of nonrenal complaints. Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.² Advanced RCC is resistant to conventional chemotherapy and radiotherapy, and outcomes for patients with metastatic or unresectable RCC remain poor. However, the recent development of new therapeutic modalities that target tumor molecular pathways has expanded the treatment options for these patients and changed the management of RCC.

EPIDEMIOLOGY AND CLASSIFICATION

Median age at diagnosis in the United States is 64 years. Men have a higher incidence of RCC than women, with the highest incidence seen in American Indian and Alaska Native men (30.1 per 100,000 population). Genetic syndromes account for 2% to 4% of all RCCs.² Risk factors for RCC include smoking, hypertension, obesity, and acquired cystic kidney disease that is associated with end-stage renal failure.³ Longer duration of tobacco use is associated with a more aggressive course.

The 2004 World Health Organization (WHO) classification of renal tumors summarizes the previous classification systems (including the Heidelberg and Mainz classification systems) to describe different categories of RCC based on histologic and molecular genetics characteristics.² Using the WHO classification criteria, RCC comprises 90% of all renal tumors, with clear cell being the most common type (80%).² Other types of renal tumors include papillary, chromophobe, oncocytoma, and collecting-duct or Bellini duct tumors. Approximately 3% to 5% of tumors are unclassified. Oncocytomas are generally considered benign, and chromophobe tumors typically have an indolent course and rarely metastasize. Sarcomatoid differentiation can be seen in any histologic type and is associated with a worse prognosis. While different types of tumors may be seen in the kidney (such as transitional cell or lymphomas), the focus of this review is the primary malignancies of the renal parenchyma.

FAMILIAL SYNDROMES

Several genetic syndromes have been identified by studying families with inherited RCC. Among these, von Hippel-Lindau (VHL) gene mutation is the most commonly found inherited genetic defect. Table 1 summarizes the incidence of gene mutations and the corresponding histologic appearance of the most common sporadic and hereditary RCCs.⁴

VHL disease is an autosomal dominant familial syndrome. Patients with this mutation are at higher risk for developing RCC (clear cell histology), retinal angiomas, pheochromocytomas, as well as hemangioblastomas of the central nervous system (CNS).⁴ Of all the genetic mutations seen in RCC, the somatic mutation in the VHL tumor-suppressor gene is by far the most common.⁵ VHL targets hypoxia–inducible factor-1 alpha (HIF-α) for ubiquitination and subsequent degradation, which has been shown to suppress the growth of clear-cell RCC in mouse models.^6–8 HIF expression under hypoxic conditions leads to activation of a number of genes important in blood vessel development, cell proliferation, and glucose metabolism, including vascular endothelial growth factor (VEGF), erythropoietin, platelet-derived growth factor beta (PDGF-β), transforming growth factor alpha (TGF-α), and glucose transporter-1 (GLUT-1). Mutation in the VHL gene prevents degradation of the HIF-α protein, thereby leading to increased expression of these downstream proteins, including MET and Axl. The upregulation of these angiogenic factors is thought to be the underlying process for increased vascularity of CNS hemangioblastomas and clear-cell renal tumors in VHL disease.^4–8

Other less common genetic syndromes seen in hereditary RCC include hereditary papillary RCC, hereditary leiomyomatosis, and Birt-Hogg-Dubé (BHD) syndrome.⁹ In hereditary papillary RCC, the MET gene is mutated. BHD syndrome is a rare, autosomal dominant syndrome characterized by hair follicle hamartomas of the face and neck. About 15% of patients have multiple renal tumors, the majority of which are of the chromophobe or mixed chromophobe-oncocytoma histology. The BHD gene encodes the protein folliculin, which is thought to be a tumor-suppressor gene.

DIAGNOSIS AND STAGING

CASE PRESENTATION

A 74-year-old man who works as an airplane mechanic repairman presents to the emergency department with sudden worsening of chronic right upper arm and shoulder pain after lifting a jug of orange juice. He does not have a significant past medical history and initially thought that his pain was due to a work-related injury. Upon initial evaluation in the emergency department he is found to have a fracture of his right humerus. Given that the fracture appears to be pathologic, further work-up is recommended.

Most patients are asymptomatic until the disease becomes advanced. The classic triad of flank pain, hematuria, and palpable abdominal mass is seen in approximately 10% of patients with RCC, partly because of earlier detection of renal masses by imaging performed for other purposes.¹⁰ Less frequently, patients present with signs or symptoms of metastatic disease such as bone pain or fracture (as seen in the case patient), painful adenopathy, and pulmonary symptoms related to mediastinal masses. Fever, weight loss, anemia, and/or varicocele often occur in young patients (≤ 46 years) and may indicate the presence of a hereditary form of the disease. Patients may present with paraneoplastic syndromes seen as abnormalities on routine blood work. These can include polycythemia or elevated liver function tests (LFTs) without the presence of liver metastases (known as Stauffer syndrome), which can be seen in localized renal tumors. Nearly half (45%) of patients present with localized disease, 25% present with locally advanced disease, and 30% present with metastatic disease.¹¹ Bone is the second most common site of distant metastatic spread (following lung) in patients with advanced RCC.

• What is the approach to initial evaluation for a patient with suspected RCC?

Initial evaluation consists of a physical exam, laboratory tests including complete blood count (CBC) and comprehensive metabolic panel (calcium, serum creatinine, LFTs, lactate dehydrogenase [LDH], and urinalysis), and imaging. Imaging studies include computed tomography (CT) scan with contrast of the abdomen and pelvis or magnetic resonance imaging (MRI) of the abdomen and chest imaging. A chest radiograph may be obtained, although a chest CT is more sensitive for the presence of pulmonary metastases. MRI can be used in patients with renal dysfunction to evaluate the renal vein and inferior vena cava (IVC) for thrombus or to determine the presence of local invasion.¹² Although bone and brain are common sites for metastases, routine imaging is not indicated unless the patient is symptomatic. The value of positron emission tomography in RCC remains undetermined at this time.

Staging is done according to the American Joint Committee on Cancer (AJCC) staging classification for RCC; the Figure summarizes the staging and 5-year survival data based on this classification scheme.^4,13

LIMITED-STAGE DISEASE

• What are the therapeutic options for limited-stage disease?

For patients with nondistant metastases, or limited-stage disease, surgical intervention with curative intent is considered. Convention suggests considering definitive surgery for patients with stage I and II disease, select patients with stage III disease with pathologically enlarged retroperitoneal lymph nodes, patients with IVC and/or cardiac atrium involvement of tumor thrombus, and patients with direct extension of the renal tumor into the ipsilateral adrenal gland if there is no evidence of distant disease. While there may be a role for aggressive surgical intervention in patients with distant metastatic disease, this topic will not be covered in this review.

SURGICAL INTERVENTION

Once patients are determined to be appropriate candidates for surgical removal of a renal tumor, the urologist will perform either a radical nephrectomy or a nephron-sparing nephrectomy, also called a partial nephrectomy. The urologist will evaluate the patient based on his or her body habitus, the location of the tumor, whether multiple tumors in one kidney or bilateral tumors are present, whether the patient has a solitary kidney or otherwise impaired kidney function, and whether the patient has a history of a hereditary syndrome involving kidney cancer as this affects the risk of future kidney tumors.

A radical nephrectomy is surgically preferred in the presence of the following factors: tumor larger than 7 cm in diameter, a more centrally located tumor, suspicion of lymph node involvement, tumor involvement with renal vein or IVC, and/or direct extension of the tumor into the ipsilateral adrenal gland. Nephrectomy involves ligation of the vascular supply (renal artery and vein) followed by removal of the kidney and surrounding Gerota’s fascia. The ipsilateral adrenal gland is removed if there is a high-risk for or presence of invasion of the adrenal gland. Removal of the adrenal gland is not standard since the literature demonstrates there is less than a 10% chance of solitary, ipsilateral adrenal gland involvement of tumor at the time of nephrectomy in the absence of high-risk features, and a recent systematic review suggests that the chance may be as low as 1.8%.¹⁴ Preoperative factors that correlated with adrenal involvement included upper pole kidney location, renal vein thrombosis, higher T stage (T3a and greater), multifocal tumors, and evidence for distant metastases or lymph node involvement. Lymphadenectomy previously had been included in radical nephrectomy but now is performed selectively. Radical nephrectomy may be performed as

Conversely, a nephron-sparing approach is preferred for tumors less than 7 cm in diameter, for patients with a solitary kidney or impaired renal function, for patients with multiple small ipsilateral tumors or with bilateral tumors, or for radical nephrectomy candidates with comorbidities for whom a limited intervention is deemed to be a lower-risk procedure. A nephron-sparing procedure may also be performed open or laparoscopically. In nephron-sparing procedures, the tumor is removed along with a small margin of normal parenchyma.¹⁵

In summary, the goal of surgical intervention is curative intent with removal of the tumor while maintaining as much residual renal function as possible to limit long-term morbidity of chronic kidney disease and associated cardiovascular events.¹⁸ Oncologic outcomes for radical nephrectomy and partial nephrectomy are similar. In one study, overall survival was slightly lower in the partial nephrectomy cohort, but only a small number of the deaths were due to RCC.¹⁹

ADJUVANT THERAPY

Adjuvant systemic therapy currently has no role following nephrectomy for RCC because no systemic therapy has been able to reduce the likelihood of relapse. Randomized trials of cytokine therapy (eg, interferon, interleukin 2) or tyrosine kinase inhibitors (TKIs; eg, sorafenib, sunitinib) with observation alone in patients with locally advanced completely resected RCC have shown no delay in time to relapse or improvement of survival with adjuvant therapy.²⁰ Similarly, adjuvant radiation therapy has not shown benefit even in patients with nodal involvement or incomplete resection.²¹ Therefore, observation remains the standard of care after nephrectomy.

RENAL TUMOR ABLATION

For patients who are deemed not to be surgical candidates due to age, comorbidities, or patient preference and who have tumors less than 4 cm in size (stage I tumors), ablative techniques may be considered. The 2 most well-studied and effective techniques at present are cryoablation and radiofrequency ablation (RFA). Microwave ablation may be an option in some facilities, but the data in RCC are limited. An emerging ablative technique under investigation is irreversible electroporation. At present, the long-term efficacy of all ablative techniques is unknown.

Patient selection is undertaken by urologists and interventional radiologists who evaluate the patient with ultrasound, CT, and/or MRI to determine the location and size of the tumor and the presence or absence of metastatic disease. A pretreatment biopsy is recommended to document the histology of the lesion to confirm a malignancy and to guide future treatment for recurrent or metastatic disease. Contraindications to the procedure include the presence of metastatic disease, a life expectancy of less than 1 year, general medical instability, or uncorrectable coagulopathy due to increased risk of bleeding complications. Tumors in close proximity to the renal hilum or collecting system are a contraindication to the procedure because of the risk for hemorrhage or damage to the collecting system. The location of the tumor in relation to the vasculature is also important to maximize efficacy because the vasculature acts as a “heat sink,” causing dissipation of the thermal energy. Occasionally, stenting of the proximal ureter due to upper tumor location is necessary to prevent thermal injury that could lead to urine leaks.

Selection of the modality to be used primarily depends on operator comfort, which translates to good patient outcomes, such as better cancer control and fewer complications. Cryoablation and RFA have both demonstrated good clinical efficacy and cancer control of 89% and 90%, respectively, with comparable complication rates.²² There have been no studies performed directly comparing the modalities.

Cryoablation

Cryoablation is performed through the insertion of a probe into the tumor, which may be done through a surgical or percutaneous approach. Once the probe is in place, a high- pressure gas (argon, nitrogen) is passed through the probe and upon entering a low pressure region the gas cools. The gas is able to cool to temperatures as low as –185°C. The tissue is then rewarmed through the use of helium, which conversely warms when entering a low pressure area. The process of freezing followed by rewarming subsequently causes cell death/tissue destruction through direct cell injury from cellular dehydration and vascular injury. Clinically, 2 freeze-thaw cycles are used to treat a tumor.^23,24

Radiofrequency ablation, or RFA, targets tumors via an electrode placed within the mass that produces intense frictional heat from medium-frequency alternating current (approximately 500 kHz) produced by a connected generator that is grounded on the patient. The thermal energy created causes coagulative necrosis. Due to the reliance on heat for tumor destruction, central lesions are less amenable to this approach because of the “heat sink” effect from the hilum.²⁴

Microwave Ablation

Microwave ablation, like RFA, relies on the generation of frictional heat to cause cell death by coagulative necrosis. In this case, the friction is created through the activation of water molecules; because of the different thermal kinetics involved with microwave ablation, the “heat sink” effect is minimized when treatment is employed near large vessels, in comparison to RFA.²⁴ The data on this mechanism of ablation are still maturing, with varied outcomes thus far. One study demonstrated outcomes comparable to RFA and cryoablation, with cancer-specific survival of 97.8% at 3 years.²⁵ However, a study by Castle and colleagues²⁶ demonstrated higher recurrence rates. The overarching impediment to widespread adoption of microwave ablation is inconclusive data gleaned from studies with small numbers of patients with limited follow up. The role of this modality will need to be revisited.

Irreversible Electroporation

Irreversible electroporation (IRE) is under investigation. IRE is a non-thermal ablative technique that employs rapid electrical pulses to create pores in cell membranes, leading to cell death. The postulated benefits of IRE include the lack of an effect from “heat sinks” and less collateral damage to the surrounding tissues, when compared with the thermal modalities. In a human phase 1 study of patients undergoing IRE prior to immediate surgical resection, the procedure appeared feasible and safe.²⁷ Significant concerns for this method of ablation possibly inducing cardiac arrhythmias, and the resultant need for sedation with neuromuscular blockade and associated electrocardiography monitoring, may impede its implementation in nonresearch settings.²⁴

ACTIVE SURVEILLANCE

Due to the more frequent use of imaging for various indications, there has been an increase in the discovery of small renal masses (SRM); 85% of RCC that present in an asymptomatic or incidental manner are tumors under 4 cm in diameter.^28,29 The role of active surveillance is evolving, but is primarily suggested for patients who are not candidates for more aggressive intervention based on comorbidities. A recent prospective, nonrandomized analysis of data from the Delayed Intervention and Surveillance for Small Renal Masses (DISSRM) registry evaluated outcomes for patients with SRM looking at primary intervention compared with active surveillance.³⁰ The primary intervention selected was at the discretion of the provider; treatments included partial nephrectomy, RFA, and cryoablation, and active surveillance patients were followed with imaging every 6 months. Progression of SRM, with recommendation for delayed intervention, was defined as a growth rate of mass greater than 0.5 cm/year, size greater than 4 cm, or hematuria. Thirty-six of 158 patients on active surveillance met criteria for progression; 21 underwent delayed intervention. Of note, even the patients who progressed but did not undergo delayed intervention did not develop metastatic disease during the follow-up interval. With a median follow-up of 2 years, cancer-specific survival was noted to be 99% and 100% at 5 years for primary intervention and active surveillance, respectively. Overall survival at 2 years for primary intervention was 98% and 96% for active surveillance; at 5 years, the survival rates were 92% and 75% (P = 0.06). Of note, 2 patients in the primary intervention arm died of RCC, while none in the active surveillance arm died. As would be expected, active surveillance patients were older, had a worse performance status, and had more comorbidities. Interestingly, 40% of patients enrolled selected active surveillance as their preferred management for SRM. The DISSRM results were consistent with data from the Renal Cell Consortium of Canada and other retrospective reviews.^31–33

• What is the approach to follow-up after treatment of localized RCC?

After a patient undergoes treatment for a localized RCC, the goal is to optimize oncologic outcomes, monitor for treatment sequelae, such as renal failure, and focus on survivorship. At this time, there is no consensus in the literature or across published national and international guidelines with regards to the appropriate schedule for surveillance to achieve these goals. In principle, the greatest risk for recurrence occurs within the first 3 years, so many guidelines focus on this timeframe. Likewise, the route of spread tends to be hematogenous, so patients present with pulmonary, bone, and brain metastases, in addition to local recurrence within the renal bed. Symptomatic recurrences often are seen

METASTATIC DISEASE

CASE CONTINUED

CT scan with contrast of the chest, abdomen, and pelvis as well as bone scan are done. CT of the abdomen and pelvis demonstrates a 7.8-cm left renal mass arising from the lower pole of the left kidney. Paraesophageal lymphadenopathy and mesenteric nodules are also noted. CT of the chest demonstrates bilateral pulmonary emboli. Bone scan is significant for increased activity related to the pathological fracture involving the right humerus. The patient undergoes surgery to stabilize the pathologic fracture of his humerus. He is diagnosed with metastatic RCC (clear cell histology) and undergoes palliative debulking nephrectomy.

• How is prognosis defined for metastatic RCC?

PROGNOSTIC MODELS

Limited-stage RCC that is found early can be cured surgically, with estimated 5-year survival rates for stage T1 and T2 disease approaching 90%; however, long-term survival for metastatic disease is poor, with rates ranging from 0% to 20%.¹³ Approximately 30% of patients have metastatic disease at diagnosis, and about one-third of patients who have undergone treatment for localized disease experience relapse.^36,37 Common sites of metastases include lung, lymph nodes, bone, liver, adrenal gland, and brain.

Prognostic scoring systems have been developed to define risk groups and assist with determining appropriate therapy in the metastatic setting. The most widely used validated prognostic factor model is that from the Memorial Sloan-Kettering Cancer Center (MSKCC), which was developed using a multivariate analysis derived from data of patients enrolled in clinical trials and treated with interferon alfa.³⁸ The factors included in the MSKCC model are Karnofsky performance status less than 80, time from diagnosis to treatment with interferon alfa less than 12 months, hemoglobin level less than lower limit of laboratory’s reference range, LDH level greater than 1.5 times the upper limit of laboratory’s reference range, and corrected serum calcium level greater than 10 mg/dL. Risk groups are categorized as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors).³⁹ Median survival for favorable-, intermediate-, and poor-risk patients was 20, 10, and 4 months, respectively.⁴⁰

Another prognostic model, the International Metastatic RCC Database Consortium, or Heng, model was developed to evaluate prognosis in patients treated with VEGF-targeted therapy.⁴¹ This model was developed from a retrospective study of patients treated with sunitinib, sorafenib, and bevacizumab plus interferon alfa or prior immunotherapy. Prognostic factors in this model include 4 of the 5 MSKCC risk factors (hemoglobin level, corrected serum calcium level, Karnofsky performance status, and time to initial diagnosis). Additionally, this model includes both absolute neutrophil and platelet counts greater than the upper limit of normal. Risk groups are identified as favorable (0 risk factors), intermediate (1 to 2 risk factors), and poor (3 or more risk factors). Median survival for favorable-, intermediate-, and poor-risk patients was not reached, 27 months, and 8.8 months, respectively. The University of California, Los Angeles scoring algorithm to predict survival after nephrectomy and immunotherapy (SANI) in patients with metastatic RCC is another prognostic model that can be used. This simplified scoring system incorporates lymph node status, constitutional symptoms, metastases location, histology, and thyroid stimulating hormone (TSH) level.⁴²

The role of debulking or cytoreductive nephrectomy in treatment of metastatic RCC is well established. Large randomized studies have demonstrated a statistically significant median survival benefit for patients undergoing nephrectomy plus interferon alfa therapy compared with patients treated with interferon alfa alone (13.6 months versus 7.8 months, respectively).⁴³ The role of cytoreductive nephrectomy in combination with antiangiogenic agents is less clear. While a retrospective study investigating outcomes of patients with metastatic RCC receiving anti-VEGF agents showed a prolonged survival with nephrectomy, results of large randomized trials are not yet available.^44,45 Patients with lung-only metastases, good prognostic features, and a good performance status are historically the most likely to benefit from cytoreductive surgery.

CASE CONTINUED

Based on the MSKCC prognostic factor model, the patient is considered to be in the intermediate-risk group (Karnofsky performance status of 80, calcium 9.5 mg/dL, LDH 204 U/L, hemoglobin 13.6 g/dL). He is started on treatment for his bilateral pulmonary emboli and recovers well from orthopedic surgery as well as palliative debulking nephrectomy.

Several approaches to systemic therapy for advanced RCC have been taken based on the histologic type of the tumor. Clear-cell is by far the predominant histologic type in RCC. Several options are available as first-line treatment for patients with metastatic clear-cell RCC (Table 2).^46–54 These include biologic agents such as high-dose interleukin-2 (IL-2) immune therapy, as well as targeted therapies including TKIs and anti-VEGF antibodies. The mammalian target of rapamycin (mTOR) inhibitor temsirolimus is recommended as first-line therapy in patients with poor prognosis only. Second-line therapies for clear-cell RCC following antiangiogenic therapy include TKIs, mTOR inhibitors, nivolumab (PD-1 inhibitor), and the combination of the TKI lenvatinib and mTOR inhibitor everolimus.⁵⁵ In addition, after initial cytokine therapy, TKIs, temsirolimus, and the anti-VEGF antibody bevacizumab are other treatment options available to patients. Best supportive care should always be provided along with initial and subsequent therapies. Clinical trials are also an appropriate choice as first-line or subsequent therapies. All of these therapies require periodic monitoring to prevent and quickly treat adverse effects. Table 3 lists recommended monitoring parameters for each of these agents.⁵⁶

Based on several studies, TKIs seem to be less effective in patients with non–clear-cell type histology.^57,58 In these patients, risk factors can guide therapy. In the ASPEN trial, where 108 patients were randomly assigned to everolimus or sunitinib, patients in the good- and intermediate-risk groups had longer overall and median progression-free survival (PFS) on sunitinib (8.3 months versus 5.3 months, respectively). However, those in the poor-risk group had a longer median overall survival with everolimus.⁵⁹ Given that the role of targeted therapies in non–clear-cell RCCs is less well established, enrollment in clinical trials should be considered as a first-line treatment option.²¹

Sarcomatoid features can be observed in any of the histologic types of RCC, and RCC with these features has an aggressive course and a poor prognosis. Currently, there is no standard therapy for treatment of patients with metastatic or unresectable RCC with sarcomatoid features.⁶⁰ Chemotherapeutic regimens used for soft tissue sarcomas, including a trial of ifosfamide and doxorubicin, did not show any objective response.⁶¹ A small trial of 10 patients treated with doxorubicin and gemcitabine resulted in complete response in 2 patients and partial response in 1 patient.⁶²

Enrollment in a clinical trial remains a first-line treatment option for these patients. More recently, a phase 2 trial of sunitinib and gemcitabine in patients with sarcomatoid (39 patients) and/or poor-risk (33 patients) metastatic RCC showed overall response rates (ORR) of 26% and 24%, respectively. A higher clinical benefit rate (defined as ORR plus stable disease) was seen in patients with tumors containing more than 10% sarcomatoid histology, as compared with patients whose tumors contained less than 10% sarcomatoid histology. Neutropenia (n = 20), anemia (n = 10), and fatigue (n = 7) were the most common grade 3 toxicities seen in all the patients. Although this was a small study, the results showed a trend towards better efficacy of the combination therapy as compared with the single-agent regimen. Currently, another study is underway to further investigate this in a larger group of patients.⁶³

BIOLOGICS

Cytokine therapy, including high-dose IL-2 and interferon alfa, had long been the only first-line treatment option for patients with metastatic or unresectable RCC. Studies of high-dose IL-2 have shown an ORR of 25% and durable response in up to 11% of patients with clear-cell histology.⁶⁴ Toxicities were similar to those previously observed with high-dose IL-2 treatment; the most commonly observed grade 3 toxicities were hypotension and capillary leak syndrome. IL-2 requires strict monitoring (Table 3). It is important to note that retrospective studies evaluating the safety and efficacy of using IL-2 as second-line treatment in patients previously treated with TKIs demonstrated significant toxicity without achieving partial or complete response in any of the patients.⁶⁵

Prior to the advent of TKIs in the treatment of RCC, interferon alfa was a first-line treatment option for those who could not receive high-dose IL-2. It has been shown to produce response rates of approximately 20%, with maximum response seen with a higher dose range of 5 to 20 million units daily in 1 study.^66,67 However, with the introduction of TKIs, which produce a higher and more durable response, interferon alfa alone is no longer recommended as a treatment option.

Bevacizumab is a recombinant humanized monoclonal antibody that binds and neutralizes VEGF-A. Given overexpression of VEGF in RCC, the role of bevacizumab both as a single agent and in combination with interferon alfa has been investigated. In a randomized phase 2 study involving patients with cytokine-refractory disease, bevacizumab produced a 10% response rate and PFS of 4.8 months compared to patients treated with placebo.⁶⁸ In the AVOREN trial, the addition of bevacizumab (10 mg/kg intravenously [IV] every 2 weeks) to interferon alfa (9 million units subcutaneously [SC] 3 times weekly) was shown to significantly increase PFS compared with interferon alfa alone (10.2 months versus 5.4 months; P = 0.0001).^47,48 Adverse effects of this combination therapy include fatigue and asthenia. Additionally, hypertension, proteinuria, and bleeding occurred.

TYROSINE KINASE INHIBITORS

TKIs have largely replaced IL-2 as first-line therapy for metastatic RCC. Axitinib, pazopanib, sorafenib, and sunitinib and can be used as first-line therapy. All of the TKIs can be used as subsequent therapy.

Sunitinib

Sunitinib is an orally administered TKI that inhibits VEGF receptor (VEGFR) types 1 and 2, PDGF receptors (PDGFR) α and β, stem cell factor receptor (c-Kit), and FLT-3 and RET kinases. Motzer and colleagues^52,53 compared sunitinib 50 mg daily orally for 4 weeks with 2 weeks off to the then standard of care, interferon alfa 9 million units SC 3 times weekly. Sunitinib significantly increased the overall objective response rate (47% versus 12%; P < 0.001), PFS (11 versus 5 months; P < 0.001), and overall survival (26.4 versus 21.8 months; hazard ratio [HR], 0.821). The most common side effects are diarrhea, fatigue, nausea/vomiting, anorexia, hypertension, stomatitis, and hand-foot syndrome, occurring in more than 30% of patients. Often patients will require dose reductions or temporary discontinuations to tolerate therapy. Alternative dosing strategies (eg, 50 mg dose orally daily for 2 weeks alternating with 1-week free interval) have been attempted but not prospectively evaluated for efficacy.^69–71

Pazopanib

Pazopanib is an oral multi-kinase inhibitor of VEGFR types 1 and 2, PDGFR, and c-KIT. Results of a phase 3 trial comparing pazopanib (800 mg orally daily) to placebo favored the TKI, with a PFS of 9.2 months versus 4.2 months. A subset of treatment-naïve patients had a longer PFS of 11.1 versus 2.8 months and a response rate of 32% versus 4%.⁷² This led to a noninferiority phase 3 trial comparing pazopanib with sunitinib as first-line therapy.⁵⁰ In this study, PFS was similar (8.4 versus 9.5 months; HR 1.05), and overall safety and quality-of-life endpoints favored pazopanib. Much less fatigue, stomatitis, hand-foot syndrome, and thrombocytopenia occurred with pazopanib, whereas hair color changes, weight loss, alopecia, and elevations of LFT enzymes occurred more frequently with pazopanib. Hypertension is common with the administration of pazopanib as well.

Sorafenib

Sorafenib is an orally administered inhibitor of Raf, serine/threonine kinase, VEGFR, PDGFR, FLT-3, c-Kit, and RET. The pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET) compared sorafenib (400 mg orally twice daily) with placebo in patients who had progressed on prior cytokine-based therapy.⁷³ A final analysis, which excluded patients who were allowed to cross over therapies, found improved overall survival times (14.3 versus 1.8 months, P = 0.029).⁵¹ Sorafenib is associated with lower rates of diarrhea, rash, fatigue, hand-foot syndrome, alopecia, hypertension, and nausea than sunitinib, although these agents have not been compared to one another.

Axitinib

Axitinib is an oral inhibitor of VEGFRs 1, 2, and 3. Results of the phase 3 AXIS trial comparing axitinib (5 mg orally twice daily) with sorafenib (400 mg orally twice daily) in patients receiving 1 prior systemic therapy showed axitinib was more active than sorafenib in improving ORR (19% versus 9%; P = 0.001) and PFS (6.7 versus 4.7 months; P < 0.001), although no difference in overall survival times was noted.⁷⁴ In a subsequent phase 3 trial comparing these drugs in the first-line setting, axitinib showed a nonsignificantly higher response rate and PFS. Despite this, the National Comprehensive Cancer Network guidelines consider axitinib an acceptable first-line therapy because activity with acceptable toxicity was demonstrated (Table 2).⁴⁶ The most common adverse effects of axitinib are diarrhea, hypertension, fatigue, decreased appetite, dysphonia, hypothyroidism, and upper abdominal pain.

CABOZANTINIB

Given that resistance eventually develops in most patients treated with standard treatments, including bevacizumab and TKIs, the need to evaluate the safety and efficacy of novel agents targeting VEGFR and overcoming this resistance is of vital importance. Cabozantinib is an oral small-molecule inhibitor of VEGFR, Met, and Axl, all tyrosine kinases implicated in metastatic RCC. Overexpression of Met and Axl, which occurs as a result of inactivation of the VHL gene, is associated with a poor prognosis in patients with RCC. In a

MTOR INHIBITORS

The mTOR inhibitors, temsirolimus and everolimus, are also approved for the treatment of metastatic or advanced RCC. These drugs block mTOR’s phosphorylation and subsequent translation of mRNA to inhibit cell proliferation, cell growth, and angiogenesis.⁷⁷ Temsirolimus can be used as first-line therapy for patients with a poor prognosis, and everolimus is appropriate as a subsequent therapy.

Temsirolimus is an intravenous prodrug of rapamycin. It was the first of the class to be approved for metastatic RCC for treatment-naïve patients with a poor prognosis (ie, at least 3 of 6 predictors of poor survival based on MSKCC model).⁵⁴ The pivotal ARCC trial compared temsirolimus (25 mg IV weekly) alone, interferon alfa (3 million units SC 3 times weekly) alone, or the combination (temsirolimus 15 mg IV weekly plus interferon alfa 6 million units SC 3 times weekly). In this trial, temsirolimus monotherapy produced a significantly longer overall survival time than interferon alfa alone (10.9 versus 7.3 months; P = 0.008) and improved PFS time when administered alone or in combination with interferon alfa (3.8 and 3.7 months, respectively, versus 1.9 months). Because no real efficacy advantage of the combination was demonstrated, temsirolimus is administered alone. The most common adverse effects of temsirolimus are asthenia, rash, anemia, nausea, anorexia, pain, and dyspnea. Additionally, hyperglycemia, hyper-cholesterolemia, and hyperlipidemia occur with these agents. Noninfectious pneumonitis is a rare but often fatal complication.

Everolimus is also an orally administered derivative of rapamycin that is approved for use after failure of VEGF-targeted therapies. The results of the landmark trial RECORD-1 demonstrated that everolimus (10 mg orally daily) is effective at prolonging PFS (4 versus 1.9 months; P < 0.001) when compared with best supportive care, a viable treatment option at the time of approval.⁷⁸ The most common adverse effects of everolimus are stomatitis, rash, fatigue, asthenia, and diarrhea. As with temsirolimus, elevations in glucose, lipids, and triglycerides and noninfectious pneumonitis can occur.

TKI + MTOR INHIBITOR

Lenvatinib is also a small molecule targeting multiple tyrosine kinases, primarily VEGF2. Combined with the mTOR inhibitor everolimus, it has been shown to be an effective regimen in patients with metastatic RCC who have failed other therapies. In a randomized phase 2 study involving patients with advanced or metastatic clear-cell RCC, patients were randomly assigned to receive either lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively). Patients received the treatment continuously on a 28-day cycle until progression or inability to tolerate toxicity. Patients in the lenvatinib plus everolimus arm had median PFS of 14.6 months (95% CI 5.9 to 20.1) versus 5.5 months (95% CI 3.5 to 7.1) with everlolimus alone (HR 0.40 [95% CI 0.24 to 0.68]; P = 0.0005). PFS with levantinib alone was 7.4 months (95% CI 5.6 to 10.20; HR 0.66 [95% CI 0.30 to 1.10]; P = 0.12). In addition, PFS with levantinib alone was significantly prolonged in comparison with everolimus alone (HR 0.61 [95% CI 0.38 to 0.98]; P = 0.048). Grade 3 or 4 toxicity were less frequent in the everolimus only arm and the most common grade 3 or 4 toxicity in the lenvatinib plus everolimus arm was diarrhea. The results of this study show that the combination of lenvatinib plus everolimus is an acceptable second-line option for treatment of patients with advanced or metastatic RCC.⁵⁵

The patient is initially started on pazopanib and tolerates the medication well, with partial response to the treatment. However, on restaging scans he is noted to have small bowel perforation. Pazopanib is discontinued until the patient has a full recovery. He is then started on everolimus. Restaging scans done 3 months after starting everolimus demonstrate disease progression.

• What is the appropriate next step in treatment?

PD1 BLOCKADE

Programmed death 1 (PD-1) protein is a T-cell inhibitory receptor with 2 ligands, PD-L1 and PD-L2. PD-L1 is expressed on many tumors. Blocking the interaction between PD-1 and PD-L1 by anti-PD-1 humanized antibodies potentiates a robust immune response and has been a breakthrough in the field of cancer immunotherapy.⁷⁹ Previous studies have demonstrated that overexpression of PD-L1 leads to worse outcomes and poor prognosis in patients with RCC.⁸⁰ Nivolumab, a fully human IgG4 PD-1 immune checkpoint inhibitor, blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. In a randomized, open-label, phase 3 study comparing nivolumab with everolimus in patients with RCC who had previously undergone treatment with other standard therapies, Motzer and colleagues⁸¹ demonstrated a longer overall survival time and fewer adverse effects with nivolumab. In this study, 821 patients with clear-cell RCC were randomly assigned to receive nivolumab (3 mg/kg of body weight IV every 2 weeks) or everolimus (10 mg orally once daily). The median overall survival time with nivolumab was 25 months versus 19.6 months with everolimus (P < 0.0148). Nineteen percent of patients receiving nivolumab experienced grade 3 or 4 toxicities, with fatigue being the most common adverse effect. Grade 3 or 4 toxicities were observed in 37% of patients treated with everolimus, with anemia being the most common. Based on the results of this trial, on November 23, 2015, the U.S. Food and Drug Administration approved nivolumab to treat patients with metastatic RCC who have received a prior antiangiogenic therapy.

CASE CONCLUSION

Both TKI and mTOR inhibitor therapy fail, and the patient is eligible for third-line therapy. Because of his previous GI perforation, other TKIs are not an option. The patient opts for enrollment in hospice due to declining performance status. For other patients in this situation with a good performance status, nivolumab would be a reasonable option.

FUTURE DIRECTIONS

With the approval of nivolumab, multiple treatment options are now available for patients with metastatic or unresectable RCC. Development of other PD-1 inhibitors and immunotherapies as well as multi-targeted TKIs will only serve to expand treatment options for these patients. Given the aggressive course and poor prognosis of non-clear cell renal cell tumors and those with sarcomatoid features, evaluation of systemic and targeted therapies for these subtypes should remain active areas of research and investigation.

Genetics are probably to blame for why some patients have significant intestinal side effects from Roferon-A (interferon alfa-2a, recombinant – Roche) while others do not, according to a new French investigation reported in issue of Cellular and Molecular Gastroenterology and Hepatology.

They cultured intestinal wall samples taken from 20 colon cancer patients when they had surgery; none of them had been exposed to chemotherapy, radiation, or immunosuppressives. The team bathed the cells in IFN-alfa 2a and other biochemicals to see how they reacted. It was bench work, but the findings could eventually be useful if the team identifies the genetic risk factors for Roferon intestinal side effects and finds better options for patients at risk. Roferon is widely used for blood cancer, melanoma, viral hepatitis, and renal and hepatocellular carcinomas.

“IFN-alfa 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN-gamma response … expressed in T cell–positive lamina propria cells,” the investigators said.

“IFN-alfa impairs human intestinal mucosa homeostasis by eliciting epithelial barrier disruption via apoptosis … The IFN-alfa–elicited impairment of intestinal mucosa homeostasis is heterogeneous among individuals,” Dr. Jarry and her associates wrote.

“This ex vivo finding parallels clinical observations of the interpatient variability of Roferon therapy side effects. … It has been reported that approximately 60% of patients with chronic hepatitis or cancer treated with Roferon have intestinal disorders, especially diarrhea,” they said.

The authors had no conflicts of interest. The work was funded by the University of Nantes.

[email protected]

Genetics are probably to blame for why some patients have significant intestinal side effects from Roferon-A (interferon alfa-2a, recombinant – Roche) while others do not, according to a new French investigation reported in issue of Cellular and Molecular Gastroenterology and Hepatology.

They cultured intestinal wall samples taken from 20 colon cancer patients when they had surgery; none of them had been exposed to chemotherapy, radiation, or immunosuppressives. The team bathed the cells in IFN-alfa 2a and other biochemicals to see how they reacted. It was bench work, but the findings could eventually be useful if the team identifies the genetic risk factors for Roferon intestinal side effects and finds better options for patients at risk. Roferon is widely used for blood cancer, melanoma, viral hepatitis, and renal and hepatocellular carcinomas.

“IFN-alfa 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN-gamma response … expressed in T cell–positive lamina propria cells,” the investigators said.

“IFN-alfa impairs human intestinal mucosa homeostasis by eliciting epithelial barrier disruption via apoptosis … The IFN-alfa–elicited impairment of intestinal mucosa homeostasis is heterogeneous among individuals,” Dr. Jarry and her associates wrote.

“This ex vivo finding parallels clinical observations of the interpatient variability of Roferon therapy side effects. … It has been reported that approximately 60% of patients with chronic hepatitis or cancer treated with Roferon have intestinal disorders, especially diarrhea,” they said.

The authors had no conflicts of interest. The work was funded by the University of Nantes.

[email protected]

Genetics are probably to blame for why some patients have significant intestinal side effects from Roferon-A (interferon alfa-2a, recombinant – Roche) while others do not, according to a new French investigation reported in issue of Cellular and Molecular Gastroenterology and Hepatology.

They cultured intestinal wall samples taken from 20 colon cancer patients when they had surgery; none of them had been exposed to chemotherapy, radiation, or immunosuppressives. The team bathed the cells in IFN-alfa 2a and other biochemicals to see how they reacted. It was bench work, but the findings could eventually be useful if the team identifies the genetic risk factors for Roferon intestinal side effects and finds better options for patients at risk. Roferon is widely used for blood cancer, melanoma, viral hepatitis, and renal and hepatocellular carcinomas.

“IFN-alfa 2a elicited a rapid (24 hours) disruption of surface and crypt colonic epithelial cells via apoptosis that was variable in intensity among the 20 individuals studied. This apoptotic effect was dependent on the initiation of an IFN-gamma response … expressed in T cell–positive lamina propria cells,” the investigators said.

“IFN-alfa impairs human intestinal mucosa homeostasis by eliciting epithelial barrier disruption via apoptosis … The IFN-alfa–elicited impairment of intestinal mucosa homeostasis is heterogeneous among individuals,” Dr. Jarry and her associates wrote.

“This ex vivo finding parallels clinical observations of the interpatient variability of Roferon therapy side effects. … It has been reported that approximately 60% of patients with chronic hepatitis or cancer treated with Roferon have intestinal disorders, especially diarrhea,” they said.

The authors had no conflicts of interest. The work was funded by the University of Nantes.

[email protected]

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

Cabozantinib showed significant improvements in progression-free survival and objective response rate over standard-of-care sunitinib in a phase II clinical trial of adults with metastatic renal cell carcinoma, according to a report published in the Journal of Clinical Oncology.

As a first-line therapy for patients with poor- to intermediate-risk renal cell carcinoma (RCC), cabozantinib improved progression-free survival by approximately 3 months, corresponding to a 34% reduction in the rate of disease progression or death. This is the first study in this patient population in which another agent demonstrated “notable and clinically meaningful” superiority over sunitinib, which has been an established standard of care for more than 10 years, wrote Toni K. Choueiri, MD, director of the Kidney Cancer Center, Dana-Farber Cancer Institute, Boston, and his associates.

In the open-label study, participants were randomly assigned to receive daily oral cabozantinib (79 patients) or daily oral sunitinib (78 patients) in 6-week cycles until disease progressed, intolerance developed, or patients withdrew from treatment. A total of 36% had bone metastases at baseline, an indicator of poor prognosis.

The primary endpoint – median duration of progression-free survival or time to death from any cause – was 8.2 months with cabozantinib and 5.6 months with sunitinib (adjusted hazard ratio, 0.66). Analyses of patient subgroups defined by disease severity consistently favored cabozantinib. Reductions in target lesion size, as measured by CT or MRI, were observed in 87% of the cabozantinib group, compared with 44% of the sunitinib group, the investigators reported (J Clin Oncol. 2016 Nov 14. doi: 10.1200/JCO.2016.70.7398).

Preliminary data showed that overall survival was 30.3 months with cabozantinib and 21.8 months with sunitinib. This represents a 20% decrease in mortality with cabozantinib.

The median number of treatment cycles was greater in the cabozantinib group (five cycles) than in the sunitinib group (two cycles), and corresponded to median treatment durations of 6.9 months and 2.8 months, respectively. Rates of treatment discontinuation due to adverse events were similar between the two study groups, as were the rates of adverse events of any grade, adverse events of grade 3 or 4, and adverse events of grade 5.

These findings indicate that cabozantinib may represent a new treatment option for previously untreated poor- or intermediate-risk metastatic RCC, Dr. Choueiri and his associates wrote.

The study was supported by the National Institutes of Health and Exelixis, which provided the cabozantinib. Dr. Choueiri and many of his associates reported ties to numerous industry sources.

The Food and Drug Administration has approved the immune checkpoint inhibitor nivolumab for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.

The FDA based its approval on an improvement in overall survival demonstrated in CheckMate-141, a randomized trial comparing nivolumab with the investigator’s choice of standard therapy, the FDA said in a written statement.

Earlier this year, the FDA granted accelerated approval to another checkpoint inhibitor targeting the PD-1/PD-L1 pathway, pembrolizumab, for the same indication, based on an objective response rate of 16% in the nonrandomized KEYNOTE-012 trial. Merck Sharp & Dohme, maker of pembrolizumab, is looking to demonstrate an improvement in overall survival with the ongoing KEYNOTE-040 study.

Checkmate-141 enrolled 361 patients with recurrent or metastatic SCCHN with disease progression on or within 6 months of receiving platinum-based chemotherapy and randomized (2:1) to nivolumab 3 mg/kg every 2 weeks intravenously or the investigator’s choice of cetuximab 400 mg/m² IV once, then 250 mg/m² IV weekly; methotrexate 40 mg/m² IV weekly; or docetaxel 30 mg/m² IV weekly until disease progression or unacceptable toxicity.

As reported at the European Society of Medical Oncology Congress and in the New England Journal of Medicine (2016;375:1856-67), the median overall survival was 7.5 months for patients on nivolumab, compared with 5.1 months for those on standard chemotherapy. The hazard ratio for death with nivolumab was 0.70 (P = .01). Estimates of 1-year survival were 36% vs. 16.6%, respectively.

Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of patients on nivolumab, compared with 35.1% of those on standard therapy. The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than with standard therapy were cough and dyspnea. The most common laboratory abnormalities occurring in 10% or more nivolumab-treated patients and at a higher incidence than with standard therapy were increased alkaline phosphatase level, increased amylase level, hypercalcemia, hyperkalemia, and increased thyroid-stimulating hormone level, the FDA said.

Nivolumab is marketed as Opdivo by Bristol-Myers Squibb and previously has been approved to treat classical Hodgkin’s lymphoma, advanced renal cell carcinoma, lung cancer, and melanoma.

[email protected]

On Twitter @NikolaidesLaura

The Food and Drug Administration has approved the immune checkpoint inhibitor nivolumab for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.

The FDA based its approval on an improvement in overall survival demonstrated in CheckMate-141, a randomized trial comparing nivolumab with the investigator’s choice of standard therapy, the FDA said in a written statement.

Earlier this year, the FDA granted accelerated approval to another checkpoint inhibitor targeting the PD-1/PD-L1 pathway, pembrolizumab, for the same indication, based on an objective response rate of 16% in the nonrandomized KEYNOTE-012 trial. Merck Sharp & Dohme, maker of pembrolizumab, is looking to demonstrate an improvement in overall survival with the ongoing KEYNOTE-040 study.

Checkmate-141 enrolled 361 patients with recurrent or metastatic SCCHN with disease progression on or within 6 months of receiving platinum-based chemotherapy and randomized (2:1) to nivolumab 3 mg/kg every 2 weeks intravenously or the investigator’s choice of cetuximab 400 mg/m² IV once, then 250 mg/m² IV weekly; methotrexate 40 mg/m² IV weekly; or docetaxel 30 mg/m² IV weekly until disease progression or unacceptable toxicity.

As reported at the European Society of Medical Oncology Congress and in the New England Journal of Medicine (2016;375:1856-67), the median overall survival was 7.5 months for patients on nivolumab, compared with 5.1 months for those on standard chemotherapy. The hazard ratio for death with nivolumab was 0.70 (P = .01). Estimates of 1-year survival were 36% vs. 16.6%, respectively.

Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of patients on nivolumab, compared with 35.1% of those on standard therapy. The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than with standard therapy were cough and dyspnea. The most common laboratory abnormalities occurring in 10% or more nivolumab-treated patients and at a higher incidence than with standard therapy were increased alkaline phosphatase level, increased amylase level, hypercalcemia, hyperkalemia, and increased thyroid-stimulating hormone level, the FDA said.

Nivolumab is marketed as Opdivo by Bristol-Myers Squibb and previously has been approved to treat classical Hodgkin’s lymphoma, advanced renal cell carcinoma, lung cancer, and melanoma.

[email protected]

On Twitter @NikolaidesLaura

The Food and Drug Administration has approved the immune checkpoint inhibitor nivolumab for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) with disease progression on or after a platinum-based therapy.

The FDA based its approval on an improvement in overall survival demonstrated in CheckMate-141, a randomized trial comparing nivolumab with the investigator’s choice of standard therapy, the FDA said in a written statement.

Earlier this year, the FDA granted accelerated approval to another checkpoint inhibitor targeting the PD-1/PD-L1 pathway, pembrolizumab, for the same indication, based on an objective response rate of 16% in the nonrandomized KEYNOTE-012 trial. Merck Sharp & Dohme, maker of pembrolizumab, is looking to demonstrate an improvement in overall survival with the ongoing KEYNOTE-040 study.

Checkmate-141 enrolled 361 patients with recurrent or metastatic SCCHN with disease progression on or within 6 months of receiving platinum-based chemotherapy and randomized (2:1) to nivolumab 3 mg/kg every 2 weeks intravenously or the investigator’s choice of cetuximab 400 mg/m² IV once, then 250 mg/m² IV weekly; methotrexate 40 mg/m² IV weekly; or docetaxel 30 mg/m² IV weekly until disease progression or unacceptable toxicity.

As reported at the European Society of Medical Oncology Congress and in the New England Journal of Medicine (2016;375:1856-67), the median overall survival was 7.5 months for patients on nivolumab, compared with 5.1 months for those on standard chemotherapy. The hazard ratio for death with nivolumab was 0.70 (P = .01). Estimates of 1-year survival were 36% vs. 16.6%, respectively.

Treatment-related adverse events of grade 3 or 4 occurred in 13.1% of patients on nivolumab, compared with 35.1% of those on standard therapy. The most frequent serious adverse reactions reported in at least 2% of patients receiving nivolumab were pneumonia, dyspnea, respiratory failure, respiratory tract infection, and sepsis.

The most common adverse reactions occurring in more than 10% of nivolumab-treated patients and at a higher incidence than with standard therapy were cough and dyspnea. The most common laboratory abnormalities occurring in 10% or more nivolumab-treated patients and at a higher incidence than with standard therapy were increased alkaline phosphatase level, increased amylase level, hypercalcemia, hyperkalemia, and increased thyroid-stimulating hormone level, the FDA said.

Nivolumab is marketed as Opdivo by Bristol-Myers Squibb and previously has been approved to treat classical Hodgkin’s lymphoma, advanced renal cell carcinoma, lung cancer, and melanoma.

[email protected]

On Twitter @NikolaidesLaura

COPENHAGEN – For patients with previously untreated intermediate- or poor-risk renal cell carcinoma (RCC), cabozantanib offers a progression-free survival benefit better than that seen with sunitinib, the current standard of care, reported investigators in the phase II CABOSUN trial.

After a median follow-up of 20.8 months, progression-free survival (PFS) for patients assigned to cabozantinib (Canbometyx) the primary endpoint, was a median 8.2 months, compared with 5.6 months for patients assigned to sunitinib, reported Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston.

Trial details

In the CABOSUN trial, 157 treatment-naive patients with clear-cell RCC with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 and intermediate- or poor-risk disease according to International Metastatic Renal Cell Carcinoma Database (IMDC) criteria were randomly assigned to receive either oral cabaozantinib 60 mg daily for 6 week cycles, or oral sunitinib 50 mg daily on a standard schedule of 4 weeks on and 2 weeks off.

Tumors were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) every other cycle, and treatment was continued to the point of disease progression or intolerable toxicity.

A total of 79 patients were assigned to cabozantinib, 78 received it, and 13 were still on the drug at the time of the data cutoff. In all, 78 patients were assigned to sunitinib, 72 received it, and 2 were continuing treatment at last follow-up. The efficacy analysis was by intention-to-treat, and the safety analysis as-treated.

As noted, median PFS was 8.2.months for cabozantinib vs. 5.6 months for sunitinib, The hazard ratio for cabozatinib was 0.69 (P = .012). A subgroup analysis showed a trend favoring cabozantinib in each risk group, but this was not significant except among patients with bone metastases (HR, 0.51; 95% confidence interval, 0.29-0.90).

The overall response rate among patients on cabozantib was 46%, compared with 18% for sunitinib. Complete responses were seen in one patient in each group, partial responses in 35 and 13, respectively, stable disease in 26 and 28, and disease progression in 14 and 20 (data on 3 and 16 patients were not evaluable).

The overall survival analysis hinted at a benefit for cabozantinib (HR, 0.80), but this was not statistically significant.

All cause grade 3 or 4 adverse events occurred in 65% of patients in the cabozantinib arm and 68% in the sunitinib arm. Events occurring more frequently with cabozantinib were hypertension (28% vs. 22%), elevated alanine aminotranseferase (5% vs. 0%), anorexia (5% vs. 0%), palmar-plantar erythrodysethesia (8% vs. 4%), and weight loss (4% vs. 0%).

Favorable data, but wait and see

“I think cabozantinib is superior to sunitinib in poor and intermediate risk metastatic renal cell cancer,” said invited discussant Bernard Escudier, MD, from the Gustave Roussy Cancer Center in Paris.

“Cabozantinib is a potent VEGF inhibitor and is probably also active in good risk patients, although we need to see the data in these patients,” he said.

He added that a phase 3 study is warranted to confirm these conclusions, and that he will likely wait until those data are available before moving patients to cabozantinib in the first line.

The trial was supported by the National Cancer Institute. Dr. Choueiri disclosed advising and institutional research funding from Exelixis, maker of cabozantinib, and Pfizer, maker of sunitinib. Dr. Escudier disclosed receiving honoraria from each company.

[email protected]

COPENHAGEN – For patients with previously untreated intermediate- or poor-risk renal cell carcinoma (RCC), cabozantanib offers a progression-free survival benefit better than that seen with sunitinib, the current standard of care, reported investigators in the phase II CABOSUN trial.

After a median follow-up of 20.8 months, progression-free survival (PFS) for patients assigned to cabozantinib (Canbometyx) the primary endpoint, was a median 8.2 months, compared with 5.6 months for patients assigned to sunitinib, reported Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston.

Trial details

In the CABOSUN trial, 157 treatment-naive patients with clear-cell RCC with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 and intermediate- or poor-risk disease according to International Metastatic Renal Cell Carcinoma Database (IMDC) criteria were randomly assigned to receive either oral cabaozantinib 60 mg daily for 6 week cycles, or oral sunitinib 50 mg daily on a standard schedule of 4 weeks on and 2 weeks off.

Tumors were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) every other cycle, and treatment was continued to the point of disease progression or intolerable toxicity.

A total of 79 patients were assigned to cabozantinib, 78 received it, and 13 were still on the drug at the time of the data cutoff. In all, 78 patients were assigned to sunitinib, 72 received it, and 2 were continuing treatment at last follow-up. The efficacy analysis was by intention-to-treat, and the safety analysis as-treated.

As noted, median PFS was 8.2.months for cabozantinib vs. 5.6 months for sunitinib, The hazard ratio for cabozatinib was 0.69 (P = .012). A subgroup analysis showed a trend favoring cabozantinib in each risk group, but this was not significant except among patients with bone metastases (HR, 0.51; 95% confidence interval, 0.29-0.90).

The overall response rate among patients on cabozantib was 46%, compared with 18% for sunitinib. Complete responses were seen in one patient in each group, partial responses in 35 and 13, respectively, stable disease in 26 and 28, and disease progression in 14 and 20 (data on 3 and 16 patients were not evaluable).

The overall survival analysis hinted at a benefit for cabozantinib (HR, 0.80), but this was not statistically significant.

All cause grade 3 or 4 adverse events occurred in 65% of patients in the cabozantinib arm and 68% in the sunitinib arm. Events occurring more frequently with cabozantinib were hypertension (28% vs. 22%), elevated alanine aminotranseferase (5% vs. 0%), anorexia (5% vs. 0%), palmar-plantar erythrodysethesia (8% vs. 4%), and weight loss (4% vs. 0%).

Favorable data, but wait and see

“I think cabozantinib is superior to sunitinib in poor and intermediate risk metastatic renal cell cancer,” said invited discussant Bernard Escudier, MD, from the Gustave Roussy Cancer Center in Paris.

“Cabozantinib is a potent VEGF inhibitor and is probably also active in good risk patients, although we need to see the data in these patients,” he said.

He added that a phase 3 study is warranted to confirm these conclusions, and that he will likely wait until those data are available before moving patients to cabozantinib in the first line.

The trial was supported by the National Cancer Institute. Dr. Choueiri disclosed advising and institutional research funding from Exelixis, maker of cabozantinib, and Pfizer, maker of sunitinib. Dr. Escudier disclosed receiving honoraria from each company.

[email protected]

COPENHAGEN – For patients with previously untreated intermediate- or poor-risk renal cell carcinoma (RCC), cabozantanib offers a progression-free survival benefit better than that seen with sunitinib, the current standard of care, reported investigators in the phase II CABOSUN trial.

After a median follow-up of 20.8 months, progression-free survival (PFS) for patients assigned to cabozantinib (Canbometyx) the primary endpoint, was a median 8.2 months, compared with 5.6 months for patients assigned to sunitinib, reported Toni K. Choueiri, MD, from the Dana-Farber Cancer Institute in Boston.

Trial details

In the CABOSUN trial, 157 treatment-naive patients with clear-cell RCC with measurable disease, Eastern Cooperative Oncology Group performance status 0-2 and intermediate- or poor-risk disease according to International Metastatic Renal Cell Carcinoma Database (IMDC) criteria were randomly assigned to receive either oral cabaozantinib 60 mg daily for 6 week cycles, or oral sunitinib 50 mg daily on a standard schedule of 4 weeks on and 2 weeks off.

Tumors were assessed according to Response Evaluation Criteria in Solid Tumors (RECIST) every other cycle, and treatment was continued to the point of disease progression or intolerable toxicity.

A total of 79 patients were assigned to cabozantinib, 78 received it, and 13 were still on the drug at the time of the data cutoff. In all, 78 patients were assigned to sunitinib, 72 received it, and 2 were continuing treatment at last follow-up. The efficacy analysis was by intention-to-treat, and the safety analysis as-treated.

As noted, median PFS was 8.2.months for cabozantinib vs. 5.6 months for sunitinib, The hazard ratio for cabozatinib was 0.69 (P = .012). A subgroup analysis showed a trend favoring cabozantinib in each risk group, but this was not significant except among patients with bone metastases (HR, 0.51; 95% confidence interval, 0.29-0.90).

The overall response rate among patients on cabozantib was 46%, compared with 18% for sunitinib. Complete responses were seen in one patient in each group, partial responses in 35 and 13, respectively, stable disease in 26 and 28, and disease progression in 14 and 20 (data on 3 and 16 patients were not evaluable).

The overall survival analysis hinted at a benefit for cabozantinib (HR, 0.80), but this was not statistically significant.

All cause grade 3 or 4 adverse events occurred in 65% of patients in the cabozantinib arm and 68% in the sunitinib arm. Events occurring more frequently with cabozantinib were hypertension (28% vs. 22%), elevated alanine aminotranseferase (5% vs. 0%), anorexia (5% vs. 0%), palmar-plantar erythrodysethesia (8% vs. 4%), and weight loss (4% vs. 0%).

Favorable data, but wait and see

“I think cabozantinib is superior to sunitinib in poor and intermediate risk metastatic renal cell cancer,” said invited discussant Bernard Escudier, MD, from the Gustave Roussy Cancer Center in Paris.

“Cabozantinib is a potent VEGF inhibitor and is probably also active in good risk patients, although we need to see the data in these patients,” he said.

He added that a phase 3 study is warranted to confirm these conclusions, and that he will likely wait until those data are available before moving patients to cabozantinib in the first line.

The trial was supported by the National Cancer Institute. Dr. Choueiri disclosed advising and institutional research funding from Exelixis, maker of cabozantinib, and Pfizer, maker of sunitinib. Dr. Escudier disclosed receiving honoraria from each company.

[email protected]

COPENHAGEN – In patients with high-risk locoregional clear cell renal cell (RCC) carcinoma, adjuvant therapy with sunitinib significantly prolonged disease-free survival, compared with placebo, reported investigators in a randomized, phase III trial.

Among 615 patients with clear cell RCC at high risk for recurrence following nephrectomy, the median duration of disease-free survival (DFS) by blinded central review was 6.8 years for patients treated with sunitinib (Sutent) for 1 year, compared with 5.6 years for patients assigned to placebo, reported Alain Ravaud, MD, PhD from Hôpital Saint André in Bordeaux, France.

Central Reviewers Yes, Investigators No

As noted before, the duration of median DFS, the primary endpoint, was 14 months longer with sunitinib, translating into a hazard ratio (HR) of 0.76 (P = .03). This determination of DFS was performed by central reviewers blinded to treatment type.

However, DFS rates by investigators review, while numerically different between trial arms (6.5 years for sunitinib vs. 4.5 years in the placebo group), were not statistically significant (HR, 0.81, P = .08).

Overall survival data were not mature at the time of the data cutoff, with the median not reached in either group.

Treatment-emergent adverse events were seen in 99.7% of the patients in the sunitinib group and in 88.5% of controls. Investigators attributed adverse events to treatment in 98.4% of patients in the sunitinib arm and 75.7% of those in the placebo arm.

The most common adverse events in the sunitinib group were diarrhea, palmar-plantar erythrodysesthesia, hypertension, fatigue, and nausea.

Grade 3 or higher adverse events were reported in 194 patients (63.4%) in the sunitinib group and in 66 (21.7%) in the placebo group.

Interestingly, there were fewer dose reductions in the sunitinib group (34.3% vs. 46.4%) and fewer dose interruptions (2.0% vs. 13.2%), although more patients on sunitinib discontinued because of adverse events (28.1% vs. 5.6%).

The most common cause of death in each group was RCC, which accounted for 47 of 62 deaths (75.8%) in the sunitinib arm and 47 of 64 (73.4%) in the placebo arm. No death was attributed to treatment-associated toxicities.

Patients on sunitinib also had generally lower scores on quality of life scales, but the between-group differences did not reach the prespecified minimally important difference of 10 patients except for the domains of diarrhea and loss of appetite.

[email protected]

COPENHAGEN – In patients with high-risk locoregional clear cell renal cell (RCC) carcinoma, adjuvant therapy with sunitinib significantly prolonged disease-free survival, compared with placebo, reported investigators in a randomized, phase III trial.

Among 615 patients with clear cell RCC at high risk for recurrence following nephrectomy, the median duration of disease-free survival (DFS) by blinded central review was 6.8 years for patients treated with sunitinib (Sutent) for 1 year, compared with 5.6 years for patients assigned to placebo, reported Alain Ravaud, MD, PhD from Hôpital Saint André in Bordeaux, France.

Central Reviewers Yes, Investigators No

As noted before, the duration of median DFS, the primary endpoint, was 14 months longer with sunitinib, translating into a hazard ratio (HR) of 0.76 (P = .03). This determination of DFS was performed by central reviewers blinded to treatment type.

However, DFS rates by investigators review, while numerically different between trial arms (6.5 years for sunitinib vs. 4.5 years in the placebo group), were not statistically significant (HR, 0.81, P = .08).

Overall survival data were not mature at the time of the data cutoff, with the median not reached in either group.

Treatment-emergent adverse events were seen in 99.7% of the patients in the sunitinib group and in 88.5% of controls. Investigators attributed adverse events to treatment in 98.4% of patients in the sunitinib arm and 75.7% of those in the placebo arm.

The most common adverse events in the sunitinib group were diarrhea, palmar-plantar erythrodysesthesia, hypertension, fatigue, and nausea.

Grade 3 or higher adverse events were reported in 194 patients (63.4%) in the sunitinib group and in 66 (21.7%) in the placebo group.

Interestingly, there were fewer dose reductions in the sunitinib group (34.3% vs. 46.4%) and fewer dose interruptions (2.0% vs. 13.2%), although more patients on sunitinib discontinued because of adverse events (28.1% vs. 5.6%).

The most common cause of death in each group was RCC, which accounted for 47 of 62 deaths (75.8%) in the sunitinib arm and 47 of 64 (73.4%) in the placebo arm. No death was attributed to treatment-associated toxicities.

Patients on sunitinib also had generally lower scores on quality of life scales, but the between-group differences did not reach the prespecified minimally important difference of 10 patients except for the domains of diarrhea and loss of appetite.

[email protected]

COPENHAGEN – In patients with high-risk locoregional clear cell renal cell (RCC) carcinoma, adjuvant therapy with sunitinib significantly prolonged disease-free survival, compared with placebo, reported investigators in a randomized, phase III trial.

Among 615 patients with clear cell RCC at high risk for recurrence following nephrectomy, the median duration of disease-free survival (DFS) by blinded central review was 6.8 years for patients treated with sunitinib (Sutent) for 1 year, compared with 5.6 years for patients assigned to placebo, reported Alain Ravaud, MD, PhD from Hôpital Saint André in Bordeaux, France.

Central Reviewers Yes, Investigators No

As noted before, the duration of median DFS, the primary endpoint, was 14 months longer with sunitinib, translating into a hazard ratio (HR) of 0.76 (P = .03). This determination of DFS was performed by central reviewers blinded to treatment type.

However, DFS rates by investigators review, while numerically different between trial arms (6.5 years for sunitinib vs. 4.5 years in the placebo group), were not statistically significant (HR, 0.81, P = .08).

Overall survival data were not mature at the time of the data cutoff, with the median not reached in either group.

Treatment-emergent adverse events were seen in 99.7% of the patients in the sunitinib group and in 88.5% of controls. Investigators attributed adverse events to treatment in 98.4% of patients in the sunitinib arm and 75.7% of those in the placebo arm.

The most common adverse events in the sunitinib group were diarrhea, palmar-plantar erythrodysesthesia, hypertension, fatigue, and nausea.

Grade 3 or higher adverse events were reported in 194 patients (63.4%) in the sunitinib group and in 66 (21.7%) in the placebo group.

Interestingly, there were fewer dose reductions in the sunitinib group (34.3% vs. 46.4%) and fewer dose interruptions (2.0% vs. 13.2%), although more patients on sunitinib discontinued because of adverse events (28.1% vs. 5.6%).

The most common cause of death in each group was RCC, which accounted for 47 of 62 deaths (75.8%) in the sunitinib arm and 47 of 64 (73.4%) in the placebo arm. No death was attributed to treatment-associated toxicities.

Patients on sunitinib also had generally lower scores on quality of life scales, but the between-group differences did not reach the prespecified minimally important difference of 10 patients except for the domains of diarrhea and loss of appetite.

[email protected]

The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.

The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.

The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.

The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.

[email protected]

The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.

The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.

The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.

The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.

[email protected]

The Food and Drug Administration has modified the dosage regimen for nivolumab for indications of renal cell carcinoma, metastatic melanoma, and non–small cell lung cancer.

The single-dose regimen of nivolumab (3 mg/kg IV every 2 weeks) is replaced with the new recommended regimen of 240 mg IV every 2 weeks until disease progression or intolerable toxicity, the FDA said in a written statement.

The nivolumab (Opdivo) dosing regimen in combination with ipilimumab for melanoma will stay the same (nivolumab 1 mg/kg IV, followed by ipilimumab on the same day, every 3 weeks for four doses); however, after completion of ipilimumab, the recommended nivolumab dose is modified to 240 mg every 2 weeks until disease progression or intolerable toxicity. The recommended dose for classical Hodgkin lymphoma remains at 3 mg/kg IV every 2 weeks until disease progression or intolerable toxicity.

The change was made based on analyses demonstrating the comparability of the pharmacokinetics exposure, safety, and efficacy of the proposed new dosing regimen with the previously approved regimen. “Based on simulations by the population pharmacokinetics model, [the] FDA determined that the overall exposure at 240 mg every 2 weeks flat dose is similar (less than 6% difference) to 3 mg/kg every 2 weeks. These differences in exposure are not likely to have a clinically meaningful effect on safety and efficacy, since dose/exposure response relationships appear to be relatively flat in these three indications,” the FDA said.

[email protected]

The combination of an mTOR complex 1 inhibitor (everolimus) plus a VEGF inhibitor (bevacizumab) showed promise against advanced non–clear cell renal cell carcinoma characterized by papillary features in a small manufacturer-sponsored phase II trial, according to a report published online Sept. 6 in the Journal of Clinical Oncology.

Non–clear cell renal cell carcinomas (ncRCCs) are a diverse mixture of heterogeneous malignancies and include papillary, chromophobe, medullary, collecting duct, and a variety of unclassified tumor types. Researchers performed a single-center trial to assess the effectiveness of combined everolimus plus bevacizumab in 35 treatment-naive patients who presented with advanced disease representing all of these histologic types. The unclassified subgroup (23 patients) included several tumors with prominent papillary architectural features that did not fulfill other criteria for papillary RCC, said Martin H. Voss, MD, of Memorial Sloan Kettering Cancer Center, New York, and his associates.

A total of 18 patients (53%) were alive and free of disease progression at 6 months, and 10 (29%) were alive and progression free at 12 months. Two patients still were receiving study treatment at the time of publication, after 20.2 and 30.4 months of therapy, respectively.

“Objective responses were observed in a sizable proportion of subjects with significant papillary (7 of 18) or chromophobe (2 of 5) tumor components but rarely in patients with unclassified RCC without papillary features (1 of 9) or those with medullary RCC (0 of 2),” Dr. Voss and his associates reported. Among patients with unclassified RCC, the 14 whose cancer had a major papillary component showed an objective response rate of 43%, a median progression-free survival of 12.9 months, and a median overall survival of 28.2 months. In contrast, the nine patients whose cancer did not have a major papillary component showed an objective response rate of 11%, a median progression-free survival of 1.9 months, and a median overall survival of 9.3 months, the investigators said (J Clin Oncol. 2016 Sept 6. doi: 10.1200/JCO.2016.67.9084).

Treatment was generally well tolerated, even though there were frequent low-grade toxicities. High-grade toxicities known to be associated with mTOR complex 1 inhibitors or VEGF inhibitors included hyperglycemia (11%), hypertriglyceridemia (14%), lymphopenia (20%), hypertension (29%), and proteinuria (18%). There were two patient deaths from gastrointestinal hemorrhage, one of which was considered possibly related to bevacizumab.

Archived tissue samples were available for genetic analysis for some patients. Acquired mutations in the ARID1A gene were noted in 5 of 14 tumors with major papillary components, and all 5 of those patients achieved more than 6 months of progression-free survival with the combination therapy. In contrast, no ARID1A mutations were detected in any of the patients who had shorter progression-free survival, and none were detected in any of the tumors that did not have papillary components. This suggests that ARID1A “merits further study for its functional role in papillary RCC variants and as a candidate biomarker for future study of everolimus plus bevacizumab,” Dr. Voss and his associates said.

Novartis supported the study. Dr. Voss reported ties to Novartis, Calithera Biosciences, Natera, GlaxoSmithKline, Exelixis, Pfizer, Bristol-Myers Squibb, Genentech, and Takeda; his associates reported ties to numerous industry sources.

The combination of an mTOR complex 1 inhibitor (everolimus) plus a VEGF inhibitor (bevacizumab) showed promise against advanced non–clear cell renal cell carcinoma characterized by papillary features in a small manufacturer-sponsored phase II trial, according to a report published online Sept. 6 in the Journal of Clinical Oncology.

Non–clear cell renal cell carcinomas (ncRCCs) are a diverse mixture of heterogeneous malignancies and include papillary, chromophobe, medullary, collecting duct, and a variety of unclassified tumor types. Researchers performed a single-center trial to assess the effectiveness of combined everolimus plus bevacizumab in 35 treatment-naive patients who presented with advanced disease representing all of these histologic types. The unclassified subgroup (23 patients) included several tumors with prominent papillary architectural features that did not fulfill other criteria for papillary RCC, said Martin H. Voss, MD, of Memorial Sloan Kettering Cancer Center, New York, and his associates.

A total of 18 patients (53%) were alive and free of disease progression at 6 months, and 10 (29%) were alive and progression free at 12 months. Two patients still were receiving study treatment at the time of publication, after 20.2 and 30.4 months of therapy, respectively.

“Objective responses were observed in a sizable proportion of subjects with significant papillary (7 of 18) or chromophobe (2 of 5) tumor components but rarely in patients with unclassified RCC without papillary features (1 of 9) or those with medullary RCC (0 of 2),” Dr. Voss and his associates reported. Among patients with unclassified RCC, the 14 whose cancer had a major papillary component showed an objective response rate of 43%, a median progression-free survival of 12.9 months, and a median overall survival of 28.2 months. In contrast, the nine patients whose cancer did not have a major papillary component showed an objective response rate of 11%, a median progression-free survival of 1.9 months, and a median overall survival of 9.3 months, the investigators said (J Clin Oncol. 2016 Sept 6. doi: 10.1200/JCO.2016.67.9084).

Treatment was generally well tolerated, even though there were frequent low-grade toxicities. High-grade toxicities known to be associated with mTOR complex 1 inhibitors or VEGF inhibitors included hyperglycemia (11%), hypertriglyceridemia (14%), lymphopenia (20%), hypertension (29%), and proteinuria (18%). There were two patient deaths from gastrointestinal hemorrhage, one of which was considered possibly related to bevacizumab.

Archived tissue samples were available for genetic analysis for some patients. Acquired mutations in the ARID1A gene were noted in 5 of 14 tumors with major papillary components, and all 5 of those patients achieved more than 6 months of progression-free survival with the combination therapy. In contrast, no ARID1A mutations were detected in any of the patients who had shorter progression-free survival, and none were detected in any of the tumors that did not have papillary components. This suggests that ARID1A “merits further study for its functional role in papillary RCC variants and as a candidate biomarker for future study of everolimus plus bevacizumab,” Dr. Voss and his associates said.

Novartis supported the study. Dr. Voss reported ties to Novartis, Calithera Biosciences, Natera, GlaxoSmithKline, Exelixis, Pfizer, Bristol-Myers Squibb, Genentech, and Takeda; his associates reported ties to numerous industry sources.

The combination of an mTOR complex 1 inhibitor (everolimus) plus a VEGF inhibitor (bevacizumab) showed promise against advanced non–clear cell renal cell carcinoma characterized by papillary features in a small manufacturer-sponsored phase II trial, according to a report published online Sept. 6 in the Journal of Clinical Oncology.

Non–clear cell renal cell carcinomas (ncRCCs) are a diverse mixture of heterogeneous malignancies and include papillary, chromophobe, medullary, collecting duct, and a variety of unclassified tumor types. Researchers performed a single-center trial to assess the effectiveness of combined everolimus plus bevacizumab in 35 treatment-naive patients who presented with advanced disease representing all of these histologic types. The unclassified subgroup (23 patients) included several tumors with prominent papillary architectural features that did not fulfill other criteria for papillary RCC, said Martin H. Voss, MD, of Memorial Sloan Kettering Cancer Center, New York, and his associates.

A total of 18 patients (53%) were alive and free of disease progression at 6 months, and 10 (29%) were alive and progression free at 12 months. Two patients still were receiving study treatment at the time of publication, after 20.2 and 30.4 months of therapy, respectively.

“Objective responses were observed in a sizable proportion of subjects with significant papillary (7 of 18) or chromophobe (2 of 5) tumor components but rarely in patients with unclassified RCC without papillary features (1 of 9) or those with medullary RCC (0 of 2),” Dr. Voss and his associates reported. Among patients with unclassified RCC, the 14 whose cancer had a major papillary component showed an objective response rate of 43%, a median progression-free survival of 12.9 months, and a median overall survival of 28.2 months. In contrast, the nine patients whose cancer did not have a major papillary component showed an objective response rate of 11%, a median progression-free survival of 1.9 months, and a median overall survival of 9.3 months, the investigators said (J Clin Oncol. 2016 Sept 6. doi: 10.1200/JCO.2016.67.9084).

Treatment was generally well tolerated, even though there were frequent low-grade toxicities. High-grade toxicities known to be associated with mTOR complex 1 inhibitors or VEGF inhibitors included hyperglycemia (11%), hypertriglyceridemia (14%), lymphopenia (20%), hypertension (29%), and proteinuria (18%). There were two patient deaths from gastrointestinal hemorrhage, one of which was considered possibly related to bevacizumab.

Archived tissue samples were available for genetic analysis for some patients. Acquired mutations in the ARID1A gene were noted in 5 of 14 tumors with major papillary components, and all 5 of those patients achieved more than 6 months of progression-free survival with the combination therapy. In contrast, no ARID1A mutations were detected in any of the patients who had shorter progression-free survival, and none were detected in any of the tumors that did not have papillary components. This suggests that ARID1A “merits further study for its functional role in papillary RCC variants and as a candidate biomarker for future study of everolimus plus bevacizumab,” Dr. Voss and his associates said.

Novartis supported the study. Dr. Voss reported ties to Novartis, Calithera Biosciences, Natera, GlaxoSmithKline, Exelixis, Pfizer, Bristol-Myers Squibb, Genentech, and Takeda; his associates reported ties to numerous industry sources.

For metastatic renal cell carcinoma patients with fewer adverse risk factors and fewer metastatic disease sites, initial active surveillance may be a safe and feasible approach to delay the toxicities of systemic therapy, investigators report.

Fifty-two patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma were enrolled in a prospective phase II trial and radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until the treating physician and patient made the decision to initiate systemic therapy.

Median follow-up time was 38.1 months and median time on surveillance before treatment initiation – the primary endpoint of the study – was 14.9 months (95% confidence interval, 10.6-25.0), reported Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute and his associates (Lancet Oncol. 2016. doi: 10.1016/S1470-2045(16)30196-6).

Forty-three (90%) of the 48 evaluable patients experienced disease progression during the study, median time to progression was 9.4 months, and 22 patients died from renal cell carcinoma. One patient developed brain metastases and died without receiving systemic therapy. In multivariable analysis, only the number of involved organs (P = .0414) and number of International Metastatic Database Consortium risk factors (P = .0403) were independently prognostic.

Using this analysis, Dr. Rini and associates identified two prognostic groups – a favorable group consisting of patients with no or one International Metastatic Database Consortium (IMDC) risk factors and two or fewer organs with metastatic disease, and an unfavorable group consisting of all other patients. The favorable group (n = 22) patients had an estimated median surveillance time of 22.2 months (95% CI, 13.8-33.3), whereas the unfavorable group (n = 19) had an estimated median surveillance time of 8.4 months (3.2-14.1; P = .0056).

Anxiety, depression, and quality of life did not change significantly over the period of surveillance, suggesting that living with untreated cancer did not cause psychological harm to patients in this study.

“Findings from our prospective trial show active surveillance to be a viable initial strategy in some patients with metastatic renal-cell carcinoma. The median surveillance period before start of systematic therapy was greater than 1 year, with no observed adverse effects on quality of life, anxiety and depression,” Dr. Rini and his associates said.

“Appropriate selection of patients and adequate monitoring, which should include CNS surveillance, is crucial in application of this approach,” they added.

This study was unfunded. One investigator reported receiving financial compensation from Pfizer and GlaxoSmithKline. All other investigators reported having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig

For metastatic renal cell carcinoma patients with fewer adverse risk factors and fewer metastatic disease sites, initial active surveillance may be a safe and feasible approach to delay the toxicities of systemic therapy, investigators report.

Fifty-two patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma were enrolled in a prospective phase II trial and radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until the treating physician and patient made the decision to initiate systemic therapy.

Median follow-up time was 38.1 months and median time on surveillance before treatment initiation – the primary endpoint of the study – was 14.9 months (95% confidence interval, 10.6-25.0), reported Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute and his associates (Lancet Oncol. 2016. doi: 10.1016/S1470-2045(16)30196-6).

Forty-three (90%) of the 48 evaluable patients experienced disease progression during the study, median time to progression was 9.4 months, and 22 patients died from renal cell carcinoma. One patient developed brain metastases and died without receiving systemic therapy. In multivariable analysis, only the number of involved organs (P = .0414) and number of International Metastatic Database Consortium risk factors (P = .0403) were independently prognostic.

Using this analysis, Dr. Rini and associates identified two prognostic groups – a favorable group consisting of patients with no or one International Metastatic Database Consortium (IMDC) risk factors and two or fewer organs with metastatic disease, and an unfavorable group consisting of all other patients. The favorable group (n = 22) patients had an estimated median surveillance time of 22.2 months (95% CI, 13.8-33.3), whereas the unfavorable group (n = 19) had an estimated median surveillance time of 8.4 months (3.2-14.1; P = .0056).

Anxiety, depression, and quality of life did not change significantly over the period of surveillance, suggesting that living with untreated cancer did not cause psychological harm to patients in this study.

“Findings from our prospective trial show active surveillance to be a viable initial strategy in some patients with metastatic renal-cell carcinoma. The median surveillance period before start of systematic therapy was greater than 1 year, with no observed adverse effects on quality of life, anxiety and depression,” Dr. Rini and his associates said.

“Appropriate selection of patients and adequate monitoring, which should include CNS surveillance, is crucial in application of this approach,” they added.

This study was unfunded. One investigator reported receiving financial compensation from Pfizer and GlaxoSmithKline. All other investigators reported having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig

For metastatic renal cell carcinoma patients with fewer adverse risk factors and fewer metastatic disease sites, initial active surveillance may be a safe and feasible approach to delay the toxicities of systemic therapy, investigators report.

Fifty-two patients with treatment-naive, asymptomatic, metastatic renal-cell carcinoma were enrolled in a prospective phase II trial and radiographically assessed at baseline, every 3 months for year 1, every 4 months for year 2, then every 6 months thereafter. Patients continued on observation until the treating physician and patient made the decision to initiate systemic therapy.

Median follow-up time was 38.1 months and median time on surveillance before treatment initiation – the primary endpoint of the study – was 14.9 months (95% confidence interval, 10.6-25.0), reported Brian Rini, MD, of the Cleveland Clinic Taussig Cancer Institute and his associates (Lancet Oncol. 2016. doi: 10.1016/S1470-2045(16)30196-6).

Forty-three (90%) of the 48 evaluable patients experienced disease progression during the study, median time to progression was 9.4 months, and 22 patients died from renal cell carcinoma. One patient developed brain metastases and died without receiving systemic therapy. In multivariable analysis, only the number of involved organs (P = .0414) and number of International Metastatic Database Consortium risk factors (P = .0403) were independently prognostic.

Using this analysis, Dr. Rini and associates identified two prognostic groups – a favorable group consisting of patients with no or one International Metastatic Database Consortium (IMDC) risk factors and two or fewer organs with metastatic disease, and an unfavorable group consisting of all other patients. The favorable group (n = 22) patients had an estimated median surveillance time of 22.2 months (95% CI, 13.8-33.3), whereas the unfavorable group (n = 19) had an estimated median surveillance time of 8.4 months (3.2-14.1; P = .0056).

Anxiety, depression, and quality of life did not change significantly over the period of surveillance, suggesting that living with untreated cancer did not cause psychological harm to patients in this study.

“Findings from our prospective trial show active surveillance to be a viable initial strategy in some patients with metastatic renal-cell carcinoma. The median surveillance period before start of systematic therapy was greater than 1 year, with no observed adverse effects on quality of life, anxiety and depression,” Dr. Rini and his associates said.

“Appropriate selection of patients and adequate monitoring, which should include CNS surveillance, is crucial in application of this approach,” they added.

This study was unfunded. One investigator reported receiving financial compensation from Pfizer and GlaxoSmithKline. All other investigators reported having no relevant disclosures.

[email protected]

On Twitter @jessnicolecraig