Renal cancer

Oxford American handbook of oncology. Second Edition. Oxford University Press (2015)


Epidemiology and etiology

  • 51 000 new cases of renal cancer were expected in 2007, nearly 13 000 U.S. deaths annually. Renal cancer accounts for approximately 2% of all malignancies.
  • Median age at diagnosis is 65 years.
  • It is 1.6 times more common in men.
  • Incidence increased from 2.3% to 419 % annually from 1975 to 1995.
  • It is associated with smoking (relative risk [RR] 2x, 20%–30% attributable risk [AR]).
  • Other major associations include obesity (30%–40% AR), family history (2%–5% AR), hypertension, long-term dialysis (8–10 years), phenacetin use, and increasing age.
  • There are relatively weak associations with urban geographic location, occupational exposure (e.g., asbestos, benzenes, cadmium, nitrosamines, petrols).
  • No strong associations with alcohol consumption, dietary factors, oral contraceptive use, or modern analgesic use have been found.

Genetics

The vast majority of adult renal cancers are sporadic, but an inherited predisposition causes 2%–5%, and these may be multifocal or bilateral.

Von Hippel-Lindau (VHL) syndrome

VHL occurs in 1 per 36,000 births.

  • The VHL gene on chromosome 3 is a tumor suppressor gene.
  • Germline loss or mutation of this gene leads to a multiorgan syndrome including cerebral and retinal hemangioblastomas, endolymphatic sac tumors, and risk of renal cell carcinoma.
  • In sporadic renal cell cancer, both parental alleles are inactivated by acquired mutations or epigenetic silencing, unlike VHL syndrome, in which the first mutation is inherited.
  • Loss of VHL function is seen in over 60% of sporadic clear cell carcinomas. Loss of function leads to activation of hypoxia-inducible genes, including vascular endothelial growth factor (VEGF), platelet-derived growth factor receptor (PDGFR), erythropoietin, and others genes implicated in tumorigenesis.

Hereditary clear cell carcinoma

This carcinoma is caused by germline mutation in chromosome 3 and is without other features of VHL.

Hereditary papillary renal carcinoma syndrome (type 1 papillary)

Hereditary papillary renal carcinoma syndrome (HPRCC) has increased predisposition to multiple, small bilateral tumors.

  • Usually found later in life and is less likely to have metastatic spread.
  • Found to involve mutations in the c-met oncogene located on chromosome 7 and linked to several other malignancies (GI, melanoma).

Hereditary leiomyoma and papillary renal cell carcinoma (type 2 papillary renal cell carcinoma)

  • Increased predisposition to unilateral large aggressive renal tumors, skin and uterine leiomyomas, and linked to chromosome 1q42 (fumarate hydratase gene in Krebs cycle)

Birt-Hogg-Dube syndrome

  • Patients have increased risk for lung cysts leading to pneumothorax, a predisposition to kidney neoplasms (chromophobe and oncocytoma subtype), and prominent skin findings (fibrofolliculomas).
  • The defect is due to loss of function of the BHD (folliculin) gene found on the short arm of chromosome 17.

Other diseases

  • Increased risk is also found in autosomal dominant polycystic kidney disease and tuberous sclerosis.
  • Pediatric renal cell carcinoma (RCC): translocation of 1:X chromosomes; very rare

Pathology

Adenocarcinomas make up 85% of renal cancers and arise from the renal tubular epithelium. The next most common type is transitional cell carcinomas of the renal pelvis (78%). These renal cell carcinomas demonstrate several histological types:

  • Clear cell (75%): Usually found to have mutations of VHL (in both sporadic and inherited cases)
    • PAS-positive cells, +RCC antigen, often CD10 positive, + cytokeratins
    • Likely derived from proximal tubule cell or progenitor
  • Type 1 papillary (5%): Usually found to have mutations in c-Met, with basophilia and small nuclei. Usually favorable prognosis
  • Type 2 papillary (10%): Usually found to have mutations in the fumarate hydratase gene in familial cases, linked to c-myc activation in sporadic cases
    • Eosinophilic with large nuclei and nucleoli, pseudostratified epithelium
    • Aggressive tumor with unfavorable prognosis
    • Unclear derivation of PRCC, but likely proximal tubule or progenitor
  • Chromophobe (5%): Usually found to have loss of function of the BHD gene in familial cases, widespread chromosomal instability in sporadic cases (loss of chromosomes 1, 6, 10, 11, 17, hypodiploidy), and positive Hale’s iron stains, + c-kit expression, PAS negative, and likely derived from intercalated cells
  • Oncoctyoma (5%): Usually found to have loss of function of the BHD gene, packed with mitochondria on electron microscopy
  • Collecting duct (Bellini tumor) (<1%): Very rare transitional cell carcinoma; very aggressive and usually presents with metastatic disease
  • Spindle cell or sarcomatoid: Highest grade variant of clear cell or other pathologic subtypes, poor prognostic feature
  • Overlapping and coexisting histologies are common.
  • Medullary carcinoma: Rare aggressive tumor arising in African Americans with sickle cell trait, likely ductal origin
  • Mucinous or multilocular cystic carcinomas: Rare, typically benign

RCC typically arises as a solitary mass in one pole of the kidney, with <4% being bilateral renal masses. As it progresses, it may invade directly through the renal capsule, along the renal vein toward the IVC or even right atrium, and via lymphatics to regional nodes (para-aortic).

Systemic metastases are common; locally advanced and macroscopic spread is present in 25% of cases at presentation, typically to lung or bone, but also liver, adrenal, and brain.

Transitional cell carcinomas (TCCs) can arise within the urothelium of the renal pelvis and represent the majority of the remaining tumors.

They vary from low-grade superficial papillary tumors to high-grade invasive TCC with a propensity for direct invasion into perinephric tissues and lymphovascular spread.

Investigations

Many RCC tumors are identified on ultrasonography, but CT is the preferred imaging modality. Increasing incidence is likely linked to increasing use of CT imaging and incidental discovery.

Contrast-enhanced CT scan of the abdomen characteristically shows an enhancing mass, at least partly solid. CT should also be used to image the following:

  • Chest, for lung and mediastinal lymph node metastases
  • Extrarenal direct tumor extension, e.g., into psoas muscle
  • Regional para-aortic lymph nodes
  • Spread to other organs, e.g., liver, adrenals

MRI of the abdomen may be preferred to look for involvement of the collecting system and inferior vena cava or renal vein invasion.

Biopsy is usually omitted prior to surgical treatment (nephrectomy or partial nephrectomy) of renal cancer because of the risk of hemorrhage and tumor seeding along the biopsy tract. Biopsy may be appropriate if no nephrectomy is to be performed for advanced or metastatic disease.

Other recommended investigations include the following:

  • CBC (searching for anemia or erythocytosis), liver and kidney function tests
  • LDH and serum calcium levels as prognostic factors
  • Bone scan in patients with poor-risk disease or in patients with bone pain or elevated alkaline phosphatase or calcium
  • CT/MRI of the brain if poor risk or clinical evidence of CNS spread
  • Isotope renogram to assess function of contralateral kidney if renal function is impaired
  • PET scanning does not have a currently defined role.

Staging

The American Joint Commission of Cancer (AJCC) staging is commonly used (Table 33.1).

Table 33.1. TNM staging of renal cancer

Primary tumor
Tx Primary tumor cannot be assessed
T0 No evidence of primary tumor
T1 Tumor <7 cm in greatest dimension, limited to kidney
T2 Tumor >7 cm in greatest dimension, limited to kidney
T3 Tumor extends into major veins or invades the adrenal gland or perinephric tissues, but not beyond Gerota’s fascia
T3a Tumor invades the adrenal gland or perinephric tissues but not beyond Georta’s facsia
T3b Tumor grossly extends into the renal vein(s) or vena cava below the diaphragm
T3c Tumor grossly extends into the renal vein(s) or vena cava above the diaphragm
T4 Tumor invades beyond the Gerota’s fascia
Regional lymph nodes
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Metastases in a single regional lymph node
N2 Metastases in more than one regional lymph node
Distant metastases
Mx Distant metastases not assessed
M0 No distant metastases
M1 Distant metastases
Stage group
Stage I T1NOMO
Stage II T2NOMO
Stage III T1N1MO, T2N1MO, T3AN0MO
T3AN1MO, T3BN0MO, T3BN1M0
T3CN0MO, T3CN0M1
Stage IV T4NOMO, T4N1MO
Any T N2M0 or any M1

Presenting symptoms and signs

Up to 30% are asymptomatic and are discovered coincidentally during abdominal imaging for other reasons. Symptoms may relate directly to the primary tumor, but paraneoplastic effects are not uncommon:

  • Hematuria (50%)
  • Groin pain (50%)
  • Palpable mass (30%)
  • Anemia (40%)
  • Weight loss (35%)
  • Pyrexia (20%)
  • Hypertension (37%)
  • Hypercalcemia (6%)
  • Polycythemia (<5%) due to elevated erythropoietin
  • Elevated liver function tests in absence of metastasis (Stauffer syndrome)

Renal tumors may invade directly into adjacent psoas muscle or lumbar spine causing pain, or may present de novo with symptoms from metastatic disease in the lungs, lymph nodes, bone, or brain.

Surgery

Resection of the entire tumor is the only potentially curative treatment and should be offered to patients with operable disease without metastases who are fit for surgery for stage I–III disease.

Anatomic extent of disease is the most consistent factor determining prognosis in newly diagnosed patients with metastatic renal cell cancer.

Patients with metastatic disease but good performance status and resectable primary tumor may benefit from nephrectomy as a palliative procedure, with two randomized trials demonstrating a survival benefit (3–7 months) with nephrectomy.

These trials were performed in the era of interferon (IFN) systemic therapy, and it is unclear why nephrectomy was done prior to the use of current targeted VEGF- or mTOR-based therapy. Most patients in clinical trials of these agents had undergone prior nephrectomy.

The reasons to consider nephrectomy in the face of metastatic disease include the following:

  • To provide control of local symptoms (pain, hematuria)
  • Although there are documented cases of regression of metastases following nephrectomy, this is extremely rare. Nephrectomy cannot be justified on this basis in patients who are frail or have extensive metastatic disease.
  • Improvement in response to immunologic therapy (high-dose IL-2)

Partial nephrectomy is occasionally performed for small, localized tumors or in patients without a second kidney, or in the rare case of bilateral renal cancer.

Radical nephrectomy includes removal of Gerota’s fascia and its contents, including the kidney and the adrenal gland, and removal of regional lymph nodes.

Some surgeons believe that adrenal-gland and lymph-node dissection can remain optional, although for upper pole lesions the unilateral adrenal gland is typically removed. Lymph node status can serve as prognostic information; however, most patients with nodal involvement experience recurrence with distant metastasis.

Laparoscopic nephrectomy is becoming increasingly established to decrease the morbidity of the open procedure—morbidity is less, and early survival seems to equate to the open procedure. Unless patients are frail or very elderly, even small tumors should be resected.

Surgery for metastases (e.g., lung, brain) is indicated for isolated metastases or oligometastatic disease that occurs after a long disease-free interval, and can result in prolonged survival in up to 30% of patients.

Although surgery is the cornerstone of management of localized disease, some patients are unfit for nephrectomy or their tumor is unresectable.

Cryotherapy and/or radiofrequency ablation may provide some tumor control for patients with small tumors. In some elderly asymptomatic patients, conservative management is appropriate, and tumor growth may be slow.

Neoadjuvant systemic therapy remains unproven but may be used in select cases that are currently unresectable. Appropriate holding of anti-VEGF/mTOR-based therapy prior to nephrectomy should be considered to prevent wound healing complications.

Adjuvant therapy

Adjuvant therapy of any type has not been proven to offer a survival benefit or decreased time to relapse when combined with nephrectomy.

Cytotoxic chemotherapies, endocrine therapy, radiotherapy, and immunotherapy have been tested. Randomized clinical trials of targeted therapy approved in the metastatic setting and immunotherapy alone or in conjunction are ongoing.

The current standard of care is observation after complete nephrectomy or a clinical trial for intermediate- to high-risk disease (T3, node positive, high grade).

Radiotherapy

In general, renal cancer is relatively radioresistant. Palliative radiotherapy is appropriate for

  • Painful or bleeding primary tumor
  • Nonresectable metastatic disease, e.g., bone, brain, soft tissue, isolated nephrectomy bed recurrences (with or without surgery)

Higher palliative doses than those used in other malignancies may be appropriate to give durable control of disease, particularly for isolated nonresectable metastases after nephrectomy in patients with good performance status.

Supportive care

Bisphosphonate (zoledronic acid) therapy should be used for patients with bone metastatic disease to prevent skeletal-related events (hypercalcemia of malignancy, fracture, bone pain, need for radiation), according to evidence from randomized controlled trials.

  • The studied schedule for this agent is 4 mg (renally dose adjusted) every 3 weeks, but alternative, less-frequent schedules may also be effective.
  • Side effects include osteonecrosis of the jaw (ONJ), renal insufficiency, and bone and joint pains.

Anemia may be treated with transfusional support, iron supplementation if deficient, and/or erythropoiesis-stimulating agents (ESA). However, renal cell carcinoma expresses erythropoietin and has functional erythropoietin receptors on the cell surface.

Numerous clinical trials for other tumor types have demonstrated evidence of increased tumor progression and lower survival when these agents were used in the absence of chemotherapy-induced anemia.

Given these concerns, future studies in RCC are warranted for the safe use of these agents. General supportive care for pain control, nausea, diarrhea, fatigue, depression, weight loss, and psychosocial stress is recommended. The reader is referred to National Comprehensive Cancer Center (NCCN) guidelines for standard management of these symptoms.

Prognostic features determining recurrence

Multiple prognostic models have been created to categorize patients with clinically relevant differences in prognosis.

For predicting recurrence in patients with localized cancer, the most common model is the UCLA integrated system, which focuses on three factors: TNM staging, Fuhrman’s histological grade, and ECOG performance status. Another model has been created by the Cleveland clinic, which also uses the number of metastatic sites as an additional validated poor prognostic factor.

A validated European nomogram has been developed for the prediction of long-term outcome in RCC. For more information on these nomograms, please refer to the references under the future readings.

For patients with metastatic disease and who have had a previous nephrectomy, the prognostic model most commonly used in clinical trials and that has shown the ability to predict a shorter survival is the Memorial Sloan Kettering Cancer Center model (Motzer criteria). This model identifies patients as poor-, intermediate-, or good-prognosis patients, with difference in overall survival by 6 months or more. Those defined as poor prognosis included patients with ≥3 of the following poor prognostic features: high LDH, low performance status, elevated corrected calcium, anemia, and absence of prior nephrectomy or <1 year from nephrectomy to recurrence.

Poor-risk patients have a median survival of 4 months in the pretargeted therapy era. Intermediate-risk patients have 1–2 risk factors and have a median survival of 10 months in the pretargeted therapy era.

Good-risk patients (zero risk factors) have a median survival of 20 months. These estimates are likely to be increased upward in the current era of VEGF- and mTOR-based systemic therapy.

Other risk factors that may be important include the number of metastatic sites of disease, pathologic subtypes (chromophobes favorable), and prior radiation therapy.

Chemotherapy

Cytotoxic drugs are of little value in treating clear cell renal carcinoma. The chemoresistance may be in part due to the high expression of a multidrug resistance phenotype in both normal and malignant renal tissue.

Response rates for single agents are generally under 10%. Chemotherapy may be indicated for transitional cell carcinomas (collecting duct tumors), using traditional cisplatin-based regimens.

Biological therapy

The goal of management of patients with advanced and/or metastatic renal cancer is palliative. However, there is good evidence that a small subset of patients (7%–10%) who have complete responses to biological therapy may enjoy long-term, disease-free survival with intensive immunologic therapy.

In general, these patients tend to fall into the good-risk Motzer subgroup. Most studies have shown that only patients with clear-cell pathology respond to biological therapy, leaving limited treatment options for patients with nonclear-cell pathology.

Biological therapy has been extensively tested in renal cancer, partly because of this cancer’s chemoresistance, but mainly because of the presumption that immunological mechanisms underlie

  • Occasional spontaneous regression of metastases
  • Very late relapses in some patients
  • Increased incidence of renal cancers in immunosuppressed patients

Interleukin-2

Interleukin-2 (IL-2) is the most widely tested biological agent in the treatment of advanced renal cancer. It induces complete responses in 10%– 25% of patients with advanced metastatic disease.

Patients with a complete radiological response have a significant survival benefit, with sustained remissions of several years in up to 70%.

Studies have shown that high doses of intravenous IL-2 given in an inpatient ICU setting, compared with subcutaneous dosing, showed no difference in overall survival, but decreased response rate with the subcutaneous dose. These regimens are associated with serious mortality (up to 4%) and morbidity, in particular capillary leak syndrome, including hypotension and pulmonary edema, renal failure, and hemorrhage.

Other toxicities include flu-like symptoms and effects on bone marrow, hepatic and renal function, and the CNS (delirium, psychosis), and thyroid dysfunction.

There is some evidence in the melanoma literature that the induction of autoimmunity with IL-2 is associated with a survival benefit.

Interferon-α

  • As a single agent, subcutaneous interferon (IFN) provides a response rate of ~15%–20% but without prolonged remissions.
  • In clinical trials comparing IFN to progesterones, IFN was demonstrated to have a 2- to 4-month survival benefit.
  • Dosing of this agent is initially 9 mU subcutaneously three times weekly, escalating as tolerated to 18 mU.
  • Toxicities of this drug are significant but not life threatening, in particular flu-like symptoms, lethargy, anorexia, and nausea.
  • Other side effects include deranged LFTs, and effects on bone marrow and renal function, hypothyroidism, neuropathy, and CNS symtoms (depression and psychosis).

Combined biological and chemotherapy

Although phase II studies have reported higher objective response rates with combinations of IL-2 and IFN, with or without chemotherapy, so far, phase III studies have failed to demonstrate a significant benefit with any combination regimen.

Management of transitional cell carcinoma

These tumors arise in the renal collecting system and may be associated with transitional cell carcinoma (TCC) in the ureter and bladder. Their biology, management, and prognosis are similar to that of TCC of the ureter.

Medullary tumors are typically chemorefractory, with some case reports indicating prolonged responses to proteasome inhibition (bortezomib) or anthracycline therapy.

Treatment outcomes

Most of the data used to determine treatment outcomes was determined in the pretyrosine kinase inhibitors era (which will be discussed in detail later). Using the previously defined Motzer criteria, one could estimate the median time to death in the favorable risk (zero risk factors: 20 months), intermediate risk (one or two risk factors: 10 months), and poor risk (three or more risk factors: 4 months). Data are limited in the posttyrosine kinase inhibitor era in each of these groups; yet, one could state that these figures can likely be adjusted upwards 2–6 months in the current era.

Molecular targeted treatments for renal cancer

Recent advances in the understanding of the pathogenesis of renal cell cancer have led to recent U.S. FDA approval of three targeted therapies for patients with advanced renal cell cancer.

By focusing on patients with loss of function of the VHL gene (which is actually seen in approximately 60%–80% of patients with sporadic clear cell pathology), it has been discovered that renal cell cancer progression is dependent on angiogenesis and its downstream and upstream effectors.

Table 33.2 shows agents that target specific members of this pathway, their approved indication, and their major side effects.

Given that these agents are not likely to be curative, enrollment in clinical trials remains a priority in first- and second-line settings and beyond.

Combination therapy or novel approaches to targeted therapy may provide additional benefit compared with the agents listed below.

Sunitinib (Sutent), U.S. Food and Drug Adminstration-approved dose 50 mg for 4 weeks daily and then 2 weeks off by mouth

Sunitinib was recently approved after a phase III trial compared this agent with IFN in newly diagnosed patients with renal cell cancer (clear-cell pathology).

  • Progression-free survival (PFS) was 11 months (sunitinib arm) vs. 5.1 months (IFN arm) and overall response rate (ORR) was 31% (sunitinib arm) vs. 6% (IFN arm).
  • Significant ORR and significant increased time to progression were shown in the sunitinib arm.
  • Atrend toward improved overall survival (not statistically significant) was shown in those treated with sunitinib. Crossover was permitted.
  • This agent was studied and showed similar activity in previously treated (cytokine-refractory) patients and was approved for this indication as well.
  • A2008 update at the American Cancer Society Oncology Annual meeting in 2008 showed a clear advantage in overal survival in the sunitinib arm (28 months) vs the IFN arm (14 months) in those patients who did not receive and poststudy treatment. The calculated P value was10033.

Sorafenib (Nexavar), U.S. Food and Drug Adminstration-approved dose 400 mg twice a day by mouth

This was studied in a large placebo-controlled trial in patients who failed previous cytokine-based therapies.

  • Median PFS was 5.5 months (sorafenib arm) vs. 2.8 months (placebo), P value <.01.
  • Sorafenib reduced the risk of death compared with a placebo (hazard ratio = 0.72, P value <102), but this did not meet the prespecified cutoff for significance. Patients crossed over from IFN to sorafenib in this study.
  • In newly diagnosed patients, the conclusions are less clear.
  • Aphase II trial comparing this agent with IFN showed improved tumor shrinkage, 68% (sorafenib arm) vs. 39% (IFN arm); no statistical benefit was seen in time to progression, 5.7 months (sorafenib arm) vs. 5.6 months (IFN arm).
  • Randomized phase II studies have not supported a routine role for sorafenib in the first line setting for metastatic RCC.

Table 33.2. Targeted therapies for renal cancer

Target Agent Indication Side effects
VEGF (vascular endothelial growth factor) Bevacizumab Not currently U.S. FDA approved Bleeding, impaired wound healing, proteinuria, hypertension, venous thromboembolism, GI perforation
mTOR Temsirolimus (Torisel) Approved for patients with advanced RCC Fatigue, hyperlipidemia, rash, stomatitis, anemia, hyperglycemia
VEGF/PDGF (platelet-derived growth factor) Sunitinib (Sutent ) Approved for patients with advanced RCC Fatigue, hypertension, hand-foot syndrome, diarrhea, rash, skin discoloration
Sorafenib (Nexavar) Approved for patients with advanced RCC Hypertension, rash, fatigue, hand-foot syndrome, diarrhea

Temsirolimus (Torisel), U.S. Food and Drug Adminstration-approved dose 25 mg IV weekly

This intravenous agent was studied in a large phase III trial of previously untreated patients. Temsirolimus was compared with IFN or the combination of temsirolimus and IFN. The study was focused on poor-risk patients categorized by Motzer criteria or multiple metastatic sites (modified criteria).

The study showed an increase in overall survival (OS), 1019 months (in the temsirolimus arm) vs. 7.3 months (in the INF arm), P = 1008. The study also showed an increased PFS, 5.5 months (in the temsirolimus arm) vs. 3.1 months (INF arm). The objective response rate was also increased in the temsirolimus vs. INF arm (8.6% vs. 4.8%).

The drug was also studied in the previously treated setting in a phase II trial and showed a rather long time to progression and overall survival in heavily pretreated individuals.

Bevacizumab (Avastin)

A phase II trial of previously treated patients or cytokine-refractory patients showed that this agent was able to increase time to progression compared with placebo; however, no benefit in overall survival was seen.

  • High doses (10 mg/kg every 2 weeks) seemed to confer a greater progression-free survival advantage.
  • Arecent phase III trial in previously untreated patients compared IFN-α + bevacizumab with IFN-. alone:
  • The ORR was 31% (IFN-α with bevacizumab arm) vs. 13% (IFN-α- alone arm), P <.0001.
  • PFS was 10.2 months (IFN-α with bevacizumab arm) vs. 5.4 months (IFN-α-alone arm), P <.0001.
  • Atrend toward improved OS was observed with the addition of bevacizumab to IFN-α2a (P = 10670).
  • This drug is currently not U.S. FDA approved for the treatment of patients with advanced renal cell cancer.
  • Two randomized phase III studies have shown improved PFS with Avastin/IFN vs. IFN (CALGB 90206 and the AVOREN study) and that this agent is approved in the European Union for RCC therapy.

Future directions

Further investigations are looking at different dosages of these molecular agents (including continuous dosage) and combinations of these agents along with other molecular agents to improve response. Investigators are also looking at the potential of using allogenic stem cell transplant and vaccine therapy to improve survival in these patients. An oral mTOR inhibitor RAD001 (everolimus) has recently shown promise in heavily treated patients (including tyrosine kinase inhibitors) in the second/third line setting with data showing improved PFS but that this agent is not currently approved. Future combination therapy with these agents and novel agents are being actively explored.

At this time, allogeneic bone marrow transplantation remains an unproven therapy in renal cell carcinoma, with recent findings indicating a lack of sufficient graft-versus-tumor effect in this disease.

Ongoing clinical trials are also being pursed to determine the best therapy for patients with nonclear-cell pathology, as most clinical trials have focused on clear-cell pathology.

Novel agents focused on upstream events that control VEGF production (HIF, VHL) are also being evaluated.

 

 

 

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