Renal Cell Carcinoma
Synonyms and related keywords: renal cell adenocarcinoma, hypernephroma, hypernephroid tumor, Grawitz tumor, von Hippel-Lindau syndrome, VHL syndrome, VHL disease, hereditary papillary renal carcinoma, HPRC, familial renal oncocytoma, FRO, Birt-Hogg-Dube syndrome, BHDS, hereditary renal carcinoma, HRC, Stauffer syndrome, renal cancer, pheochromocytoma, pancreatic cysts, epididymal cystadenomas, endolymphatic sac tumors, central nervous system hemangioblastomas, retinal angiomas, islet cell tumors, fibrofolliculomas, colonic polyps, colonic tumors, pulmonary cysts, paraneoplastic syndromes, hypercalcemia, nonmetastatic hepatic dysfunction, polyneuromyopathy, amyloidosis, anemia, dermatomyositis, hypertension, varicocele, cigarette smoking, obesity, unopposed estrogen therapy, asbestos exposure, cystic kidney disease, renal dialysis, tuberous sclerosis, renal cell carcinoma
INTRODUCTION
- Renal cell carcinoma with clear cell histologic features
- Pheochromocytoma
- Pancreatic cysts and islet cell tumors
- Retinal angiomas
- Central nervous system hemangioblastomas
- Endolymphatic sac tumors
- Epididymal cystadenomas
Sex: Renal cell carcinoma is twice as common in men as in women. The male-to-female ratio is 2:1.
CLINICAL
- Cytokine release by tumor (eg, IL-6, erythropoietin, nitric oxide) causes these paraneoplastic conditions.
- Resolution of symptoms or biochemical abnormalities frequently follows successful treatment of the primary tumor or metastatic foci.
Physical:
- Gross hematuria with vermiform clots suggests upper urinary tract bleeding.
- Look for hypertension, supraclavicular adenopathy, and flank or abdominal mass with bruit.
- Approximately 30% of patients with renal carcinoma present with metastatic disease. Physical examination should include thorough evaluation for metastatic disease. Organs involved include:
- Lung (75%)
- Soft tissues (36%)
- Bone (20%)
- Liver (18%)
- Cutaneous sites (8%)
- Central nervous system (8%)
- Varicocele and findings of paraneoplastic syndromes raise clinical suspicion for this diagnosis.
DIFFERENTIALS
Lymphoma, Non-Hodgkin
Pyelonephritis, Acute
Pyelonephritis, Chronic
Wilms Tumor
Other Problems to be Considered:
Abscess
Angiomyolipoma (benign neoplasm)
Oncocytoma (benign neoplasm)
Metastasis from distant primary
Metastatic melanoma
Renal adenoma (benign neoplasm)
Renal cyst
Renal infarct
Sarcoma
Transitional cell carcinoma of renal pelvis
WORKUP
Histologic Findings: Renal cell carcinoma has 5 histologic subtypes, as follows: clear cell (75%), chromophilic (15%), chromophobic (5%), oncocytoma (3%), and collecting duct (2%).
- Unusually clear cells with a cytoplasm rich in lipids and glycogen characterize clear cell carcinoma, which is most likely to show 3p deletion.
- Chromophilic tumors tend to be bilateral and multifocal and may have trisomy 7 and/or trisomy 17.
- Large polygonal cells with pale reticular cytoplasm characterize chromophobic carcinoma, which does not exhibit 3p deletion.
- Renal oncocytoma consists predominantly of eosinophilic cells, in a characteristic nested or organoid pattern, that rarely metastasize and do not exhibit 3p deletion or trisomy 7 or 17.
- Collecting duct carcinoma is an unusual variant characterized by a very aggressive clinical course. This tends to affect younger patients and may present with local or widespread advanced disease. These cells can have 3 different types of growth patterns, (1) acinar, (2) sarcomatoid, and (3) tubulopapillary. The sarcomatoid variant, which can occur with any histologic cell type, is associated with a significantly poorer prognosis.
Table 1. Pathologic Classification of Renal Cell Carcinoma
| Cell Type | Features | Growth Pattern | Cell of Origin | Cytogenetics |
| Clear cell | Most common | Acinar or sarcomatoid | Proximal tubule | 3p- |
| Chromophilic | Bilateral and multifocal | Papillary or sarcomatoid | Proximal tubule | +7, +17, -Y |
| Chromophobic | Indolent course | Solid, tubular, or sarcomatoid | Cortical collecting duct | Hypodiploid |
| Oncocytic | Rarely metastasize | Tumor nests | Cortical collecting duct | Undetermined |
| Collecting duct | Very aggressive | Papillary or sarcomatoid | Medullary collecting duct | Undetermined |
- Primary tumor (T)
- TX - Primary tumor cannot be assessed
- T0 - No evidence of primary tumor
- T1 - Tumor 7 cm or smaller in greatest dimension, limited to the kidney
- T2 - Tumor larger than 7 cm in greatest dimension, limited to the kidney
- T3 - Tumor extends into major veins or invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
- T3a - Tumor invades adrenal gland or perinephric tissues but not beyond the Gerota fascia
- 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 invading beyond the Gerota fascia
TREATMENT
- Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Objective response rates, either for single or combination chemotherapy, usually are lower than 15%. Therefore, various biologic therapies have been evaluated.
- Renal cell carcinoma is an immunogenic tumor, and spontaneous regressions have been documented. Many immune modulators, such as interferon, IL-2 (aldesleukin [Proleukin]), bacillus Calmette-Guérin (BCG) vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation, have been tried.
- Multi-kinase inhibitors
- Sorafenib
- On December 20, 2005, the US Food and Drug Administration granted approval for sorafenib (Nexavar), a small molecule Raf kinase and VEGF multi-receptor kinase inhibitor, for the treatment of patients with advanced renal cell carcinoma. This indication is based on the demonstration of improved progression-free survival in a large, multinational, randomized double-blind, placebo-controlled phase 3 study and a supportive phase 2 study. Overall survival results from the phase 3 study are preliminary at this time.
- The sorafenib phase 3 study was conducted in patients with advanced (unresectable or metastatic) renal cell carcinoma who had received one prior systemic treatment. Study endpoints included overall survival, progression-free survival, and response rate. Among 769 patients randomized, the median age was 59 years and 70% were male. Baseline patient and disease characteristics were well balanced. Regarding prior therapies, 93% had prior nephrectomies; 99% had received prior systemic therapies, including interleukin 2 (44%) and an interferon (68%). The median progression-free survival was 167 days in the sorafenib group versus 84 days in the placebo control group (HR 0.44; 95% CI for HR: 0.35-0.55), logrank p less than 0.000001). Time-to-progression was similarly improved. Tumor response was determined by independent radiologic review according to RECIST criteria. Overall, of 672 patients who were able to be evaluated for response, 7 (2%) sorafenib patients and 0 (0%) placebo patients had confirmed partialresponses.
- Sorafenib toxicities (based on an updated phase 3 study database of 902 patients) included reversible skin rashes in 40% and hand-foot skin reaction in 30%. Diarrhea was reported in 43%, treatment-emergent hypertension in 17%, and sensory neuropathic changes in 13%. Alopecia, oral mucositis, and hemorrhage also were reported more commonly on the sorafenib arm. The incidence of treatment-emergent cardiac ischemia/infarction events was higher in the sorafenib group (2.9%) compared with the placebo group (0.4%).
- Grade 3 and 4 AEs were unusual; only hand-foot skin reaction occurred at 5% or greater frequency in the sorafenib arm. Laboratory findings included asymptomatic hypophosphatemia in 45% versus 12% and serum lipase elevations in 41% versus 30% of sorafenib versus placebo patients, respectively. Grade 4 pancreatitis was reported in 2 sorafenib patients, although both patients subsequently resumed sorafenib, one at full dose.
- Physicians should be aware of the importance of frequent blood pressure monitoring and management, especially during the first 6 weeks after starting sorafenib, and the unusual laboratory alterations on sorafenib therapy. The recommended dose is 400 mg (two 200 mg tab) twice daily taken either 1 hour before or 2 hours after meals. Adverse events were accommodated by temporary dose interruptions or reductions to 400 mg once daily or 400 mg every other day.
- Sorafenib targets serine/threonine and receptor tyrosine kinases, including those of RAF, VEGFR-2,3, PDGFR-b, KIT, FLT-3, and RET.
- Further clinical studies evaluating the role of sorafenib in the first-line setting, in combination with other immunomodulators, are underway. Preliminary results appear promising.
- Sunitinib (Sutent)
- Sunitinib is another multi-kinase inhibitor approved by the FDA in January 2006 for the treatment of metastatic kidney cancer that has progressed after a trial of immunotherapy. The approval was based on the high response rate (40% partial responses) and a median time to progression of 8.7 months and an overall survival of 16.4 months.
- The receptor tyrosine kinases inhibited by sunitinib include VEGFR 1-3 and PDGFR a and b.
- Major toxicities (grade II or higher) include fatigue (38%), diarrhea (24%), nausea (19%), dyspepsia (16%), stomatitis (19%), and decline in cardiac ejection fraction (11%). Dermatitis occurred in 8%, and hypertension occurred in 5% of patients.
- A recent phase 3 study evaluating sunitinib in the first-line setting, compared against IFN-a, in patients with metastatic RCC demonstrated significant improvement in PFS and response rates compared against the control arm. These results are considered to be preliminary, and longer-term follow-up is necessary for conclusive results.
- Other multi-kinase inhibitors undergoing investigation for RCC
- Lapatinib is an EGFR and ErbB-2 dual tyrosine kinase inhibitor, which appears to have efficacy in the treatment of tumors, including RCC, which overexpress EGFR. This was recently reported in a phase 3 study in advanced RCC evaluating lapatinib against hormonal therapy in patients who had failed prior therapy.
- RAD001 (Everolimus) is a serine-threonine kinase inhibitor of mTOR, an important regulatory protein in cell signaling. A recent phase 2 trial in patients with metastatic RCC demonstrated promising preliminary clinical results.
- Future treatment strategies for advanced renal cell carcinoma will likely incorporate a combination of molecular approaches, using multidrug regimens consisting of small molecule kinase inhibitors with biologic therapies and/or immunomodulatory therapies.
- For early stage RCC, current and future treatment strategies would utilize these molecular approaches earlier in the adjuvant setting in order to improve overall survival rates. Indeed, a randomized phase 3 trial of sunitinib versus sorafenib versus placebo as adjuvant therapy in patients with resected RCC is currently ongoing and open for patient enrollment.
- Sorafenib
- Chemotherapy
- A recent phase 2 trial of weekly intravenous gemcitabine (600 mg/m2 on days 1, 8, and 15) with continuous infusion fluorouracil (150 mg/m2/d for 21 d in 28-d cycle) in patients with metastatic renal cell cancer produced a partial response rate of 17%. No complete responses were noted. Eighty percent of patients had multiple metastases, and 83% had received previous treatment. The mean progression-free survival duration of 28.7 weeks was significantly longer than that of historic controls.
- Floxuridine (5-fluoro 2'-deoxyuridine [FUDR]), 5-fluorouracil (5-FU), and vinblastine, paclitaxel (Taxol), carboplatin, ifosfamide, gemcitabine, and anthracycline (doxorubicin) all have been used. Floxuridine infusion has a mean response rate of 12%, while vinblastine infusion yielded an overall response rate of 7%. 5-FU alone has a response rate of 10%, but when used in combination with interferon, it had a 19% response rate in some studies.
- Renal cell carcinoma is refractory to most chemotherapeutic agents because of multidrug resistance mediated by p-glycoprotein. Normal renal proximal tubules and renal cell carcinoma both express high levels of p-glycoprotein. Calcium channel blockers or other drugs that interfere with the function of p-glycoprotein can diminish resistance to vinblastine and anthracycline in human renal cell carcinoma cell lines.
- Biologic therapies
- The interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. The interferons have a direct antiproliferative effect on renal tumor cells in vitro, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. Interferon-alpha, which is derived from leukocytes, has an objective response rate of approximately 15% (range 0-29%).
- Preclinical studies have shown synergy between interferons and cytotoxic drugs. In several prospective randomized trials, combinations do not appear to provide major advantages over single-agent therapy. Many different types and preparations of interferons have been used without any difference in efficacy.
- IL-2 is a T-cell growth factor and activator of T cells and natural killer cells. IL-2 affects tumor growth by activating lymphoid cells in vivo without affecting tumor proliferation directly.
- In the initial study by the National Cancer Institute, bolus intravenous infusions of high-dose IL-2 combined with LAK cells produced objective response rates of 33%. In subsequent multicenter trials, the response rate was 16%. Subsequent studies also showed that LAK cells add no definite therapeutic benefit and can be eliminated from the treatment. A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) resulted in a 19% response rate with 5% complete responses. The majority of responses to IL-2 were durable, with median response duration of 20 months. Eighty percent of patients who responded completely to therapy with IL-2 were alive at 10 years.
- Most patients responded after the first cycle, and those who did not respond after the second cycle did not respond to any further treatment. Therefore, the current recommendation is to continue treatment with high-dose IL-2 to best response (up to 6 cycles) or until toxic effects become intolerable. Treatment should be discontinued after 2 cycles if the patient has had no regression. Combinations of IL-2 and interferon or other chemotherapeutic agents such as 5-FU have not been shown to be more effective than high-dose IL-2 alone.
- Toxic effects associated with high-dose IL-2 are related to increased vascular permeability and secondary cytokine secretion (eg, IL-1, interferon gamma, tumor necrosis factor, nitric oxide). The management of high-dose IL-2 toxicities requires inpatient monitoring, often in an intensive care unit. The major toxic effect of high-dose IL-2 is a sepsis-like syndrome, which includes a progressive decrease in systemic vascular resistance and an associated decrease in intravascular volume due to capillary leak. Other toxic effects are fever, chills, fatigue, infection, and hypotension. High-dose IL-2 has been associated with a 1-4% incidence of treatment-related death and should be offered only to patients with no cardiac ischemia or significant impairment of renal or pulmonary functions. Management includes judicious use of fluids and vasopressor support to maintain blood pressure and intravascular volume and at the same time to avoid pulmonary toxicity due to noncardiogenic pulmonary edema from thecapillary leak. This syndrome is normally reversible.
- Other experimental approaches for treatment include immunomodulatory drugs, vaccines, and nonmyeloablative allogeneic peripheral blood stem-cell transplantation.
- The immunomodulator, lenalidomide (Revlimid), a derivative of thalidomide, inhibits VEGF, stimulates T and NK cells, and inhibits inflammatory cytokines. It has been evaluated extensively in hematologic malignancies and recently was reported to demonstrate efficacy in RCC regression and delayed time to progression in a phase 2 study of metastatic RCC.
- Vaccine trials are in early stages of development. Few antigens have been identified that induce T-cell responses from renal cell carcinoma. One example of vaccine strategy is to induce the gene for granulocyte-macrophage colony-stimulating factor (GM-CSF) into autologous cultured renal cell cancer lines by retroviral transduction. Patients then are immunized with irradiated tumor cells secreting large amounts of GM-CSF and are evaluated for immune responses and clinical tumor regression. Other approaches to vaccination include tumor lysates and dendritic cells. Autologous vaccine therapy is now being tried in combination with cytokine therapy.
- Nonmyeloablative allogeneic stem-cell transplantation is another research approach. This can induce sustained regression of metastatic renal cell carcinoma in patients who have had no response to conventional immunotherapy. In one recent trial, 19 patients with refractory metastatic renal cell carcinoma who had suitable donors received a preparative regimen of cyclophosphamide and fludarabine, followed by an infusion of peripheral blood stem cells from a human leukocyte antigen (HLA)-identical sibling or a sibling with a mismatch of a single HLA antigen. Patients with no response received as many as 3 infusions of donor lymphocytes. Two patients died of transplantation-related causes, and 8 died from progressive disease. In 10 patients (53%), metastatic disease regressed; 3 patients had a complete response, and 7 had a partial response. The durations of these responses continue to be assessed. Further trials are needed to confirm these findings and to evaluate long-term benefits.
- A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy.
- Preoperative radiation therapy yields no survival advantage.
- Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with perinephric fat extension, adrenal invasion, or involved margins. A dose of 4500 cGy is delivered, with consideration of a boost.
- Palliative radiation therapy often is used for local or symptomatic metastatic disease, such as painful osseous lesions or brain metastasis, to halt potential neurological progression. Surgery also should be considered for solitary brain or spine lesions, followed by postoperative radiotherapy.
MEDICATION
The goals of pharmacotherapy are to induce remission, reduce morbidity, and prevent complications.
| Drug Name | Aldesleukin (Proleukin) -- IL-2; T-cell growth factor and activator of T cells and natural killer cells. Affects tumor growth by activating lymphoid cells in vivo, without affecting tumor proliferation directly. |
|---|---|
| Adult Dose | 600,000-720,000 IU/kg q8h for as many as 5 d or per protocol |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment |
| Interactions | Corticosteroids may decrease antitumor effect; NSAIDs increase capillary leak syndrome; potentiates effects of antihypertensive medications |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Caution in patients with preexisting cardiac, pulmonary, CNS, hepatic, or renal impairment May cause sepsis-like syndrome due to "capillary leak"; other toxic effects are flu-like syndrome, fever, chills, fatigue, infection, myelosuppression, hepatic toxicity, neurological and neuropsychiatric findings, hypotension, erythema, rash, urticaria, and alteration in thyroid function (including hyperthyroidism and hypothyroidism); high-dose IL-2 has been associated with treatment-related deaths |
| Drug Name | Vinblastine (Velban, Alkaban-AQ) -- Vinca alkaloid with cytotoxic effect via mitotic arrest. Binds to specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. |
|---|---|
| Adult Dose | Per protocol |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; IT use may result in death; severe bone marrow suppression; uncontrolled bacterial infection |
| Interactions | May reduce phenytoin plasma levels; mitomycin-C may increase toxicity significantly |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | IT use may result in death Dose-limiting toxicity is myelosuppression; other toxic effects include nausea, vomiting, alopecia, neurologic effects, local skin damage (if extravasated) |
| Drug Name | Gemcitabine (Gemzar) -- Cytidine analog. After intracellular metabolism to active nucleotide, inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. |
|---|---|
| Adult Dose | Per protocol |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | None reported |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | May cause myelosuppression (particularly thrombocytopenia); toxic effects include flu-like syndrome, LFT abnormalities, maculopapular rash, pruritus, nausea, vomiting, dyspnea, hematuria, proteinuria, and hemolytic-uremic syndrome |
| Drug Name | 5-fluorouracil (Adrucil) -- Fluorinated pyrimidine antimetabolite that inhibits thymidylate synthase (TS) and interferes with RNA synthesis and function. Has cell-cycle specificity with activity in S phase. Inhibits thymidylate synthase by 5-FU metabolite F-dUMP. Metabolite FUTMP incorporates into RNA and F-dUTP incorporates into DNA, resulting in alteration of RNA processing and inhibition of DNA synthesis. |
|---|---|
| Adult Dose | Per protocol |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; poor nutritional status; myelosuppression |
| Interactions | Increased risk of bleeding with anticoagulants, NSAIDs, platelet inhibitors, thrombolytic agents; other immunosuppressants exacerbate bone marrow toxicity; leucovorin enhances toxicity and antitumor activity when given before 5-FU; antifolate analogs (methotrexate and trimetrexate) increase formation of 5-FU metabolite; thymidine and uridine rescue host toxic effect |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Nausea, oral and GI ulcers, depression of immune system, and hemopoiesis failure (eg, bone marrow suppression) may occur; main toxic effects include myelosuppression, mucositis, diarrhea, metallic taste in mouth, hand-foot syndrome, alopecia, dermatitis, increased pigmentation, cerebellar ataxia, somnolence, confusion, seizure, rarely acute encephalopathy, chest pain syndrome, ECG changes, cardiac enzyme elevation, blepharitis, tear duct stenosis, and cholestatic jaundice with biliary stenosis |
| Drug Name | Sorafenib (Nexavar) -- First oral multikinase inhibitor that targets serine/threonine and tyrosine receptor kinases in both the tumor cell and the tumor vasculature. Targets kinases involved in tumor cell proliferation and angiogenesis, thereby decreasing tumor cell proliferation. These kinases included RAF kinase, VEGFR-2, VEGFR-3, PDGFR-beta, KIT, and FLT-3. Indicated for advanced renal cell carcinoma. |
|---|---|
| Adult Dose | 400 mg PO bid 1 h ac or 2 h pc |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity |
| Interactions | CYP450 2B6 and 2C8 inhibitor; predominantly eliminated by UGT1A1 pathway (caution when coadministered with other drugs eliminated by UGT1A1 [eg, irinotecan]); coadministration with warfarin may increase INR or bleeding |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Common adverse reactions include hand or foot skin reaction and rash (modify dose); may increase risk of hemorrhage, cardiac ischemia and/or infarction, alopecia, pruritus, or diarrhea; caution with severe hepatic impairment (ie, Child-Pugh C) |
| Drug Name | Sunitinib (Sutent) -- Mulitkinase inhibitor that targets several tyrosine kinase inhibitors implicated in tumor growth, pathologic angiogenesis, and metastatic progression. Inhibits platelet-derived growth factor receptors (ie, PDGFR-alpha, PDGFR-beta), vascular endothelial growth factor receptors (ie, VEGFR1, VEGFR2, VEGFR3), stem cell factor receptor (KIT), Fms-like tyrosine kinase-3 (FLT3), colony-stimulating factor receptor type 1 (CSF-1R), and the glial cell-line–derived neurotrophic factor receptor (RET). Indicated for advanced renal cell carcinoma. Reduces tumor size in patients with metastatic kidney cancer whose tumors have progressed following cytokine-based therapy. |
|---|---|
| Adult Dose | Standard dose: 50 mg PO qd on a schedule of 4 wk on treatment followed by 2 wk off treatment, then repeat cycle Dose modification: Increase or reduce dose in 12.5-mg increments based on individual safety and tolerability Coadministration with potent CYP4503A4 inhibitors: Minimum dose of 37.5 mg PO qd during treatment phase of cycle Coadministration with CYP4503A4 inducers: Maximum dose of 87.5 mg PO qd during treatment phase of cycle |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; concurrent administration with St John's wort |
| Interactions | Potent CYP4503A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) may increase plasma concentrations; CYP4503A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) may decrease plasma concentrations; St John's wort induces metabolism and decreases plasma concentrations unpredictably (do not take concurrently) |
| Pregnancy | D - Unsafe in pregnancy |
| Precautions | Common adverse effects include diarrhea, skin discoloration, mouth irritation, weakness, and altered taste; may cause fatigue, hypertension, bleeding, swelling, and hypothyroidism; in clinical trials, decreased left ventricular ejection fraction to below lower limits of normal in 15% of patients (monitor for CHF and discontinue if clinical manifestations of CHF develop); may cause hemorrhagic events that may include epistaxis or rectal, gingival, GI, genital, or wound bleeding |
| Drug Name | Interferon alfa 2a (Roferon A) and 2b (Intron A) -- Interferons are natural glycoproteins with antiviral, antiproliferative, and immunomodulatory properties. They have direct antiproliferative effect on renal tumor cells, stimulate host mononuclear cells, and enhance expression of major histocompatibility complex molecules. |
|---|---|
| Adult Dose | 6 million IU/m2 SC in combination with low-dose IL-2 or per protocol |
| Pediatric Dose | Not established |
| Contraindications | Documented hypersensitivity; vaccination with live vaccine during and for 3 mo after completion of therapy |
| Interactions | Inhibits antitumor effects of cyclophosphamide; increases effects of phenytoin and phenobarbital; theophylline may increase toxicity; cimetidine may increase antitumor effects; zidovudine and vinblastine may increase toxicity |
| Pregnancy | C - Safety for use during pregnancy has not been established. |
| Precautions | Caution in brain metastases, severe hepatic or renal insufficiency, seizure disorders, multiple sclerosis, or compromised CNS; main toxic effects include flu-like syndrome, fatigue, anorexia, somnolence, confusion, depression, myelosuppression, mild and transient elevation in serum transaminases, mild proteinuria, hypocalcemia, acute renal failure, nephrotic syndrome, alopecia rashes, pruritus, irritation at injection site, chest pain, arrhythmias, congestive heart failure, impotence, decreased libido, menstrual irregularities, and increased incidence of spontaneous abortion |
FOLLOW-UP
- Avoidance of causative factors such as smoking, obesity, and other factors as described in Causes is recommended.
- Careful surveillance of patients with end-stage renal disease or VHL disease, those who have undergone renal transplantation, and other high-risk groups by ultrasonography and CT scan is recommended.
Complications:
- Excruciating, sharp, bandlike back pain may be an early warning for cord compression due to metastatic renal cell carcinoma and should not be ignored. Urgent MRI should be performed to rule out cord compression, and high-dose dexamethasone therapy should be started.
Prognosis:
- Metastatic disease has increased survival with (1) a long disease-free interval between initial nephrectomy and the appearance of metastases, (2) the presence of only pulmonary metastases, (3) good performance status, and (4) removal of the primary tumor. Five-year survival rates are as follows:
- After radical nephrectomy for stage I renal cell carcinoma, the 5-year survival rate is approximately 94%, and patients with stage II lesions have a survival rate of 79%. A tumor confined to the kidney is associated with a better prognosis.
- The 5-year disease-specific survival rate associated with T1 renal carcinoma is 95% and with stage T2 disease, 88%. Patients with T3 renal carcinoma had a 5-year survival rate of 59%, and those with T4 disease had a 5-year disease-specific survival rate of 20%.
- Patients with regional lymph node involvement or extracapsular extension have a survival rate of 12-25%. Although renal vein involvement does not have a markedly negative effect on prognosis, the 5-year survival rate for patients with stage IIIB renal cell carcinoma is 18%. In patients with effective surgical removal of the renal vein or inferior vena caval thrombus, the 5-year survival rate is 25-50%.
- Five-year survival rates for patients with stage IV disease are low (0-20%).
- A recent trial identified 5 prognostic factors for predicting survival in patients with metastatic renal-cell carcinoma. These factors are used to categorize patients with metastatic renal cell carcinoma into 3 risk groups. Patients in the favorable-risk group (zero risk factors) had a median survival of 20 months. Patients with intermediate risk (1 or 2 risk factors) had a median survival of 10 months, while patients in the poor-risk group (3 or more risk factors) had a median survival of only 4 months. The prognostic factors were as follows:
- Low Karnofsky performance status (less than 80%)
- High serum lactate dehydrogenase level (>1.5 times upper limit of normal)
- Low hemoglobin (below lower limit of normal)
- High "corrected" serum calcium (>10 mg/dL)
- No prior nephrectomy
Patient Education:
- Patients in the high-risk group should be made aware of the early signs and symptoms, and the need for early intervention for possible cure should be stressed.
- Patients in early stages who have undergone treatment should be educated about possible relapse.
- For excellent patient education resources, visit eMedicine's Kidneys and Urinary System Center and Cancer and Tumors Center. Also, see eMedicine's patient education articles Blood in the Urine and Renal Cell Cancer.
MISCELLANEOUS
