Renal cell carcimoma (RCC) is the third most common genitourinary cancer after prostate and bladder. Majority (80% to 85%) of kidney tumors are malignant. It is the most lethal malignancy of all urological cancers.
Unique characteristics of RCC
lack of early warning signs,
diverse clinical manifestations,
resistance to radiation and chemotherapy, and
immunogenic nature and spontaneous regressions.
RCC diagnosed early can be managed with nephron sparing or radical nephrectomy with excellent 5 year survival and prognosis. The problematic cases are those presenting as advanced disease at the initial presentation. The advanced disease includes: T4 N0 M0, or any T, any N, M1. These cases are associated with poor survival and limited treatment options. This information aims to throw some light on our current understanding of the pathogenic mechanisms, and the available treatment options for the management of advanced RCC.
Pretreatment features associated with shorter survival
There are various studies identifying the pretreatment factors associated with poor survival. These are
– Low Karnofsky performance status (< 80%)
– High lactate dehydrogenase level (> 1.5 x normal)
– Low hemoglobin level
– High serum calcium
– Absence of nephrectomy
• Nephrectomy and resection of metastases has been reported to prolong the survival. Effect is enhanced with long disease-free interval between initial nephrectomy and development of metastases.
• Survival also depends on the site of metastasis. Patients with lung metastasis only have better survival than those with other site metastasis. (Flanigan RC, et al. N Engl J Med. 2001; 345: 1655-1659.)
Available treatment modalities
Options for chemotherapy and endocrine-based approaches are limited, and no hormonal or chemotherapeutic regimen is accepted as a standard of care. Therefore, various biologic therapies have been evaluated. New agents, such as sorafenib and sunitinib, having anti-angiogenic effects through targeting multiple receptor kinases, and have been investigated in patients failing immunotherapy.
Role of Surgery
Palliative nephrectomy should be considered in patients with metastatic disease for alleviation of symptoms such as pain, hemorrhage, malaise. Several randomized studies are now showing improved overall survival in patients presenting with metastatic kidney cancer who have nephrectomy followed by either interferon or IL-2. If the patient has good physiological status, then nephrectomy should be performed prior to immunotherapy. There are anecdotal reports documenting regression of metastatic renal cell carcinoma after removal of the primary tumor but adjuvant nephrectomy is not recommended for inducing spontaneous regression; rather, it is performed to decrease symptoms or to decrease tumor burden for subsequent therapy in carefully controlled environments. About 25-30% of patients have metastatic disease at diagnosis, and fewer than 5% have solitary metastasis. Surgical resection is recommended in selected patients with metastatic renal carcinoma. This procedure may not be curative in all patients but may produce some long-term survivors. The possibility of disease-free survival increases after resection of primary tumor and isolated metastasis excision.
Radiation therapy may be considered as the primary therapy for palliation in patients whose clinical condition precludes surgery, either because of extensive disease or poor overall condition. A dose of 4500 centigray (cGy) is delivered, with consideration of a boost up to 5500 cGy. Preoperative radiation therapy has not been found to yield any survival advantage. Controversies exist concerning postoperative radiation therapy, but it may be considered in patients with peri-nephric 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. Stereotactic radiosurgery is more effective than surgical extirpation for local control and can be performed on multiple lesions.
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. A recent phase 2 trial of weekly intravenous gemcitabine (600 mg/m2 on days 1, 8, and 15) with continuous infusion 5-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. The role of chemotherapy is questionable with limited efficacy and more morbidity.
Many immune modulators, such as interferon, interleukins (IL-2), vaccination, lymphokine-activated killer (LAK) cells plus IL-2, tumor-infiltrating lymphocytes, and non-myeloablative allogeneic peripheral blood stem-cell transplantation, have been tried.
A : Interferons -The interferons are natural glycoproteins with antiviral, anti-proliferative, and immuno-modulatory properties. They have a direct anti-proliferative 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.
Interlukin -IL-2 is a T-cell growth factor and activator of T cells and natural killer cells. It hampers tumor growth by activating lymphoid cells in vivo without directly affecting tumor proliferation. It can be administered as high dose and low dose regimen.
A high-dose regimen (600,000-720,000 IU/kg q8h for a maximum of 14 doses) results 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. 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 therapeutic benefit and can be eliminated from the treatment. Combination HD IL-2/IFN alfa slightly has been reported to be slightly better than HD IL-2 alone (Rosenberg SA, et al. N Engl J Med. 1987;316:889-897). The interferons can be given as inpatient, subcutaneous, and home-administered regimens.
Toxicity is dose dependent. Most common dose dependant toxicity is hypotension requiring vasopressors. Also malaise, diarrhea, pyrexia, and rashes are commonly reported toxicities.
Approved for treatment of patients with metastatic RCC.
Durability of response: Approximately 60% of CRs remain disease free at > 10 yrs follow-up
Prognostic factors for favorable response with IL-2 and IFN alfa therapy
ECOG performance status (0 vs ≥ 1)
Time from diagnosis to treatment (≤ 12 mos)
Number of metastatic sites (1 vs ≥ 2)
(Canobbio L, et al. J Cancer Res Clin Oncol. 1995;121:753-756
B: cG250 THERAPY:
Immunotherapy targeting for the induction of a T-cell-mediated antitumor response in patients with RCC appears to hold significant promise. G250, a widely expressed RCC associated antigen; and granulocyte/macrophage-colony stimulating factor (GM-CSF), an immunomodulatory factor for antigen-presenting cells. The G250-GM-CSF fusion gene was constructed and expressed in Sf9 cells using a baculovirus expression vector system. The purified FP retains GM-CSF bioactivity, which is comparable, on a molar basis, to that of recombinant GM-CSF when tested in a GM-CSF-dependent cell line. When combined with interleukin 4, it induced differentiation of monocytes (CD14+) into dendritic cells (DCs) expressing surface markers characteristic for antigen-presenting cells. Up-regulation of mature DCs with enhanced expression of HLA class I and class II antigens was detected in FP-cultured DCs as compared with DCs cultured with recombinant GM-CSF. Treatment of peripheral blood mononuclear cells (PBMCs) with FP alone (2.7 microg/10(7) cells) augments both T-cell helper 1 (Th1) and Th2 cytokine mRNA expression (IL-2, IL-4, GM-CSF, IFN-gamma, and tumor necrosis factor-alpha). Comparison of various immune manipulation strategies in parallel, bulk PBMCs treated with FP (0.34 microg/ml) plus IL-4 (1000 units/ml) for 1 week and restimulated weekly with FP plus IL-2 (20 IU/ml) induced maximal growth expansion of active T cells expressing the T-cell receptor and specific anti-RCC cytotoxicity, which could be blocked by the addition of anti-HLA class I, anti-CD3, or anti-CD8 antibodies. In one tested patient, an augmented cytotoxicity against lymph node-derived RCC target was determined as compared to that against primary tumor targets, which corresponded to an 8-fold higher G250 mRNA expression in lymph node tumor as compared with primary tumor. The replacement of FP with recombinant GM-CSF as an immunostimulant completely abrogated the selection of RCC-specific killer cells in peripheral blood mononuclear cell cultures. All FP-modulated peripheral blood mononuclear cell cultures with antitumor activity showed an up-regulated CD3+CD4+ cell population. These results suggest that GM-CSF-G250 FP is a potent immunostimulant with the capacity for activating immunomodulatory DCs and inducing a T-helper cell-supported, G250-targeted, and CD8+-mediated antitumor response. These findings may have important implications for the use of GM-CSF-G250 FP as a tumor vaccine for the treatment of patients with advanced kidney cancer
With the better understanding of molecular biology of the tumor and the mechanisms of tissue invasion and metastasis, various agents targeting the angiogenesis have been tried in the treatment of metastatic RCC.
A: NEOVASTAT(Marketed in India as Requar Powder)
Neovastat is a naturally occurring anti-angiogenic compound, extracted from shark cartilage, with multiple anti-angiogenic mechanisms of action that provide broad therapeutic potential for a number of diseases. It is currently in international Phase III trials for renal cell carcinoma and non-small-cell lung cancer. Neovastat is administered orally and can be used alone or in combination with other therapies.
Anti-angiogenic mechanisms of Neovastat
1. Blocking VEGF binding.
Studies reveal that Neovastat contains a component that specifically prevents the binding of VEGF (Vascular Endothelial Growth Factor) to its receptors. The prevention of the binding of VEGF to its receptors is an important factor in the prevention and containment of tumor growth. .
2. Inhibiting MMP’s.
Results of studies reveal strong inhibition of gelatinolytic and elastinolytic activities for MMP-2, MMP-9, and MMP-12. The MMP's are often over expressed in tumors and play an important role in the degradation of the matrix that surrounds the cell (extracellular matrix), which allows tumor growth and invasion (metastasis).
3. Induction of endothelial cell specific apoptosis.
Induction of apoptosis (programmed cell death) is an additional Anti angiogenic activity found in Neovastat. The induction of endothelial cell apoptosis by Neovastat may thus prevent the formation of new blood vessels.
4. Increase in the level and the activity of tissue-type plasminogen activator (t-PA).
Data from an experimental study (glioblastoma) shows that Neovastat is capable of increasing the level and activity of t-PA from endothelial cells present within the tumor. The t-PA may induce the disintegration of blood vessels present inside the tumor.
5. Anti-metastatic properties:
Results of animal studies of the effect of Neovastat on lung metastasis show a significant decrease in the number of lung nodules when Neovastat was used alone or in combination with Cisplatin. Neovastat was also shown to decrease bone metastasis in mice.
Studies performed with a mouse model of breast cancer (DA3 adenocarcinoma) demonstrates that oral administration of Neovastat for 54 days inhibits the progression of tumor volume by 60% compared to the control group. In experimental glioblastoma implanted in the brain, Neovastat was shown to significantly increase mice survival.
Neovastat has shown a consistently excellent safety and tolerability profile in clinical studies involving more than 850 patients. Some patients have been receiving treatment for almost four years.
Survival benefit in patients with renal cell carcinoma (RCC): Among the patients included in a Phase II open-label trial, a prospective survival analysis was performed in 22 patients with metastatic RCC refractory to standard therapies or for whom no treatment was available. Patients were treated with 60 ml/day (8 patients) or 240 ml/day (14 patients). Median survival time in patients receiving 240 ml/day has been found significantly longer as compared to the median survival time in patients receiving 60 ml/day (16.3 vs 7.1 months; p=0.01)
Thalidomide is reported to suppress levels of several cytokines, angiogenic growth factors including TNF- , basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6). The resulting anti-angiogenic, immunomodulatory and growth suppressive effects form the rationale for investigating thalidomide in the treatment of malignancies. Studies have been carried out where high dose thalidomide have been administered to the patients with renal cell carcinoma (600 mg daily).Thalidomide has been given to patient s who are refractory to the immunotherapy. The partial response occurs in 9-10% patients with 30-50% patients show stable disease for a period ranging from 6 -12 months.
Other experimental approaches
Other therapies which hold promise include immunomodulatory allogeneic peripheral blood stem-cell drugs, vaccines, and nonmyeloablative 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. Several tumorcell and dendritic cell based vaccines are in clinical trials now-a-days. Potential DC activators include HSP (Heat Shock Protein), dead cells, bacterial products etc. HSPPC-96(HSP-peptide complex -96) is currently in phase 3 trials.
Another strategy to augment the immune system include using anti-CTLA-4 (cytotoxic T-lymphocyte associated antigen-4) to block the suppression of the lymphocyte activity. Gene modified autologous tumor cell expressing B-7-1(CD-80), a T-cell co-stimulatory molecule, combined with systemic IL-2 also represent a safe and active biological approach. Due to its critical role in RCC biology CA-9 has been exploited as a potential target for immunotherapy. CA-9 based vaccine strategy is currently being developed, including granulocyte-macrophage colony stimulating factor-CA 9 fusion protein vaccine in an attempt to enhance immunogenic activity of CA-9.
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.
Multiple studies have been conducted using megestrol (Megace) in the treatment of renal cell carcinoma. No benefit has been shown except for appetite stimulation, so megestrol currently is not recommended. Antiestrogens such as tamoxifen (100 mg/m2/d or more) and toremifene (300 mg/d) also have been tried, with a response rate as low as that of most chemotherapeutic agents.
Binding antibodies to the VEGF protein
VEGF receptor inhibitors
Others under investigation (eg, valatinib, axitinib)
A recombinant anti-VEGF antibody created by transferring the VEGF-binding regions of the murine antibody to a humanized IgG1 framework (93% human, 7% murine). Produces a humanized IgG. Mediates blockade of VEGF protein (ligand). Binds and neutralizes all biologically active isoforms of VEGF.
Advanced and metastatic renal cell cancer (RCC) is resistant to conventional chemotherapy. Only a very small number of patients survive long term after immunotherapy. However, any effect of interleukin-2 (IL-2) and/or interferon on median overall survival is small, and treatment-associated toxicities may be severe. The disease is therefore an area of high unmet medical need. Activation of the VEGF and EGF/RAS/RAF/MAP kinase pathways is frequent in solid tumours such as RCC. Such activation is implicated in tumour angiogenesis and proliferation. VEGF and EGF receptors and molecules (such as RAF kinase) involved in downstream signalling are therefore potential appropriate targets for drug therapy. Several antibodies and low molecular weight tyrosine kinase inhibitors (TKIs) have completed phase II clinical trials. Phase II studies of multitargeted agents, which include inhibition of VEGFR tyrosine kinase in their repertoire (sorafenib, sunitinib and AG 013736), show clear second-line activity in metastatic RCC. The same is true of the anti-VEGF antibody, bevacizumab. In a randomised phase III comparison against placebo in pretreated patients, sorafenib doubled median progression free survival (24 versus 12 weeks). Studies now in progress will determine whether benefits seen second-line will also be evident first-line, and whether the activity of novel agents can be increased by combining them with each other, with cytokines, or with chemotherapy
Sorafenib. 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 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 < 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. 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-, 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 and . 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-, 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