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By David Quinn, PhD, MBBS, FRACP

The last decade has seen remarkable advances in the options available for treating metastatic renal cell carcinoma (RCC). New drugs have been developed that can starve tumor cells and cause extensive tumor shrinkage. At the same time, immunotherapy offers the possibility of durable cures for some patients.

RCC begins with a single tumor originating in the kidney. But some tumor cells may spread, or metastasize, thus allowing new tumors to grow in other parts of the body. While some tumors can be removed by surgery, metastatic RCC often requires the use of systemic treatments, which are drugs that circulate throughout the body.

The increased range of treatment choices has been very beneficial to the RCC community. But as a patient with metastatic disease, you may feel overwhelmed by the many treatment options.

My aim is for this article is to describe the available systemic therapies and to help you understand the potential risks and benefits of each option. Patients can use this brief guide to talk with their doctor about available treatments and play an active part in selecting the most appropriate treatment for their situation.

What treatments are available for me?

Most patients have a type of RCC called “clear cell” RCC. This article focuses on treatment for clear cell disease, but some of these treatments are also appropriate for patients with non-clear cell disease.

Some patients may have only a single metastatic tumor that can be removed by surgery. But most patients with metastatic disease have tumors in many parts of the body. In order to treat all of these tumors, patients are given systemic therapies, which are drugs that travel through the bloodstream and can directly reach cells throughout the body.

Immunotherapy is a type of treatment that gives a boost to the immune system. The goal of immunotherapy is to help the patient’s immune system attack the cancer cells. Immunotherapy treatments have been available for decades and have generated renewed interest for treating metastatic RCC patients. Two types of immunotherapy may be used for treating patients with metastatic RCC: interleukin-2 (IL-2), which is given intravenously, and interferon (IFN), which is injected under the skin.¹

Several systemic therapies available for RCC patients are called “anti-angiogenic” drugs. During angiogenesis, tumors create blood vessels inside the tumor. These blood vessels supply nutrients and help the tumor to grow. Anti-angiogenic drugs can help to reduce the growth of tumor blood vessels, which in turn can make the tumor stop growing or shrink. Anti-angiogenic drugs that are used for treating RCC include sunitinib, pazopanib, sorafenib, and axitinib.¹ All of these drugs come in a tablet or pill form and are taken by mouth.

Bevacizumab is another type of anti-angiogenic drug that is appropriate for some metastatic RCC patients. Patients who are treated with bevacizumab are treated with IFN at the same time.¹ Bevacizumab is given intravenously.

Temsirolimus and everolimus are two drugs that attack a specific molecule that helps cancer cells to grow and proliferate. Temsirolimus is administered intravenously and everolimus is a tablet.

How to choose the best first-line therapy

The first treatment that you receive for your metastatic RCC is called “first-line” or “front-line” therapy.

When thinking about which treatment is best for you, it is helpful to keep the following questions in mind:

• How is the treatment delivered?
• How long does the treatment last?
• What are the chances of achieving a cure?
• What are the possible side effects?

These questions will help you discuss your treatment options with your doctor to help determine which treatment makes the most sense for you.

IL-2 immunotherapy

For an appropriate candidate, one first-line option may be Interleukin-2, also known as IL-2. IL-2 is the only systemic treatment that has been proven to cure metastatic RCC in some patients. For example, in phase II clinical trials, 7% of the patients experienced a complete response, meaning that there was no evidence of their RCC disease after they received IL-2 treatment.² For some of these patients, the response lasted a long time, with a median response duration of over 80 months.

Patients who do not experience a complete cure may have a partial response to IL-2 treatment. In the studies mentioned above, 8% of the patients experienced a partial response. Again, the response tended to last a long time, with a median response duration of 20 months.

Because IL-2 must be given in a high dose, some patients may experience side effects that could be severe or life-threatening. However, most of these side effects can be managed with the right treatment. Therefore, it is extremely important that IL-2 is administered at a recognized high dose IL-2 treatment center, by a team of experienced oncology experts who know how to manage a patient’s side effects during and immediately after treatment.

IL-2 treatment occurs in a hospital setting. The therapy involves 5 days of treatment, 9 days of rest, and then another 5 days of treatment. In contrast, the treatments described below are ongoing.

Oral anti-angiogenic drugs

Sunitinib, sorafenib, and pazopanib are other first-line treatment options. These therapies may prevent existing tumors from growing and may cause tumor shrinkage in some patients.^3-5 This effect can help to reduce the pain or other symptoms caused by the tumor. In a phase II clinical trial of sorafenib as first-line treatment in patients with metastatic RCC, the patients who received sorafenib reported fewer symptoms, higher quality of life, and better treatment satisfaction in comparison to the patients who received treatment with IFN in the same trial.³

Side effects from the oral anti-angiogenic drugs vary. Some common side effects seen with these drugs include diarrhea, hypertension, and fatigue. These side effects are usually mild and the more severe side effects can be managed in most patients.

These drugs are a good treatment options for many patients with metastatic RCC, including patients for whom IL-2 treatment is not an option.

Bevacizumab plus IFN

In patients with metastatic RCC, treatment with bevacizumab and IFN has been shown to increase the time of progression-free survival (PFS) in comparison to treatment with IFN alone.⁶ PFS is the time a patient is alive and the disease is not getting worse—in other words, tumors are not growing larger and may actually be shrinking. Fatigue and physical weakness were the most common severe side effects for patients receiving either treatment, and the side effects were mild for most patients. Like the oral anti-angiogenic drugs, bevacizumab plus IFN has not been shown to induce long-term cures in patients with metastatic RCC and is a good option for patients who are not candidates for IL-2 treatment.

Temsirolimus

Temsirolimus was evaluated in a phase III clinical trial of patients with metastatic RCC and a poor prognosis. In this trial, temsirolimus improved median overall survival compared to treatment with IFN.⁷ Median overall survival was 10.9 months for patients who received temsirolimus and was 7.3 months for patients who received IFN. In other words, the patients who received temsirolimus tended to live longer than those who received IFN.

The most common side effects in patients who received temsirolimus were physical weakness, rash and anemia. Serious side effects were less common in patients who received temsirolimus compared to those who received IFN, and most side effects were manageable.

Temsirolimus is a reasonable first-line treatment option for patients with factors that suggest a poor prognosis, such as anemia and other factors that can be determined by your doctor.

Other treatment options

Some patients may wish to consider enrolling in a clinical trial that is testing treatments for patients with metastatic RCC. Ask your doctor about clinical trials that may be appropriate for you. Each clinical trial is designed with a specific focus, and your doctor can help you find out if a clinical trial is appropriate for your situation.

Patients may also choose supportive care, which can include surgery, radiation therapy, systemic drugs, or a combination of these. The goal of supportive care is to relieve the symptoms, such as pain, associated with metastatic disease.

Second-line treatment

Often, when first-line treatment stops working, a different drug or treatment strategy can still attack the cancer cells.

There is strong evidence that, for patients who received first-line immunotherapy such as IL-2, sorafenib or axitinib can be an effective second-line agent.^8,9

There is also strong evidence that, for patients who received first-line sunitinib or sorafenib, everolimus can be an effective second-line treatment.⁹

If your first-line treatment was temsirolimus, your second-line treatment would likely be an oral anti-angiogenic drug. However, it is not clear how effective these oral anti-angiogenic drugs are as second-line therapy.¹

Treatment options on the horizon

Ongoing clinical trials are investigating the drugs described above as first- and second-line therapies, as well as testing new agents. Dovitinib and tivozanib are two new oral anti-angiogenic drugs being tested in clinical trials of patients with metastatic RCC. In a randomized phase III registration trial, first-line tivozanib yielded a superior PFS compared to sorafenib in patients with advanced RCC.¹⁰ FDA approval of tivozanib is being sought in 2012. Other experimental therapies under investigation include vaccine therapy, which attempts to induce an immune reaction against the patient’s own cancer cells, and a new immunotherapy called anti-PD-1. These treatments may become available after clinical trials have been completed.

Summary

Treatment options for patients with metastatic RCC have expanded dramatically during the last decade. And as a patient with metastatic RCC, you deserve to get the best treatment available. By discussing the various treatment options with your doctor, you will be able to take part in choosing the most appropriate treatment for your condition.

REFERENCES

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines). Kidney Cancer. Version 1.2012. 2011.

2. Fisher RI, Rosenberg SA, Fyfe G. Long-term survival update for high-dose recombinant interleukin-2 in patients with renal cell carcinoma. Cancer J Sci Am. 2000;6 Suppl 1:S55-57.

3. Escudier B, Szczylik C, Hutson TE, et al. Randomized phase II trial of first-line treatment with sorafenib versus interferon Alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol. 2009;27:1280-1289.

4. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol. 2010;28:1061-1068.

5. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med. 2007;356:115-124.

6. Escudier B, Pluzanska A, Koralewski P, et al. Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: a randomised, double-blind phase III trial. Lancet. 2007;370:2103-2111.

7. Hudes G, Carducci M, Tomczak P, et al. Temsirolimus, interferon alfa, or both for advanced renal-cell carcinoma. N Engl J Med. 2007;356:2271-2281.

8. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet. 2011;378:1931-1939.

9. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456.

10. AVEO and Astellas announce tivozanib successfully demonstrated progression-free survival superiority over sorafenib in patients with advanced renal cell cancer in phase 3 TIVO-1 trial. AVEO Pharmaceuticals web site, 2012. (Accessed January 16, 2012, at http://aveopharma.com/product_candidates/tivozanib_av-951/.)