The emergence and development of multiple VEGF pathway and mTOR inhibitors for metastatic renal cancer has revolutionized our approach to treatment and provides greater hope than ever for these patients.
It has nevertheless created confusion amongst practitioners, since there are such a variety of options; there are only a handful of well-performed trials to guide evidenced-based practice, the available trials do not address many of the common clinical questions; and the disease is highly variable and heterogeneous, thus necessitating a highly individualized approach.
Furthermore, metastatic renal cancer is sufficiently uncommon that individual physician experience with the variety of presentations and the various therapeutic options is sometimes limited.
The first major issues I consider when seeing a patient with metastatic renal cancer for the first time are the histologic subtype and whether the primary tumor is still in place.
While the majority of renal cancers are conventional (clear cell), a variety of more unusual subtypes including papillary, chromophobe, collecting duct, and translocation tumors have been described. These variants comprise approximately 10 to 15 percent of the patients with metastatic disease.
Of note, pathologic expertise in recognizing these subtypes is variable, and unless the reviewing pathologist is a genitourinary cancer expert, I generally suggest a second pathologic opinion whenever the possibility of a non-clear cell variant is raised.
Unfortunately, there is no good evidence-based medicine guiding therapy of metastatic non-clear cell renal cancer. Although management in a manner similar to that described below for clear cell renal cancers is often appropriate, referral to an institution with experience in renal cancer should be considered.
In regards to nephrectomy in patients with metastatic disease, there are once again no rigorous studies to define practice in the context of modern systemic treatments.
My general rule of thumb is that if the patient has an excellent performance status, at least half of the total tumor burden is contained within the primary, or if high-dose interleukin-2 is being considered, then nephrectomy should be performed first.
The next unique situation to consider is the patient who has only one or two metastatic sites. Especially if there has been a long interval between primary nephrectomy and the development of metastases, surgical resection or other definitive ablative therapy should be considered.
In exceptional circumstances more than two lesions can be considered for such an approach -- more typically with palliation rather than long-term disease control in mind.
The next issue to consider is the timing of treatment.
Patients with good prognostic features (asymptomatic, a long interval between nephrectomy and disease recurrence, and normal laboratories) can often have a very long natural history even in the absence of any therapy. A period of active surveillance to assess tumor growth rate and to potentially delay toxic therapy is often indicated.
Once I elect to proceed with systemic therapy for a metastatic clear cell renal cancer, a number of options can be considered. In this era of multiple therapies, often marketed heavily by the pharmaceutical industry, it is easy to forget about high dose IL-2. This remains the only therapy for which long-term complete responses and apparent cure have been described. Although such a favorable outcome occurs in only five to seven percent of highly selected patients, additional patients experience dramatic responses with likely clinical benefit.
There is some limited evidence that use of high-dose IL-2 in a post VEGFR tyrosine kinase inhibitor treatment scenario is more toxic and less effective.
I thus generally recommend that if high-dose IL2 is considered, it should be the initial therapy. Because of the toxicities, I generally limit this treatment to patients with excellent performance status, normal cardiorespiratory status, and who are under the age of 60.
It is also critical that this therapy be administered at an institution with extensive experience utilizing this treatment so that morbidity and treatment-related mortality are minimized.
Once I choose to begin therapy with one of the newer VEGF or mTOR targeted agents I find there is a certain degree of consternation amongst patients and my colleagues as to which specific agent to start. Given the lack of comparative data, and the evidence that sequential therapies can have clinical activity, this is, in my opinion, not particularly important.
There are Phase III data that patients with poor-prognosis disease have a survival advantage with temsirolimus, and given the rather limited Phase III data for poor-prognosis patients utilizing VEGF pathway inhibitors. This would likely be my first choice in such a patient.
For VEGF pathway inhibitor therapy, it is my opinion that dose intensity and aggressive management of the myriad toxicities associated with these drugs is critical. It is sobering to note that duration of treatment in the definitive Phase III trials is typically much longer than duration of treatment derived from post-marketing studies.
Whether shorter durations of treatment and lower doses will have the same efficacy has not been tested, and thus I utilize full doses and prolonged therapy whenever possible.
Because of the long natural history, aggressive management to prevent morbidity from locally aggressive disease is often indicated. This is especially critical for bone and central nervous system metastases.
Because of the relative radioresistance of renal cancer, I am typically quite aggressive with surgery and stereotactic radiosurgery.
I additionally utilize bisphosphonates for prevention of further bony morbidity in patients with bone metastases.
Finally, I make a brief note on radiologic follow-up of patients. I generally do not perform routine brain imaging in the absence of any symptoms.
I also do not routinely utilize bone scans and FDG-PET scans due to their limited sensitivity. I do carefully review all x-rays and CT scans with particular attention to historical scans to assess changes in tumor burden over a greater time frame than just the interval since the last radiologic examination.
WALTER STADLER, MD, is the Fred C. Buffett Professor of Medicine & Surgery in the Sections of Hematology/Oncology & Urology at the University of Chicago