Despite definitive treatment with nephrectomy, locally advanced renal cancer recurs in 20%–30% of patients, substantially reducing their chance for long-term survival. To prevent such recurrences and prolong survival, urologic oncologists are studying the integration of targeted molecular therapies with surgical treatments.
Patients with metastatic disease surviving longer
The new approaches for locally advanced renal cancers have emerged from what has been learned by treating metastatic disease.
Targeted therapies fight cancer by inhibiting proteins such as vascular endothelial growth factor receptors and tyrosine kinases that stimulate tumor angiogenesis or promote tumor growth in other ways.
Since the introduction of these agents for the treatment of renal cancer, said Christopher Wood, M.D., a professor in the Department of Urology at The University of Texas MD Anderson Cancer Center, “Many patients with metastatic disease are living significantly longer than expected; the overall survival time has more than doubled. Some of these patients are now living for years, whereas before the median survival was less than 1 year.”
Targeted therapy for locally advanced disease
The promising results of targeted therapy in patients with metastatic renal cancer prompted urologic oncologists to ask whether targeted agents could be effective in prolonging survival in patients with nonmetastatic disease. For these patients, surgery in the form of partial or radical nephrectomy offers a chance at a cure; however, the disease may recur after surgery, significantly shortening survival.
The first trials of the targeted agents in nonmetastatic renal cancer looked at their effectiveness in the adjuvant therapy setting (i.e., after resection) with the goal of decreasing risk of recurrence. The final results of these trials have not yet been reported, but the investigators agree on one point: the targeted agents were not well tolerated after surgery, especially for a prolonged duration.
Dr. Wood said, “Many patients were not able to tolerate the toxic effects while recovering from surgery and had to take a lower dose or drop out altogether. Others were not willing to tolerate the agents’ toxic effects in the face of a recurrence risk of only 20%–30%.”
These findings led the researchers to test the agents in the neoadjuvant therapy setting (i.e., before surgery) in patients whose tumors were considered resectable.
The neoadjuvant therapy approach in these patients has several potential benefits: elimination of micrometastatic disease, which may decrease the chance of recurrence and prolong survival; shrinking of the primary tumor, which might allow a change in the surgical approach to nephron-sparing partial nephrectomy rather than radical nephrectomy or from open surgery to a minimally invasive approach; and conversion of an unresectable tumor to a resectable one.
One risk of the neoadjuvant therapy approach is that the toxicity of the targeted agent might debilitate patients to the extent that surgery would be more difficult for them. Also, because many targeted agents are antiangiogenic, they may interfere with postoperative wound healing. This is a formidable problem if surgery is “sandwiched” between two periods of targeted therapy.
In the early neoadjuvant therapy trials, patients with locally advanced or metastatic renal cancer were treated with a targeted agent, underwent surgery, and then resumed targeted therapy as soon as possible afterward. The goal of these early trials was to determine whether this approach was safe and effective in preventing recurrence.
Dr. Wood said, “These trials showed that the agents generally were better tolerated as neoadjuvant therapy than as adjuvant therapy. They also showed that the tumor’s response to the therapy was a good litmus test for whether the patient was likely to benefit from surgery.”
Tumors that progressed while the patient was receiving targeted therapy were considered unlikely to be curable by surgery, while tumors that remained stable or, better yet, shrunk were considered very likely to be curable by surgery.
Neoadjuvant axitinib shrinks locally advanced tumors
While the results of the early trials of neoadjuvant targeted therapy for advanced renal cancer were promising, they were not as persuasive as they could have been because the trials’ broad selection criteria did not allow researchers to assess treatment efficacy according to tumor resectability or specific tumor subtypes or stages. Also, patients in these studies received varying doses, which allowed researchers to assess safety but limited the efficacy data for each dose. In 2010, Dr. Wood and his colleagues at MD Anderson initiated a trial designed to address these limitations by standardizing patient selection criteria and treatment.
“While there was nothing new about neoadjuvant targeted therapy, this trial was different than the trials that had been reported up until that point,” said Jose Karam, M.D., an assistant professor in the Department of Urology and the lead author on the initial report of the trial, which was published in European Urology earlier this year. “It was a prospective trial focused on a very specific group of patients: those with stage II or III, biopsy-proven clear cell renal cell carcinoma—the most common type of renal cell carcinoma.”
The therapy, the tyrosine kinase inhibitor axitinib, was initiated in all patients at the same dose and schedule. Not only was the duration of therapy standardized, at 12 weeks, but the time between stopping therapy and undergoing surgery also was standardized, at 36 hours. The standardized approach increased the likelihood that any effects observed were actually due to the study drug.
The 12-week treatment duration was chosen on the basis of previous study findings. “We looked at previous trials, most of which had much longer treatment intervals, and noticed that, in most patients who had a response to the targeted agent, that response occurred within the first 60–90 days of treatment,” Dr. Wood said. “The data indicated overwhelmingly that if there was no response in the first 90 days, there wasn’t going to be a response.”
The results of the axitinib trial were exciting: while the objective response rate by internationally accepted statistical criteria was 46%, 100% of the tumors showed some degree of shrinkage, and the median extent of this shrinkage was 28%. The mean tumor diameter decreased from 10.0 cm to 6.9 cm. None of the patients had evidence of progressive disease during the treatment period. In addition, no complications that could be attributed to the study drug were encountered during or after surgery.
The trial also showed that, owing to its tumor-shrinking effects, neoadjuvant axitinib reduced the extent of surgery for some patients. Five of the 24 patients in the trial were able to undergo partial nephrectomy rather than radical nephrectomy; and of the 19 radical nephrectomies, 5 were accomplished by a minimally invasive approach.
“We chose tumor shrinkage as the study endpoint in the axitinib trial because it is an objective measure,” Dr. Wood said. He pointed out, however, that some questions remain unanswered. “While the substantial tumor shrinkage we observed seems beneficial, is it clinically meaningful? Does shrinking tumors by 28% allow us to do significantly more partial nephrectomies or more laparoscopic nephrectomies? Does it translate to fewer recurrences or longer survival? We will learn that only through more clinical trials.”
“The conversion from radical nephrectomy to partial nephrectomy was meaningful for patients, but they all started the trial with a resectable tumor,” Dr. Karam said. “We envision that, ultimately, tumors that are initially considered unresectable might become resectable with neoadjuvant targeted therapy. This could change the outlook for a lot of patients with ‘unresectable’ disease.”
Resectability and surgical approach
The choice of surgical approach is a subjective judgment by the urologists evaluating the case. Criteria for partial nephrectomy can vary among institutions and from urologist to urologist within an institution. This variability complicates attempts to draw conclusions from clinical trial results. Dr. Karam said, “The axitinib trial had an independent radiologist reviewer who documented tumor size on each scan, but determination of surgical approach at the end of treatment was up to the urologists.” Drs. Wood and Karam and some of their colleagues are undertaking a study that will attempt to improve understanding of the criteria urologists use to determine which renal tumors are suitable for partial nephrectomy.
Drs. Wood and Karam are asking colleagues at other centers to independently evaluate computed tomography images from the axitinib trial and say whether a partial nephrectomy approach is appropriate for each tumor. The evaluating urologists will be blinded to the patients’ identities and characteristics and to the timing of the imaging studies. Drs. Wood and Karam hope to obtain information that can be applied to establish more objective criteria for determining surgical approach in clinical trials.
Drs. Wood and Karam emphasized that the neoadjuvant therapy approach to locally advanced renal cancer is not ready for general oncologic practice. Although the axitinib trial showed that neoadjuvant targeted therapy is safe and effective at reducing tumor size, the trial was small and limited to one cancer center. Only larger trials at multiple cancer centers can confirm that neoadjuvant targeted therapy prolongs recurrence-free survival.
While no clinical trials of neoadjuvant targeted therapy in patients with locally advanced renal cancer are currently under way at MD Anderson, Drs. Wood and Karam and their colleagues are planning more phase II trials that will look at recurrence rate and survival in these patients as well as combinations of targeted agents or of a targeted agent with an immune checkpoint inhibitor. These studies will culminate in a phase III trial that the researchers hope will determine the role of neoadjuvant targeted therapy for locally advanced renal cancer.
One of the most important questions in targeted therapy is how to determine which patients will benefit from which agent or combination of agents. Dr. Karam said, “One of the advantages of a prospective trial like the axitinib trial is that we were able to build into the trial a strategy for systematic collection of patient tissue and fluid specimens through all stages of treatment and follow-up.” Drs. Wood and Karam and their collaborators at MD Anderson’s Institute for Personalized Cancer Therapy are now analyzing these samples to identify molecular biomarkers that might help identify and select patients most likely to benefit from neoadjuvant axitinib.
“This is the great promise of targeted therapy,” Dr. Karam said, “and the data we are generating from this trial should be a big help in designing better targeted therapeutic strategies for patients with renal cancer in the future.”
For more information, contact Dr. Christopher Wood at 713-792-3250 or Dr. Jose Karam at 713-745-0374.
OncoLog, October 2014, Volume 59, Issue 10