Some patients with slow-growing metastatic renal cell carcinoma can be safely treated with a "watch and wait" approach, which allows them to avoid the toxicity of noncurative systemic therapy for months or even years, say researchers.
"There is a perception that all cancers should be treated immediately because they are equally lethal. But what we've seen in this small phase 2 study is that a subset of adults with advanced kidney cancer have slow-growing disease that can be safely managed using active surveillance, which could spare them the inconvenience and debilitating side effects of aggressive treatments for about a year, and in some cases, several years," lead author Brian I. Rini, MD, professor of medicine at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Ohio, commented in a statement.
The phase 2 trial, which enrolled 52 patients, is ongoing, but initial results were published online August 3 in the Lancet Oncology.
The team reports that 29 patients who had ≤2 sites of metastatic disease and ≤1 poor prognosis factors, such as anemia or thrombocytosis, were able to safely remain on active surveillance for an average of 22.2 months.
This compared with an average of 8.4 months in 19 patients with more disability.
Many patients who discontinued surveillance went on to receive subsequent systemic therapy. The median overall survival from the start of surveillance for the 31 patients who received systemic therapy was 38.6 months, the researchers note.
Concerns about central nervous system progression were successfully addressed with routine CT imaging during surveillance. Moreover, the watchful waiting approach did not negatively affect patients' quality of life or make them feel overly worried, anxious, or depressed.
"To our knowledge, this is the first prospective assessment of observation for patients with metastatic renal-cell carcinoma," the researchers note.
They conclude that "for some select patients with metastatic renal carcinoma, active surveillance might be the optimum approach to avoid the certain toxicity of systemic therapy without clearly compromising the benefit of therapy when initiated."
Experts Agree: Treatment Can Be Deferred
Approached for comment, Gurkamal Chatta, MD, professor of oncology and clinical chief of genitourinary medicine at Roswell Park Cancer Institute in Buffalo, New York, said the study, although small, was "very useful."
"As long as patients are carefully selected with agreed-to criteria, treatment can definitely be deferred and unnecessary toxicity can be avoided," he told Medscape Medical News
Dr Chatta emphasized that "the results of this study need to be validated in a larger cohort of patients to make this practice changing."
Consensus guidelines are needed about patient stratification, as recommended and already performed at many institutions using the Memorial Sloan Kettering Cancer Center (MSKCC) risk score and Heng prognostic criteria, he explained. Stringent criteria for deferral in good-risk patients are also needed.
In an interview, Toni K. Choueiri, MD, associate professor of medicine at Harvard Medical School and director of the Kidney Cancer Center at the Lank Center for Genitourinary Oncology, Dana- Farber Cancer Institute, Boston, Massachusetts, called the study "important and relevant" to the clinical care of patients with metastatic renal cell carcinoma.
"This paper will reassure physicians and patients that observation, when appropriate, is an option," Dr Choueiri told Medscape Medical News.
Clinically, patients with fewer adverse clinical factors, as determined on the basis of International Metastatic Database Consortium (IMDC) criteria, appear to be the best candidates for observation. Those with less immune suppression appear to be good candidates from a biologic perspective, he points out.
Close follow-up as well as evaluation of symptoms are key to optimal timing of systemic therapy, Dr Choueiri said. Also important is frank discussion with patients about the pros and cons of deferring therapy, he added: "At the end of the day, therapies are palliative even if they extend survival."
"This paper provides guidance to both medical and surgical oncologists," writes Paul Russo, MD, in an accompanying editorial. Dr Russo is with the Urologic Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, Weill Cornell College of Medicine, in New York City.
"There is no evidence from this study that such a period of close surveillance jeopardizes the patient's safety or survival," Dr Russo points out. "Although no patients were cured," he adds, "they achieved a degree of prolonged survival not imaginable a generation ago."
Balancing the patient's desire for active intervention with treatment delay takes "a calm presentation of data such as these," he says. The decision-making for deferral in this study "relied on this important physician-patient relationship."
Whether genes can be identified to further refine selection of patients suitable for initial surveillance "remains to be seen," Dr Russo says.
Details of the Study
In the trial, which is ongoing, 52 patients with treatment-naive, asymptomatic, metastatic renal cell carcinoma from five hospitals in the United States, Spain, and the United Kingdom were enrolled between August 21, 2008, and June 7, 2013. Patients were offered close surveillance with frequent CT imaging and the option of initiating systemic therapies at any time.
Of 48 patients included in the analysis, median time on surveillance was 14.9 months. The median tumor growth rate was 0.09 cm per month, and the median change in tumor burden was 1.3 cm.
A total of 39 patients — including 37 with documented disease progression — dropped out of the surveillance program after a median follow-up of 38.1 months.
Following univariable analysis of baseline prognostic factors, it was shown that the length of active surveillance was associated with the number of organs with metastases (one vs two vs more than two; P = .0239). It was also associated with the location of the metastases (lung only vs other organs only vs both; P = .0280) and the number of IMDC (P = .0213) and MSKCC (P = .0184) risk factors, the researchers say.
In multivariable analysis, only the number of involved organs (P = .0414) and number of IMDC risk factors (P = .0403) were independently prognostic.
During the study, 22 (46%) patients died, all from metastatic renal cell carcinoma.
Seven patients underwent local therapy during the surveillance period (range, 2-31 months after registration), as follows: six patients underwent resection of metastatic disease (two for adrenal disease, two for renal mass, one for renal vein thrombosis, and one for an abdominal mass), and one patient received radiotherapy to treat metastasis to the bone.
Many patients who discontinued surveillance went on to receive subsequent systemic therapy, and data are available for 31 of the 39 patients who did so, the researchers note. Most patients received therapy with pazopanib (Votrient, Novartis) (n = 11 [35%] of 31 patients), or sunitinib (Sutent, CPPI CV) (n = 11 [35%]). Three patients (10%) received pazopanib or sunitinib in combination with an investigational drug. Other treatments included temsirolimus (Torisel, PF Prism CV) (n = 2 [6%]); and axitinib (Inlyta, PF Prism CV) (n = 1 [3%]), bevacizumab (Avastin, Genentech) (n = 1 [3%]), nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb) (n = 1 [3%]), and celecoxib (Celebrex, GD Searle) plus interferon (n = 1 [3%]).
Objective partial responses were documented in 10 (32%) patients who received systemic therapy. As already mentioned, the median overall survival from the start of surveillance for the 31 patients who received systemic therapy was 38.6 months.
Other Therapeutic Options
"The present data should be interpreted in light of other therapeutic options in this disease," Dr Rini and colleagues comment.
In particular, in light of recent results with novel immunotherapies in kidney cancer (including overall improvement in survival with nivolumab), more work is needed to understand the risk and benefits of this initial observational approach, they add.
They note that "there is an opportunity for long-term cancer-free survival with interleukin 2, making this an appropriate strategy for a subset of patients with metastatic renal-cell carcinoma." However, none of the patients in this trial received interleukin-2, and this treatment is rarely used because of severe toxicity, even though it offers a chance of cure, as previously reported by Medscape Medical News.
The authors also highlight results from a phase 3 trial from 2013 that compared sunitinib with pazopanib in patients with metastatic renal cell carcinoma (303 [27%] good-risk patients and 470 [58%] intermediate-risk, per MSKCC criteria). This trial reported a median progression-free survival of 9 months and an overall survival of 29 months.
The results from the current obervational trial, in a cohort of patients with a similar distribution of good-risk and intermediate-risk patients, show comparable clinical outcomes, the authors comment. However, they note "the important caveat that patients enrolled on our trial were highly selected and no direct comparison can be drawn for long-term survival."
No funding for the study has been disclosed. Dr Rini and all but one of the study authors have disclosed no relevant financial relationships. Coauthor James H Finke, MD, has received grants from Pfizer and GlaxoSmithKline. Editorialist Paul Russo, MD, has disclosed no relevant financial relationships. Dr Choueira has a consulting or advisory role with AstraZeneca, Bayer, BMS, Cerulean, Eisai, Foundation Medicine Inc, Genetech, GlaxoSmithKline, Merck, Novartis, Peloton, Pfizer, Prometheus Labs Inc, and Roche. He also received research funding from AstraZeneca, BMS, Exelixis, Genentech, GSK, Merck, Novartis, Peloton, Pfizer, Roche, and Tracon. Dr Chatta has disclosed no relevant financial relationships.
Lancet Oncol. Published online August 3, 2016
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