Carefully selected patients with metastatic renal cell carcinoma (RCC) safely delayed aggressive treatment with a period of active surveillance, a multicenter phase II trial showed.
The 48 evaluable patients remained on active surveillance for an average of 14.9 months before starting treatment. All but five of the patients met Response Evaluation Criteria in Solid Tumors (RECIST) for disease progression. Six patients opted to continue active surveillance at progression, Brian I. Rini, MD, of the Cleveland Clinic, and co-authors reported online in The Lancet Oncology.
"Given the toxicity and noncurative nature of our present drugs, perhaps the timing of their application can be considered," Rini told MedPage Today. "We don't necessarily have to treat every patient on day one. There's probably some time to figure out how aggressive the patient's disease is and whether they need treatment.
"As we pointed out in the article, some patients went on to resection, so the observation period can give you the chance to know what is really disease and what is not and whether a patient is a candidate for resection."
Patients were selected because of their disease's indolent characteristics, so delaying treatment did not cause patients to miss an opportunity for treatment.
The trial also showed investigators that some patients are not reluctant to delay treatment: "Patients either want treatment or they don't," said Rini. "If you take the time to convince patients that observation is a good approach, most patients love not to be treated -- more so than I would have imagined."
The study provided guidance to medical and surgical oncologists, demonstrating that patients with newly diagnosed, limited-extent metastatic RCC and otherwise good performance status can enter active surveillance without untoward consequences, according to the author of an invited commentary.
"There is no evidence from this study that such a period of close surveillance jeopardizes the patient's safety or survival," wrote Paul Russo, MD, of Memorial Sloan Kettering Cancer Center (MSKCC) in New York City. "It remains to be seen whether current genomic research can identify genes that can be used in conjunction with ... selection factors to better choose patients suitable for initial active surveillance.
"Further work is needed to establish whether new checkpoint inhibitors as second-line therapies can further improve survival in patients with metastatic renal cell carcinoma who have a period of active surveillance before treatment," Russo added.
The rationale for the trial came from observational evidence that a subset of patients with metastatic RCC have indolent disease. Rini and colleagues sought to inform decision making about active surveillance for such patients by characterizing the time to initiation of systemic therapy.
Investigators at five hospitals in the United States, Spain, and the United Kingdom enrolled patients with previously untreated, asymptomatic, metastatic RCC. More than 90% of the patients had good performance status (Karnofsky 90% to 100%). Histology was clear cell in 96% of cases, although patients with any histology were eligible. A fourth of patients had no adverse prognostic factors, and only one patient had three or more factors. All of the patients met MSKCC criteria for good or intermediate risk disease. Half of the patients had one involved organ site and 31% had two.
The primary endpoint was time to initiation of systemic therapy. Investigators reported outcomes after a median follow-up of 38.1 months, and follow-up continued in surviving patients. The interquartile range of follow-up was 29.4 to 48.9 months. Of the 48 evaluable patients, 43 met RECIST criteria for disease progression at some point during follow-up, and 37 of the 43 initiated systemic therapy.
Rini and colleagues reported that 23 of 43 patients started systemic therapy immediately at progression, whereas 20 continued active surveillance, including the six patients who did not initiate systemic treatment during follow-up.
The 43 patients with RECIST-defined progression had growth of existing metastatic sites in 32 cases, development of new metastatic sites in eight, and the remaining three had both worsening of existing sites and development of new sites. An exploratory analysis showed a 12-month progression-free survival rate of 41%, decreasing to 22% at 18 months.
Multivariate analysis showed that a higher number of adverse risk factors and a higher number of metastatic sites were associated with shorter-duration surveillance periods. Available laboratory data suggested that the cohort, as a whole, had a more favorable immune-cell population. Quality of life, anxiety, and depression did not worsen during the study.
The authors reported that 22 patients died during the study, all from metastatic RCC.
Rini disclosed no relevant relationships with industry. One or more co-authors disclosed relationships with Pfizer and GlaxoSmithKline.
Russo disclosed no relevant relationships with industry.
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