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Deferred cytoreductive nephrectomy fails to improve progression-free rate in renal cell cancer
Pretreatment with sunitinib followed by deferred cytoreductive nephrectomy did not improve 28-week progression-free rates compared with immediate nephrectomy followed by sunitinib among patients with primary metastatic renal cell carcinoma, according to results of a phase 3 randomized trial published in JAMA Oncology.
However, more patients who received the deferred approach were able to receive sunitinib (Sutent, Pfizer), a multitargeted tyrosine kinase inhibitor, and result showed improved OS in this group.
Further, pretreatment with sunitinib may help identify patients with inherent resistance to systemic therapy before planned nephrectomy, according to the researchers.
“Since 2006, more effective vascular endothelial growth factor receptor tyrosine kinase inhibitors have been the standard of care for the treatment of metastatic renal cell carcinoma,” Axel Bex, MD, PhD, of the department of urology at Netherlands Cancer Institute, and colleagues wrote. “Guidelines recommend cytoreductive nephrectomy in patients with good performance, absence of poor risk features, and solitary or oligometastatic disease, but the role of cytoreductive nephrectomy for patients who require medical treatment in the targeted therapy era is unknown.”
The randomized phase 3 CARMENA trial found the addition of cytoreductive nephrectomy to sunitinib therapy provided no survival benefit for intermediate- and poor-risk patients.
Bex and colleagues sought to determine whether three cycles of sunitinib therapy before cytoreductive nephrectomy improved PFS compared with immediate nephrectomy followed by sunitinib.
The current study needed a sample size of 458 patients for the primary endpoint of PFS. However, they were only able to enroll 99 patients (mean age, 60 years; men, n = 80). An independent monitoring committee endorsed reporting the intention-to-treat 28-week progression-free rate instead.
Secondary endpoints included OS, adverse events and postoperative progression.
Nineteen institutions in the Netherlands, Belgium, the U.K. and Canada enrolled patients, with 50 randomly assigned to the immediate cytoreductive nephrectomy group and 49 to the deferred nephrectomy group.
In the immediate nephrectomy group, 40 (80%; 95% CI, 67-89) patients received sunitinib and 46 (92%; 95% CI, 81-97) underwent nephrectomy. In the deferred group, 48 patients (98%; 95% CI, 80-100) received sunitinib. Forty of these patients underwent three cycles of sunitinib whereas eight discontinued the therapy because of adverse events.
Median follow-up was 3.3 years.
Results showed a 28-week progression-free rate of 42% in the immediate cytoreductive nephrectomy group vs. 43% in the deferred group.
Median OS was 32.4 months (95% CI, 14.5-65.3) in the deferred group compared with 15 months (95% CI, 9.3-29.5) in the immediate group (HR = 0.57; 95% CI, 0.34-0.95).
Systemic progression prompted a per-protocol recommendation against nephrectomy for 14 patients (29%; 95% CI, 18-43) in the deferred group.
Surgical complications occurred in 24 patients (52%) who underwent immediate nephrectomy vs. 18 patients (53%) in the deferred arm. One patient died during immediate nephrectomy due to cardiac arrest caused by caval vein tumor thrombus. Two other patients died 3 and 6 days after nephrectomy due to myocardial infarction and pulmonary embolism.
The study had several limitations, including local regulatory decisions that prevented two European countries from participating.
Additionally, the clinical superiority of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) over sunitinib for first-line treatment in patients with metastatic renal cell cancer limits the applicability of the trial.
“With hindsight, PFS and progression-free rate endpoints require complex timing, and OS as the primary end point would have been preferable,” Bex and colleagues wrote. “Despite these limitations, our results may be meaningful ... for treatment decisions in patients with primary clear cell metastatic renal cell carcinoma who require sunitinib.”
In an accompanying editorial, Primo N. Lara Jr., MD, associate director for translational research and co-leader of the cancer therapeutics program at UC Davis Comprehensive Cancer Center, and Christopher P. Evans, MD, chair of the department of urologic surgery at the UC Davis School of Medicine, said the limitations of the study in failing to find enough patients highlight a common challenge in studying this particular disease. However, the study still provides valuable data.
“Despite the apparent limitations ... both trials ultimately provided prospective level 1 guidance to guide clinical practice and are best viewed as practice-confirming rather than practice-changing,” Lara and Evans wrote. “Both affirm the current requirement for careful patient selection and the abandonment of indiscriminate use of cytoreductive nephrectomy in certain high-risk patient subsets for whom immediate systemic therapy alone is likely to be best unless local tumor morbidity mandates surgical intervention.”– by John DeRosier
Disclosures : Pfizer, Kankerbestrijding and the EORTC funded this study. Bex reports grants from Pfizer during conduct of the study, personal fees from Bristol-Myers Squibb, Eisai Co., EUSA, Ipsen and Pfizer, and steering committee membership in the IMMotion OIO trial from Roche. Please see the study for all other authors’ relevant financial disclosures. Lara reports consultant/advisory roles with AbbVie, AstraZeneca, Bayer, Bristol-Myers Squibb, CellMax Life, Exelixis, Foundation Medicine, Genentech, Janssen, Merck, Nektar, Pfizer and Turnstone Bio and honoraria from Pfizer. Evans reports consultant/advisory roles with Astellas, Janssen and MDxHealth and honoraria from with Astellas, Janssen and MDxHealth and Pfizer.