Cytoreductive nephrectomy may benefit certain patients with renal cell carcinoma
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Cytoreductive nephrectomy may extend OS for a well-selected population of patients with metastatic renal cell carcinoma, according to study results published in Cancer.
“The role of cytoreductive nephrectomy remains controversial in the management of patients with metastatic renal cell carcinoma with their primary in place. The French phase 3 randomized CARMENA trial put its utility into doubt when it showed that sunitinib alone was not inferior to cytoreductive nephrectomy followed by sunitinib [Sutent, Pfizer] in this setting, but the trial has many elements about it that place that conclusion into doubt,” Christopher G. Wood, MD, surgical oncologist in the department of urology of the division of surgery at The University of Texas MD Anderson Cancer Center, told Healio. “At best, the patients enrolled in that trial were borderline candidates for cytoreductive surgery, and we would not have considered many of the patients enrolled for cytoreductive surgery. What is clear is that proper patient selection is paramount to getting patients through the surgery and onto effective systemic therapy. Our group believes there is still a role for cytoreductive surgery in properly selected patients.”
Wood and colleagues sought to assess OS and identify risk factors associated with a lower likelihood of benefit from cytoreductive nephrectomy among 608 patients with metastatic renal cell carcinoma who underwent planned nephrectomy between 2005 and 2017.
Researchers used Kaplan-Meier methods and Cox proportional hazards regression analyses to assess OS and risk-stratify patients based on preoperative clinical and laboratory data.
Most patients (95.2%) had an ECOG performance status of 1 or less, and nearly 70% had a single metastatic site of disease.
Researchers classified 42.8% of patients as intermediate risk and 44.4% as poor risk per the International Metastatic RCC Database Consortium (IMDC) model. One patient qualified as favorable risk. Nearly 13% of patients had at least one missing component that left researchers unable to risk-stratify them according to IMDC criteria.
Median follow-up was 29.4 months (interquartile range [IQR], 15-54.9).
Results of multivariable analysis showed nine preoperative features independently associated with all-cause mortality. They included:
- systemic symptoms at diagnosis (HR = 1.24; 95% CI, 1.01-1.52);
- retroperitoneal lymphadenopathy (HR = 1.39; 95% CI, 1.12-1.71);
- supradiaphragmatic lymphadenopathy (HR = 1.41; 95% CI, 1.07-1.86);
- bone metastasis (HR = 1.42; 95% CI, 1.14-1.77);
- clinical T4 disease (HR = 1.87; 95% CI, 1.18-2.95);
- hemoglobin level less than the lower limit of normal (HR = 1.33; 95% CI, 1.08-1.66);
- serum albumin level less than the lower limit of normal (HR = 1.41; 95% CI, 1.07-1.85);
- serum lactate dehydrogenase level greater than the upper limit of normal (HR = 1.55; 95% CI, 1.23-1.96); and
- neutrophil/lymphocyte ratio greater than or equal to four (HR = 1.46; 95% CI, 1.14-1.86).
Investigators then categorized patients into three risk groups: low (fewer than two risk factors); intermediate (two or three risk factors) and high (more than three risk factors).
Results showed median OS of 58.9 months (95% CI, 44.3-66.6) among patients in the low-risk group, 30.6 months (95% CI, 27-35) for the intermediate-risk group and 19.2 months (95% CI, 13.9-22.6) for the high-risk group (P < .0001).
Median time to postoperative systemic therapy was 45 days (IQR, 30-90).
“This study is a follow-up to our paper published in 2010 in Cancer, where we identified clinical factors in the era of targeted therapy and immunotherapy that are predictive of good outcomes with cytoreductive nephrectomy,” Wood said. “Ultimately, we believe that we need another phase 3 randomized trial in the setting of immunotherapy to prove the utility of cytoreductive surgery. My understanding is that such a trial is being developed now through the cooperative groups.”
Survival outcomes across risk groups, as reported in the study by Wood and colleagues, underscore the fact that cytoreductive nephrectomy remains part of the armamentarium of the urologic oncologist caring for patients with metastatic renal cell carcinoma, according to an editorial accompanying the study by Sarah P. Psutka, MD, MS, urologist in the department of urology at the University of Washington School of Medicine.
“However, the nine risk factors presented here, although potentially beneficial for the refinement of patient selection for cytoreductive nephrectomy, cannot be considered to be the only relevant criteria,” Psutka wrote. “A comprehensive approach to risk assessment when one is considering cytoreductive nephrectomy for a patient with metastatic renal cell carcinoma might include a first-line evaluation of a patient’s physiologic age and performance status and the relative severity of his or her competing comorbidities. Importantly, it must be determined whether the primary tumor is surgically resectable without unacceptable collateral damage. Following these essential initial assessments, the [study’s] criteria permit further refinement of the assessment of risk by providing a determination of adequate nutritional reserve and assessing the threat of any other unresectable disease.”
References:
McIntosh AG, et al. Cancer. 2020;doi:10.1002/cncr.32991.
Psutka SP. Cancer. 2020;doi:10.1002/cncr.32993.
For more information:
Christopher G. Wood, MD, can be reached at The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1373, Houston, TX 77030; email: cgwood@mdanderson.org.
Perspective
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Peter E. Clark, MD
For almost 20 years, urologists and medical oncologists have relied primarily on data from the cytokine era to contextualize the role of cytoreductive nephrectomy in the management of metastatic renal cell carcinoma.
The older randomized trials demonstrated a benefit of cytoreductive nephrectomy when combined with interferon, which has not been standard of care for more than a decade. More recently, a series of large, retrospective cohort and consortium studies further supported the value of cytoreductive nephrectomy when combined with modern targeted therapeutics, such as tyrosine kinase inhibitors and mTOR inhibitors. However, the well-publicized CARMENA trial called this paradigm into question, showing in a prospective randomized trial that the TKI sunitinib, when used alone, was noninferior to cytoreductive nephrectomy followed by sunitinib with respect to all-cause mortality. Although a purist might say that, as a result, cytoreductive nephrectomy has no role to play in metastatic renal cell carcinoma, a more thoughtful assessment is that CARMENA demonstrates that patient selection matters and, if considered carefully, can drive significantly better outcomes for our patients.
This is exemplified by this study by Wood and colleagues, which shows that nine risk factors can be used to risk stratify patients into those who are likely to do well with cytoreductive nephrectomy vs. those who will not. Data such as these can be utilized to determine which patients should be considered for upfront cytoreductive nephrectomy vs. those who are better served by upfront systemic therapy with consideration of cytoreductive nephrectomy later depending on response.
It is noteworthy that a number of likely critical variables were not included in this analysis. These include more precise measures of frailty and nutritional status that play an important role in patient outcomes. It is also worth remembering that our standard for systemic therapy has again changed. Sunitinib, the main systemic therapy in CARMENA, is no longer the standard first-line therapy in metastatic renal cell carcinoma. Instead, immune checkpoint inhibitors have taken over, either alone or in combination with TKIs. The role of cytoreductive nephrectomy in the context of immune checkpoint inhibitor-based therapy remains largely unknown and awaits more study. Nevertheless, the study by McIntosh and colleagues offers a valuable tool that can be used in a comprehensive, multidisciplinary approach to individualizing the role of cytoreductive nephrectomy for any given patient.
Reference:
Méjean A, et al. N Engl J Med. 2018;doi:10.1056/NEJMoa1803675.
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