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Reality Check: What Is the Latest Paradigm

for Cytoreductive Nephrectomy vs

Targeted Therapy in mRCC?

 

 

 

Petar Bajic, MD

Fellow, Division of Urology

Rush University Medical Center

Chicago, Illinois

 

 

 

 

 

Robert C. Flanigan, MD

Professor, Department of Urology

Loyola University Chicago Stritch School of Medicine

Maywood, Illinois

 

 

 

 

Keywords: cytoreductive nephrectomy, metastatic renal cell carcinoma, targeted therapy,
tyrosine kinase inhibitor, SURTIME, CARMENA, interferon-alpha.

 

Corresponding Author: Petar Bajic, MD. Rush University Medical Center, 1725 W Harrison St,
Suite 352, Chicago, IL 60612  Email: pbajicmd@gmail.com

 

 

Have we reached an inflection point in the debate over the role of cytoreductive nephrectomy (CN) in metastatic renal cell carcinoma (RCC)? Controversy remains regarding the sequencing of CN and targeted therapy in mRCC, and this controversy has been heightened with the availability of new and more promising agents for the treatment of metastatic renal cancers. The current literature also points toward an improved understanding of the most appropriate selection criteria for determining the best candidates for CN using prognostic and predictive factors to optimize clinical outcomes. Overall, there still remains a role for upfront CN in appropriately selected candidates.

 

From the early landmark papers in the cytokine era to recent analyses of retrospective observational data and additional studies of CN in the era of targeted therapy, the role of cytoreductive nephrectomy has undergone virtually continuous reevaluation and considerable confusion persists over the appropriate selection of surgical candidates for cytoreductive nephrectomy. Without question, the role of CN will continue to be modified by the evolution of new and more effective systemic therapies including the use of targeted therapies which have dramatically reshaped the evidence-based paradigm of advanced RCC treatment. Therefore, with the introduction of these new systemic therapies, the widely accepted rationale for the use of CN (either as an initial or delayed therapy) has been reexamined and upgraded. In addition, more information regarding the importance of prognostic risk factors and predictive markers that are associated with the value of CN has continued to evolve.

Within the last few years, the debate over CN in metastatic RCC has been reassessed, largely due to the publication of two trials (the CARMENA and SURTIME trials). Furthermore, the debate over the validity of data from these two trials has dominated the narrative on CN and targeted therapy. Therefore, the controversy surrounding these trials – particularly the limitations and flaws of each – has become a focus of the recent literature.

The CARMENA trial, a phase 3 study, concluded that overall survival (OS) in patients treated with sunitinib alone is not inferior to those treated with CN followed by sunitinib.1 Another pivotal trial, the European Organization for Research and Treatment of Cancer (EORTC) SURTIME trial explored a period of sunitinib prior to CN as an alternative approach to immediate CN. In this trial, the sequence of CN and sunitinib did not affect the progression-free rate, but higher OS was seen for deferred CN.2

These trials were also preceded by a long list of studies on the use of CN, beginning in the cytokine era. A brief chronicle of the highlights from these earlier studies offers important perspectives on how the rationale for the use of CN has evolved over the last 20 years. Furthermore, a review of the findings from these earlier studies offers a valuable vantage point from which to analyze the results of more recent reports.

 

Cytoreductive nephrectomy
in the Cytokine Era

At the beginning of the cytokine era, surgery was the main treatment for localized RCC, but the use of nephrectomy for metastatic disease was controversial and generally considered not of value. Two pivotal studies from the cytokine era addressed the question of whether combined treatment with CN followed by systemic interferon-alfa lengthens time to progression and confers a survival benefit in patients with metastatic RCC, and, secondarily, whether nephrectomy before immunotherapy increases the response rate to immunotherapy.3,4 In one of these studies, by Flanigan et al, the median survival of 120 eligible patients assigned to surgery followed by interferon was 11.1 months, compared to was 8.1 months in 121 patient assigned to interferon alone.4 In patients with PS0, OS with CN was 17.4 mo vs. 11.7 mo without CN. This data was supported by another study by Mickisch et al3 which demonstrated that time to progression (5 vs 3 months) and median duration of survival (17 vs 7 months) were significantly better in patients receiving combined CN and IFN treatment vs IFN alone.

Both of the above mentioned trials found that systemic therapy in the era of interferon therapy could be given safely to patients at a short interval after nephrectomy.  Both studies also addressed prognostic factors that seemed to affect outcomes, including especially performance status, lung only metastases, liver metastases and bulky retroperitoneal lymphadenop-athy.3,4  Additional reports in the literature studied other risk factors that might also be useful in selecting patients less suitable for  CN, including LDH > 600, albumin < 3.5, liver metastases, and retroperitoneal lymphadenopathy.5

The “take-home” message from these studies in the cytokine era is that, in select patients with good performance status, absence of significant health comorbidities or central nervous system metastases, CN is associated with a low likelihood of surgical morbidity and a statistically significant 6-month survival advantage (Figure 1).6

 

Figure 1.  Removal of kidney during nephrectomy.

 

Cytoreductive Nephrectomy in the Era of Targeted Therapies

The advent of targeted therapies for cancer treatment heralded in a new era in the systemic treatment of renal cancers, and the value of role of CN was questioned anew. A study by Choueiri et al7 was among the first reports to suggest that CN may confer an independent survival benefit in patients with metastatic RCC who subsequently received contemporary VEGF targeted therapy. Retrospectively reviewing the outcomes of 314 patients, this report found that patients who underwent CN (n=201) demonstrated a median OS of 19.8 months vs 9.4 months for patients who did not undergo CN (n=113). When this study’s results were adjusted for established prognostic risk factors, the OS difference persisted in favor of the CN group.

Choueiri et al also studied two prognostic models; one derived in the era of VEGF targeted therapy and another from the immunotherapy era, and found that both models showed a benefit of CN on survival. Not surprisingly, on subgroup analyses, the benefit was marginal in patients with poor performance status, brain metastases, or in those categorized as poor risk by the MSKCC criteria. These authors suggested that these three groups of patients may therefore represent new criteria to help stratify patients who should or should not undergo CN.

 

Do the IMDC Prognostic Factors Reshape the CN Narrative?

We have, from the beginning of our experience with cytoreductive nephrectomy, insisted that all candidate patients be seen by their surgeon and a medical oncologist who was a part of our CN team. We feel that this protocol maximizes decision making and patient selection process and insures a more effective transition from surgery to systemic therapy. As CN has evolved (Figure 2) from the cytokine to the targeted therapy eras, the prognostic factors found to be important have also evolved. Compelling evidence for the importance of prognostic profiles in selecting patients for CN in the targeted therapy era emerged from the study by Heng et al.8 In their retrospective review of results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC), these authors   demonstrated that CN provided a significant OS benefit in patients treated with targeted therapy when adjusting for known prognostic factors. The Median OS of patients with CN vs without CN was 20.6 vs 9.5 months respectively. However, in this study, patients who received CN had better IMDC prognostic profiles (IMDC risk factors - less than 1 year from diagnosis to surgery, Karnofsky PS < 80%, hemoglobin < lower limit of normal, calcium > upper limit of normal, neutrophil > upper limit of normal and platelet count > upper limit of normal) than the patients not receiving CN. The study’s incremental benefit analysis also suggested that those with one, two, and three IMDC risk factors seemed to benefit from CN while those with four, five, and six risk factors did not. In addition, patients who were expected to survive less than 12 months also demonstrated limited benefit from a CN.

 

Figure 2. A 66 year old male post right nephrectomy with recurrent tumor and metastatic renal carcinoma. Axial fused Whole Body FDG PET CT Scan following intravenous administration of 9.7 mCi of
18-FDG reveal confluent metabolically active tumor in retroperitoneum in the retrocaval region, para-aortic and aortocaval space.

 

 

Database studies analyzing large patient populations in the targeted era (2005 and later) have also shown a value for CN. Abern et al9 employed the Surveillance, Epidemiology, and End Results (SEER) database, describing   the primary outcome of OS in patients with metastatic RCC. Out of 7,143 mRCC cases, they reported that 37% underwent CN. Patients who underwent CN were more likely to be younger, white, male, married, and to have stage T3 tumors. Patients who underwent CN had an improved one-year survival (61% vs 22%). Although this report favored the role of CN in the management of metastatic RCC, the authors acknowledged limitations and confounding factors in the analysis. This analysis was not able to control for prognostic variables, the location or number or volume of metastatic sites (shown by other studies to be of prognostic significance).10,11 In addition, other prognostic factors, including serum hemoglobin, lactate dehydrogenase (LDH), calcium and albumin were also unavailable from their dataset and could have varied between the groups receiving CN or not.

Another study reported on a large and robust sample cohort from the National Cancer Data Base reviewed between 2006 and 2013. The report by Hanna et al12 also found an OS benefit when CN was combined with targeted therapy: the median OS of CN vs non-CN patients was 17.1 months vs 7.7 months respectively. CN was also found to be associated with (Figures 3, 4) a lower risk of any death (HR, 0.45, P<.001).

 

Fig 3. Kaplan-Meier survival analyses of patients with metastatic renal cell carcinoma treated with targeted therapy stratified according to cytoreductive nephrectomy (CN) status (yes or no), National Cancer Data Base, 2006 to 2012. Data were restricted to 12,995 patients with no missing information on vital status or follow-up time.

 

 

 

 

 

 

Fig 4. Kaplan-Meier survival analyses of patients with metastatic renal cell carcinoma treated with cytoreductive nephrectomy and targeted therapy (TT) stratified according to timing of surgery (before or after systemic therapy), National Cancer Data Base, 2006 to 2012. Data were restricted to 4,223 patients with available information on timing of surgery and targeted therapy.

 

 

 

 

 

Two Pivotal Randomized Trials (the SURTIME and CARMENA trials):
Are They a Turning Point in Debate Regarding CN?

The CARMENA Trial  This phase 3, randomized study attempted to delineate the value of CN and systemic therapy in the era of targeted therapy – specifically sunitinib. In this study, the median OS was 18.4 months in the sunitinib only arm versus 13.9 months in the CN/ sunitinib arm. Thus, the CARMENA trial did not support the conclusions of previously reported retrospective and database studies of CN as it failed to show an overall OS benefit with CN in patients treated with sunitinib therapy. However, over the last two years, the validity and application of CARMENA’s results have been questioned based on widely ranging criticisms. One of the criticisms is related to this trial’s slow and likely incomplete recruitment, as noted in a report by Arora et al.13 During 8 years of accrual to this study, 450 patients were enrolled at 79 centers, considerably short of the target of 576 patients. This fact raised questions about whether the recruitment process was biased, especially since patients with a lower metastatic burden were “selectively treated outside the trial.” The extent to which the results from CARMENA can be generalized to all patients with metastatic RCC has also been scrutinized. For example, the 18.4-month OS in the sunitinib arm is lower than in other recently published studies.14 Arora et al further criticized CARMENA because the trial recruited patients with a higher number of metastatic sites than in the National Cancer Data Base trial. There is a strong suggestion that candidates for CARMENA (due to their lower metastatic burden) underwent a nephrectomy outside the trial.

Perhaps most importantly, there was a sizeable degree of crossover in the trial which utilized  intention to treat criteria. Specifically, 17% of patients who were randomized to sunitinib alone actually underwent CN and 7% of the patients in the CN arm did not undergo CN. IN addition, he higher percentage of patients with advanced disease in the CN/sunitinib arm(70% vs 51%) could have also  influenced outcomes.15

The SURTIME Trial  This randomized phase 3 trial attempted to evaluate whether a period of sunitinib therapy before CN might improve outcomes in patients with metastatic renal cancer compared with immediate CN followed by sunitinib therapy.  The objective of the SURTIME trial was also to investigate whether pretreatment with sunitinib before planned surgery improves outcome by identifying patients with inherent resistance to VEGF-TKI therapy who are unlikely to benefit from CN. SURTIME also examined whether a deferred approach to CN could reduce cancer-related morbidity, primary tumor size, and neovascularization, which, in turn, may decrease surgical risk and morbidity. Very importantly, although this trial was planned to recruit 458 patients, poor accrual prompted its data monitoring committee to close the trial prematurely in response to a finding that the 28-week PFS was 42% in the immediate CN arm (n=50) and 43% in the deferred CN arm (n=49), a difference that was obviously not significant. However, later report by Bex et al,2 using the same dataset, concluded that OS was positively impacted with the deferred CN approach because, potentially because more patients received sunitinib. Median OS was 32.4 months in the deferred CN arm versus 15 months in the immediate CN arm.

Although this study’s conclusions are potentially flawed by early termination of the study, one of the key messages from the SURTIME trial is related to the suggestion that patient selection for CN might be based on early response to systemic therapy. In other words, progression on systemic therapy, given before planned CN, might  be used to identify patients likely to be resistant any targeted therapy and therefore unlikely to benefit from CN. Other  studies, have also have shown that pre-surgical VEGFR-TKI therapy in which progressive disease occurred in those treated with sunitinib or pazopanib before CN was associated with shorter survival.

 

Beyond SURTIME and CARMENA:

A New Algorithm to Determine the Role of CN?

As stated above, numerous studies have addressed the implications of the SURTIME and CARMENA trials given the fact that both trials left a trail of unanswered questions regarding the role of CN in patients treated with sunitinib. Subsequent papers have also attempted to provide a useful guide directed to the appropriate selection of candidates for CN after careful consideration of prognostic risk factors. Updated guidelines from the European Association of Urology and the AUA have further clarified the role of CN.

To what extent are prognostic and predictive factors an important part of determining survival outcomes? Bindhi’ s review of patients with metastatic RCC16 suggested the following:

  • Poor performance status and poor IMDC/MSKCC risk classification is associated with a poor prognosis, and a lack of OS benefit with CN.
  • Good performance status and good/intermediate IMDC/MSKCC risk classification is predictive of OS benefit with CN in patients without adverse IMDC/ MSKCC risk factors, who demonstrate good performance status and low-volume metastatic burden and initial CN generally should be considered before systemic therapy.
  • Metastectomy, when possible, markedly improves survival and may allow patients to remain off systemic therapy, thereby avoiding associated toxicities.
  • In patients with poor IMDC/MSKCC risk disease, poor performance status, and large-volume metastatic burden, initial treatment with systemic therapy is generally advised. In patients with brain metastases, spinal metastases, and bone metastases with risk of fracture, systemic therapy combined with radiation of the lesions is preferred before considering CN

 

Future Directions: How Will Checkpoint Inhibitors Be Integrated in the Paradigm?

One of the key issues to be addressed by planned trials is the need to reassess the role of CN in the setting of checkpoint inhibitor therapies that have now attained first-line treatment status. An intriguing hypothesis is that cytoreduction and the resultant reduction of immunosuppressive signals may enhance the benefit of PD-L1 blockade. As trials like Checkmate-214 move forward, the sequencing of systemic therapy and/or CN will continue to be an essential focus of interest.

 

Conclusion

Although more level 1 evidence for the use of initial CN in the era of targeted therapy is still needed, a consensus is taking shape based on  large analyses of population-based data and randomized clinical trials. Initial CN is likely underutilized, particularly in non-academic centers where this underuse may contribute to inferior survival outcomes among patients who present with mRCC. We believe that it is  important for medical oncologists and urologists (working as a team) to seriously consider CN for every patient who presents with mRCC. The choice of the most appropriate treatment options should be based on guidelines established by groups like the AUA and EAU and should reflect careful evaluation of risk stratification. Patients with favorable to intermediate risk metastatic RCC constitute the group with the greatest likelihood of benefiting from initial CN.

 

References

1. Méajean A, Ravaud A, Thezanas S, et al. Sunitinib alone or after nephrectomy in metastatic renal cell carcinoma. N Engl J Med. 2018;379: 41-427.

2.Bex A, Mulders P, Jewett M, et al. Comparison of immediate vs deferred cytoreductive nephrectomy in patients with synchronous metastatic renal cell carcinoma receiving sunitinib: the SURTIME randomized clinical trial. JAMA Oncol. 2019;5: 164-10

3. Mickisch GHJ, Garin A, van Poppel H, et al. Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial. Lancet. 2001;358:966-970.

4. Flanigan RC, Salmon SE, Blumenstein BA, et al. Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer. N Engl J Med. 2001;345:1655-1659.

5. Culp SH, Tannir NM, Abel EJ, et al.Can we better select patients with metastatic renal cell carcinoma for cytoreductive nephrectomy. Cancer. 2010;116:3378-3388.

6. Flanigan RC, Mickisch G, Sylvester R, et al. Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol. 2004;171:1071-1076.

7. Choueiri TK, Xie W, Kollmannsberger C, et al. The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy. J Urol. 2011;185:60-66.

8. Heng DYC, Wells JC, Rini BI, et al. Cytoreductive nephrectomy in patients with synchronous metastases from renal cell carcinoma: results from the International Metastatic Renal Cell Carcinoma Database Consortium. Eur Urol. 2014; 66:704-710.

9. Abern MR, Scosyrev E, Tsivian M, et al. Survival of patients undergoing cytoreductive surgery for metastatic renal cell carcinoma in the targeted-therapy era. Anticancer Res. 2014.34:2405-2412.

10. Alt AL, Boorjian SA, Lohse CM, et al. Survival after complete surgical resection of multiple metastases from renal cell carcinoma. Cancer. 2011;117:2873-2882.

11. Capitanio U, Abdollah F, Matloob R, et al. Effect of number and location of distant metastases on renal cell carcinoma mortality in candidates for cytoreductive nephrectomy: implications for multimodal therapy. Int J Urol Assoc. 2013;20:572-579.

12. Hanna N, Sun M, Meyeer CP, et al. Survival analyses of patients with metastatic renal cancer treated with targeted therapy with or without cytoreductive nephrectomy: a National Cancer Data Base Study. J Clin Oncol. 2016;34:326-3275.

13. Arora S, Sood A, Dalela D, et al. Cytoreductive nephrectomy: assessing the generalizability of the CARMENA trial to real-world National Cancer Data Base cases. Eur Urol. 2019;5:349-353.

14. Motzer RJ, Russo P. Cytoreductive nephrectomy—patient selection is key. N Engl J Med. 2018;379:417-427.

15. Bajic P, Flanigan RC, Joyce CJ, et al. Sunitinib and cytoreductive nephrectomy for metastatic renal cell carcinoma. J Urol. 2019;201:453-454.

16. Bhindi B, Abel EJ, Albiges L, et al. Systematic review of the role of cytoreductive nephrectomy in the targeted therapy era and beyond: an individualized approach to metastatic renal cell carcinoma. Eur Urol. 2019;75:111-128. KCJ

 

Copyright © 2019

 

Vol 17, No 3    2019

The Official Journal of the Kidney Cancer Association

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To what extent are prognostic and predictive factors an important part of determining survival outcomes? Bindhi’ s review of patients with metastatic RCC16 suggested the following: