Cytoreductive Nephrectomy in this Era

• 28 Apr 2020 08:04:22 PM
• |Onco Urology

Narrative:

To know about cytoreductive nephrectomy we need to traverse through three eras.

1.       Cytokine

2.       TKIs

3.       ICI (Immune check point) therapy era

CYTOKINE ERA:

The notion of cytoreductive nephrectomy (CN), removal of the kidney and primary tumor in the face of metastatic disease, was based on a series of observations.  First, patients treated with the primary tumor in-situ who underwent treatment with interferon fared particularly poorly. Second, case reports demonstrated that a small number of patients treated with CN experienced regression of their metastatic disease. As a result, two randomized controlled trials were undertaken to assess the value of CN in the era of cytokine-based therapy. In these two methodologically similar randomized controlled trials, Flanigan et al. and Mickish et al. randomized patients to CN plus interferon vs interferon alone. Reported in 2001, they demonstrated a 3-month & a 10-month survival benefit respectively. Subsequent pooled analyses (Flanigan et al 2004) showed a strongly statistically significant benefit with overall survival of 13.6 months among patients receiving CN plus interferon and 7.8 months among those receiving interferon alone (difference = 5.8 months). 

These findings built the foundation for Cytoreductive nephrectomy as a treatment paradigm in patients with RCC and synchronous metastases.

Despite the proven survival benefits, the mechanism of CN is unclear. Notably, the response to systemic therapy did not differ in the two pivotal RCTs. Thus, CN does not potentiate the response to (cytokine-based) systemic therapy.

Postulated mechanisms include removal of the “immunologic sink”, decreased production of cytokines and growth factors by the primary tumour, delayed metastatic progression and survival benefit from nephrectomy induced azotemia.

We all know that the introduction of targeted therapies revolutionized the systemic therapy of metastatic RCC. In fact it was even postulated that from the aforementioned 10-month median overall survival in the cytokine-era, median overall survival for patients receiving a sequential regime of targeted therapies may exceed 40 months (Escudier et al).

 

TKI ERA:

This era witnessed a surge of trials and studies looking into various aspects of tyrosine-kinase inhibitors as a potential treatment option in metastatic renal cell cancer +/- CN.

Retrospective trials: A number of studies (Choueiri et al 2011, Heng et al 2014 & Hanna et al 2016) re-evaluated CN in the VEGF TKI era, all finding it to be associated with improved overall survival. Notably, all of these studies were retrospective and therefore limited by the inherent selection bias of which patients were referred for CN.

Prospective Trials: To of the most prominent trials which come to my mind are the CARMENA and SURTIME trial. To briefly summarize, CARMENA randomized 450 patients with intermediate or poor-risk confirmed clear cell renal cell carcinoma [Using the Memorial Sloan Kettering Cancer Center (MSKCC) risk stratification ] in a 1:1 fashion to nephrectomy followed by sunitinib or sunitinib alone. After a median follow-up of 51 months, the median overall survival for patients receiving systemic therapy alone was 18.4 months and was 13.9 months for those patients undergoing cytoreductive nephrectomy followed by sunitinib. The resulting Cox models demonstrated non-inferiority with a hazard ratio of 0.89 based on an intention to treat analysis wrt PFS and OS.

The international prospective phase III randomized SURTIME trial was designed to evaluate the significance of the sequence of cytoreductive surgery and systemic therapy. It randomized 99 patients to either immediate CN followed by sunitinib, or three 6-week courses of sunitininb followed by CN followed by 2 courses of adjuvant sunitinib. Deferred CN did not improve the 28-week PFR. With the deferred approach, more patients received sunitinib and OS was higher on ITT analysis (although this finding was not statistically significant). Pretreatment with sunitinib may identify patients with inherent resistance to systemic therapy before planned CN.

The aforementioned findings do appear to build on CARMENA and indicate an opportunity to better clarify how the timing and initial results of systemic therapy can be integrated into decisions for surgery. With this it has also been proposed that deferred approach to surgery may decrease cancer-related morbidity, reduce primary tumor size, and limit neovascularization, which may subsequently decrease surgical risk and morbidity

Criticisms: Both the trials had their own share of criticisms.

CARMENA:

1.          Investigators required eight years at 79 sites to accrue 450 of an initially planned 576 patients – 78%. Thus, each institution enrolled fewer than a single patient each year – suggesting either clinician’s lack of equipoise or the patients’ own unwillingness to be randomized. 
2.          43% of pts were poor risk
3.          17.7% pts in combined arm never received sunitinib. 16.9% in sunitinib arm underwent CRN.
4.          Significant cross-over within the study, with a large proportion of patients assigned to sunitinib alone eventually undergoing palliative nephrectomy for symptomatic control.
5.          Surgical intangilbles such as no data on tumor size extent ofLNpathy RV/IVC extension, adjacent organ involvement etc

 

SURTIME:

1.          Accrual was affected by several factors, including local regulatory decisions (that prevented 2 European countries from participating) complexity of timing of surgery and systemic treatment, and the use of surgical risk factors for eligibility rather than WHO performance status. 18% of patients were ineligible, although reasons were unrelated to performance, surgical risk factors, or oncologic eligibility criteria.
2.          Also superiority of nivolumab and ipilimumab over sunitinib in terms of survival and quality of life changes first-line treatment for patients with intermediate- and poor-risk mRCC and limits the applicability of the results of both trials

 

Take Aways: Every dark cloud has a silver lining

The results of CARMENA highlight the importance of identifying the correct therapies and sequence on a case-by-case basis. Treatment remains multimodal, and tradeoffs and patient preferences must be considered. 

SURTIME appears to question the rationale for upfront cytoreductive nephrectomy & does suggest that a subset of mRCC patients will achieve maximal benefit by receiving systemic therapy as their initial Rx.

ICI Era:

Currently, there is limited evidence to address the utility of cytoreductive surgery in combination with ICI, which is primarily in the form of case reports and small institutional studies.

Singla et al (ASCO 2019), recently highlighted three case studies where patients experienced either complete response or radiographic response from nivolumab prior to cytoreductive nephrectomy

Road Ahead:

It is promising for sure! As I mentioned earlier that careful selection of the right patient for the right therapy is prudent. Wing K Liu et al looked into a multi-disciplinary, algorithm-driven approach to selecting patients for CN or other options. Their data suggests that patients suitable for CN could be identified through an MDT pathway that utilises a combination of IMDC scoring, PS and metastatic disease burden. This further has the option of a joint surgical-oncology consultation, for more ambiguous cases. Their findings suggest that an MDT approach constitutes an important and viable strategy for the management of mRCC, particularly in identifying patients suitable for CN. Potential benefits for identifying candidates for CN include deferring the onset of ST and its potential toxicities. Additionally, results suggest that there may be a PFS and OS advantage if suitable patients undergo CN.

ASCO 2020

Dr. Bakouny and his team assessed patients retrospectively who had been diagnosed with de novo metastatic renal cell carcinoma and who had started first-line systemic therapy (immune checkpoint inhibition or targeted therapy) between 2009 and 2019 using the International Metastatic RCC Database Consortium (IMDC).

A total of 4639 patients had been treated with targeted therapy and 437 with immune checkpoint inhibition. In both the groups some had received CN and some had not. They were followed for a median of 42.0 and 14.1 months in the targeted therapy and immune checkpoint inhibitor arms, respectively. Overall survival was compared between patients receiving cytoreductive nephrectomy and systemic therapies vs those treated by systemic therapies alone using the Kaplan-Meier method and Cox regressions, in the targeted therapy and immune checkpoint inhibition arms, separately. To account for treatment selection bias, propensity score analysis was used. They found that CN was more likely in patients with the following characteristics: less than 65 years old, no adverse metastases, IMDC risk score of 0 or 1, and adverse histology (non-clear cell or sarcomatoid features). This was consistent across both the first-line TT and first-line ICI cohorts.  On univariate analysis, CN was associated with improved overall survival in patients treated with either first-line TT or first-line ICI. Multivariable analysis and propensity score-matched analysis both demonstrated similar results. The interaction p-value in each of these analyses was non-significant, meaning that the amount of benefit for CN did not differ between patients treated with first-line TT versus first-line ICI. Inspite of the possibility of confounders data from this propensity-score matched analysis demonstrates a significant overall survival benefit to CN irrespective of first-line treatment &that CN should be considered only for select patients 

Markers

Molecular determinants of primary and metastatic mRCC may further aid in the clinical selection of candidates most likely to benefit from surgical resection (Martin H Voss et al) (TRACERx Renal). But these are still experimental.

Guidelines

1. EAU Guidelines dissuades from doing CN in MSKCC poor-risk patients.
2. ASCO 2020 recommends:

CN should be rarely performed in

• ·         Poor risk disease
• ·         Rapidly progressive or high disease burden pts.

 

Upfront CN to be considered in

• ·         Pts with favourable/intermediate risk disease
• ·         Oligometastatic disease favouring oligometastectomy with an intention to NED
• ·         Symptomatic kidney masses.

 

Deferred CN:

• Pts with strong responses to systemic therapy.

Take Home Message:

1.          Until then, a cautious balance between perceived oncologic benefit and risks of intervention must be exercised
2.          Systemic Disease generally needs systemic therapy
3.          Systemic therapy alone is inferior
4.          CN remains Selective: Individualised to patient (Low risk or few intermediate risk pts)
5.          MDT approach  
6.          Prospective analysis evaluating ICI NORDIC-SUN, CYTOSHRINK, PROBE Results of these trials will be key to provide further information as to the role of local kidney tumor control in patients with metastatic renal cell carcinoma.
7.          Patient safety is always the priority

 I am sharing a link to my presentation for your perusal.

https://prezi.com/view/n8VA1TFlcgbFzQz4ggqZ/

Santosh Waigankar

Comments(3)

• 

  Ravindra Sabnis

  01 May 2020 10:19:39 AM

  Very nice overview Dr Santosh. This overview give fair idea - what we are supposed & pros & cons of each. Your take home message is very good. 

• 

  Dr. Anil Takvani

  01 May 2020 06:36:38 PM

  I concur with Prof. Sabnis Sir.

  We all would like to congratulate you for such a comprehensive overview...

  thanks

• 

  Santosh Subhash Waigankar

  03 May 2020 01:24:52 PM

  Thank you.

  Will continue similar efforts