Keywords: Late relapsing renal cell carcinoma, recurrence of kidney cancer more than 5 years following nephrectomy, targeted therapy.
Corresponding Author: Dr. Marc R. Matrana, Third Floor, Benson Cancer Center, 1514 Jefferson Highway, New Orleans, LA 70121, E-mail: MaMatrana@ochsner.org
In the past decade, the treatment of renal cell carcinoma (RCC) has advanced more rapidly than at any other time in medical history. Better imaging techniques have led to increased detection of small, localized lesions, leading to higher rates of resection with curative intent.1 Partial nephrectomies and other nephron-sparing approaches have also been refined. And, of course, major advancements in systemic therapies including the development of oral targeted therapies and immune checkpoint inhibitors have led to unprecedented improvements in outcomes for patients with advanced, unresectable disease. However, despite these advances, of those patients who undergo resection of RCC with curative intent, approximately 30% still recur with most of those developing distant metastatic disease.2 Adjuvant therapy to prevent such recurrence is still largely under investigation with many negative trials to date. Only sunitinib has recently been approved for adjuvant use, and is generally recommended for selected patients at higher risk of recurrence.
Most post-surgical relapses of RCC occur within 2 years of resection. Rapid recurrence, especially within one year of definitive surgery, is associated with poorer prognosis and more aggressive disease. The widely used Motzer/MSKCC risk stratification model3 uses recurrence within a year as one of its elements used to categorize risk, as does the Heng criteria4 and other risk stratification models. So, if early recurrence is associated with poorer outcomes, is later recurrence associated with better outcomes?
Late Relapse – Beyond Five Years
Adamy and colleagues analyzed characteristics in patients with recurrent RCC 5 years or later after nephrectomy to determine predictors of survival after recurrence. They analyzed a total of 2,368 nephrectomy cases and found that 256 patients had disease recurrence, and 44 of those had their disease relapse 5 years or more after nephrectomy. They found that patients with late recurrence originally had fewer symptoms at initial presentation, smaller primary tumors (median 8.5 vs 7 cm) and less aggressive disease (pT1 in 18% vs 39%). Median overall survival from the time of recurrence was 6.1 years. A multi-variant analysis found that longer survival was associated with a favorable Motzer/MSKCC risk score and the absence of symptoms related to metastasis.5
Our group conducted a retrospective study to access outcomes in patients with recurrence >5 years after definitive nephrectomy. We retrospectively reviewed clinical data on consecutive patients treated with targeted therapy for mRCC who were diagnosed > 5 years after nephrectomy with curative intent between November 1, 2006, and November 1, 2013. Patients with a history of either radical or partial nephrectomy were included. Patients were excluded if they had evidence of metastases at the time of surgery or at any time prior to five years beyond surgery. Of the 520 patients with stage I-III RCC who underwent definitive complete or partial nephrectomies, 28 were found to have relapsed beyond 5 years, with a median time between nephrectomy and recurrence of 8.3 years. Most were categorized as favorable risk (71%) with only 1 patient having poor risk features, and all had clear cell histology. Most (83%) presented with multiple sites of metastases, with lung being the most common (79%) and bone and pancreases as second most common (both 33%). We also noted a high number of unusual sites of metastases including bowel, pleura, muscle, and abdominal wall, a phenomenon that has been reported in other studies of late relapsing RCC and in several case reports.6,7,8
The estimated median overall survival time in our patients was 60.5 months after detection of metastatic disease, and the 3-year overall survival rate after detection of metastatic disease was 71.78% (95% CI, 47.98%-84.77%). This is similar to that reported in Adamy’s finding and other analyses. All of our patients were treated with targeted therapy, with median time to treatment failure on first-line therapy of 19.7 months (range, 0.5- 41.6). We found no significant difference in time to treatment failure between therapies, although our analysis was certainly not powered or designed to do so.
Park, et al undertook an analysis of 747 patients who had undergone curative surgery for RCC, with 41 patients found to have developed recurrent RCC >5 years. The researchers focused their analysis on clinic-pathological features found in late relapsing patients and indentifying risk factors associated with late relapse. They found that late relapsing patients had a higher hemoglobin level and lower ESR, in addition to favorable pathological features, such as lower pT stage, favorable Fuhrman’s nuclear grade, and absence of: tumor necrosis, sarcomatoid differentiation, and lymphovascular invasion. They identified several clinical and pathological factors that were strongly associated with high-er risk of late recurrence in patients with RCC—the most important were more advanced age and higher serum hs-CRP levels at diagnosis.
The five-year cancer-specific survival rate in this series of late relapsing patients was 73.7%, compared to 41.1% in earlier relapsing patients (P=<0.001). As in previous studies Park and colleagues also showed that a significant number of patients with late recurrence developed metastatic disease at unusual sites, such as the pancreas, thyroid, scalp, and submandibular gland.9
Santoni and colleagues pooled data 21 Italian centers and that out of 2,490 patients who had relapsed RCC after nephrectomy, 269 (11%) occurred >5 years after surgery.10 Their study focused on outcomes with first line therapies, of which 190 patients (71%) were treated with sunitinib, 58 (21%) with sorafenib and 21 (8%) with pazopanib. Median progression-free survival was 20.0 months for sunitinib (95% CI 17.0-25.1), and 14.1 months for both sorafenib (95% CI 11.0-29.0) and pazopanib (95% CI 11.2-NA). They found that MSKCC score and lymph nodes, liver, and brain metastases were associated with worst overall survival, while pancreatic metastases were associated with longer survival, an observation Kalra and others have also made.11
Santoni et al undertook another analysis aimed at assessing the prognostic role of pretreatment immune status as measured by neutrophilia, lymphocytopenia, and neutrophil to lymphocyte ratio (NLR) in patients treated with vascular endothelial growth factor-tyrosine kinase inhibitors (VEGFR-TKIs) for late relapsing (>5 years) RCC. Data was pooled from 13 medical centers in Italy. They identified 151 patients, 56 (37 %) had NLR ≥3 at the start of VEGFR-TKI therapy, while 95 had NLR <3 (63 %). They found a significant difference in median overall survival (OS) in the two groups with those with the higher NLR having a medical OS of 28.8 months and those with a lower NLR achieving an median OS of 68.7 months (p < 0.001). The median progression-free survival (PFS) was 15.8 months higher NLR group and 25.1 months in lower NLR group, also a significant difference (p = 0.03). A multivariate analysis revealed that MSKCC risk group and NLR were independent prognostic factors for both OS and PFS in patients with late relapsing RCC.12
While most studies suggest that higher stage is a risk factor for relapse, late relapse can occur in early stage RCC following nephrectomy. Ha and colleagues undertook a large retrospective study of 3,567 patients who underwent partial or complete nephrectomy for T1 clear cell RCC between 1999 and 2011 at 5 institutions in Korea. 423 patients remained free of disease for at least 5 years and had adequate follow-up for analysis. During a median follow-up period of 83.9 months (range 60.0- 156.4 months) recurrence was observed in 14 of the 423 (3.3%) patients studied. Symptoms at diagnosis and pathologic T stage were independent predictive factors for late recurrence and patients who presented with symptoms at the time of original diagnosis or who originally had stage T1b disease had a significantly shorter time to late recurrence as compared to those who were asymptomatic or had stage T1a disease at original diagnosis.13
Very Late Relapse – Beyond Ten Years
Single cases in the published literature report relapses of RCC occurring 25 years or more following nephrectomy,14 but little is known about outcomes in patients with very late relapsed RCC (greater than 10 years after initial surgery). It is generally thought that these patients tend to have more indolent disease, and small retrospective series tend to suggest this as well.
We undertook a retrospective study on consecutive patients with RCC who had disease recurrence >10 years after nephrectomy for curative intent and were treated with targeted therapies between 11/1/2006 and 11/1/ 2013 at our center. Among 720 RCC patients treated with nephrectomy, we identified 8 who developed recurrent metastatic disease after a >10 year disease free interval (median: 16.7 years; range: 11.7-29.0). We were careful to exclude patients who may have developed a second primary RCC years after their first diagnosis. Although the number is very small, the results were intriguing. All 8 patients presented with clear cell histology and 88% had favorable disease by IMDC and MSKCC risk stratification models.
“As next generation sequencing becomes more widespread and informatics continues to improve, it will be fascinating to see if patterns emerge that might be able to select those at higher risk for late recurrence based on mutational analysis or whole tumor genomic sequencing.”
All patients presented with multiple metastatic lesions, with the most common sites being lung and bone, although unusual sites, such as soft tissue, pancreas and adrenal were also detected. These patients responded well to targeted therapies (pazopanib and sunitinib) with the median time on first-line treatment of 20.1 months. The median number of sequential targeted therapies received was 2 (with a range of 1-4). Four patients died prior to the analysis. Median OS was found to be 46.6 months (range: 9.8-129), 3 year OS rate was 63%. The most common adverse events to targeted therapies in these patients were fatigue (88%), anorexia (38%) and diarrhea (50%), with 94% of all AEs reported being grade 1 or 2.15
Based on the above data, although rare, it is clear that patients are at life-long risk of recurrence after resection of localized RCC as it is possible for metastases to present >10 years after resection. Patients in our study had relatively large metastatic burden and a wide distribution of metastatic sites, insights that may be useful clinically during surveillance. Our cohort demonstrated favorable prognostic features and outcomes when compared to historical controls.
Carrobio and colleagues examined the records of 554 RCC patients who had a negative follow-up during their first 10 years following radical or partial nephrectomy. They found patients 29 (5.2%) patients who experienced disease progression after 10 years, with median occurrence in this group occurring at 13.4 years following surgery. Relapse occurred most commonly in the contralateral kidney (suggesting possible second primary in some of these cases), lung, bone, and liver. Relapse was also seen atypical sites, such as the pancreas and thyroid.16
Abara et al reported three cases of RCC relapsing more than 10 years following nephrectomy. All of the patients had relatively indolent recurrent disease, with two of them having developed oligometastatic disease and where rendered no evidence of disease after metastectomy. The third had stable disease for over four years on sorafenib.17
Late recurrence of RCC following definitive surgical resection is a known biologic behavior of RCC. Studies have characterized patients with late relapse, occurring after a disease-free interval >5 years or more, in terms of patient and tumor prognostic features and outcomes. Patients with late relapse seem to have lower T stage initial diagnosis, lower Furhman grade tumors, and generally less aggressive disease. It is certainly not surprising, as patients with more higher grade features and more aggressive disease likely recur earlier, leaving most only those patients with more indolent disease vulnerable to late recurrences.
Outcomes in patients with late relapse generally appear to be better than those relapsing earlier with longer survival times and longer response to systemic therapies, although much more research is needed to draw definitive conclusions.
The data which do exists suggest that an individualized approach to adjusting surveillance protocols may be necessary, perhaps by increasing the length of surveillance in patients with a higher propensity to relapse after 5 years.
As research in this area evolves, a next rational step would be to look beyond clinical and pathologic makers that might be associated with late relapsing RCC and explore associations with genetic and molecular markers. As next generation sequencing becomes more widespread and informatics continues to improve, it will be fascinating to see if patterns emerge that might be able to select those at higher risk for late recurrence based on mutational analysis or whole tumor genomic sequencing. Doing so may allow for more accurate selection of patients for longer term screening following definitive surgery, bringing us one step closer to true precision oncology in this subset of patients.
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