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Renal fossa recurrence after radical nephrectomy: Current management, and oncological outcomes
ARTICLE IN PRESS
Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−6
Clinical-Kidney cancer
Renal fossa recurrence after radical nephrectomy: Current management, and oncological outcomes Agustin Romeo, MD*, Patricio Garcia Marchi~ nena, MD, Alberto M. Jurado, MD, Guillermo Gueglio, MD, PhD Urology Department, Hospital Italiano de Buenos Aires, Argentina Received 12 May 2019; received in revised form 30 July 2019; accepted 7 October 2019
Abstract Introduction and objectives: Kidney cancers represent 2% of cancers worldwide; the most common type is renal clear cell carcinoma (RCC). Surgical treatment remains the only effective therapy for localized renal cell carcinoma. Approximately 20% to 38% of patients undergoing radical nephrectomy (RN) for localized RCC will have subsequent disease progression, with 0.8% to 3.6% of local recurrences within the ipsilateral retroperitoneum (RFR). The main objective of this study is to evaluate prognostic features, oncological outcomes, and current management for renal fossa recurrence in patients with history of RN for RCC. Materials and methods: We retrospectively analyzed 733 patients who underwent open or laparoscopic RN for unilateral T1-T4 N0 M0 RCC between 2010 and 2016 at the Urology Department of Hospital Italiano de Buenos Aires. Results: During the mentioned period, of a total of 733 RNs (open/laparoscopic), 561 patients with RCC were included in the study. After a median follow-up time of 24 months (12−36) (interquartile range), 21 (3.74%) patients out of 561, developed renal fossa recurrence. Of these, 13 (2.31%) patients were diagnosed with isolated local renal fossa recurrence and different treatment approaches were adopted; 11 patients underwent open surgical resection, 1 patient laparoscopic surgical resection, and 1 case was treated with cryoablation. Regarding cancer-specific survival, estimated 4-year cancer-specific survival in patients without RFR, with isolated RFR (iRFR) and not isolated RFR (niRFR) was 82.7% (CI 95% 70.2−95.2), 69.2% (IC 44.2−94.2) and 0%, respectively (log rank test P < 0.0001 being niRFR group different to others. Non isolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. Overall, 51% (IC 26.6−71.2) of patients with any RFR died at 4 years follow-up. Conclusion: Although RFR is a rare condition, in the absence of distant metastatic disease, aggressive surgical resection should be our aim. High pathological tumoral stage at original nephrectomy and high tumoral grade are independent risk factors for RFR. This group of patients needs closer follow-up to detect earlier recurrences and decide a treatment strategy. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Renal cell carcinoma; Renal fossa recurrence; Management
1. Introduction Kidney cancers represent 2% of cancers worldwide; the most common type is renal clear cell carcinoma (RCC) [1]. Surgical treatment remains the only effective therapy for localized renal cell carcinoma. In the past, about 25% of patients presented with metastatic disease at diagnosis, while today this proportion has decreased to about 13% due
*Corresponding author. Tel.: (5411) 4959-0200. E-mail address: [email protected] (A. Romeo). https://doi.org/10.1016/j.urolonc.2019.10.004 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
to increased use of improved imaging techniques leading to an earlier diagnosis. [2] Approximately 20% to 38% of patients undergoing radical nephrectomy (RN) for localized RCC will have subsequent disease progression, with 0.8% to 3.6% of local recurrences within the ipsilateral retroperitoneum including soft tissue recurrences within the renal fossa, ipsilateral psoas muscle, ipsilateral adrenal gland, and regional lymph nodes [3]. The reported incidence of recurrences isolated to the renal fossa alone is 1% to 2% of which 50% to 80% are asymptomatic and discovered on routine follow-up [3].
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A. Romeo et al. / Urologic Oncology: Seminars and Original Investigations 00 (2019) 1−6
Isolated renal fossa recurrence (iRFR) is rare but important to distinguish from local recurrence with synchronous metastasis, which would benefit from surgical resection in selected cases (solitary metastasis). Isolated local recurrence of renal cell carcinoma after RN represents a difficult therapeutic decision because patients with local recurrence must be considered at high risk of developing metastatic disease. On the other hand, the sometimes long course of disease progression in renal cell carcinoma may be considered a reason to treat an isolated local recurrence with the same principles as localized primary renal cell carcinoma [4]. Data on natural history, patient outcomes and prognostic factors associated with RFR are scarce and there is no standardized management strategy. In the era of targeted therapy for locally advanced and metastatic RCC, treatment strategies using combinations of medical and surgical therapies in patients diagnosed with localized recurrence after nephrectomy are paramount in maximizing oncological outcomes [5]. The main objective of this study is to evaluate prognostic features and oncological outcomes for renal fossa recurrence in patients with history of RN for renal cell carcinoma. Also, we evaluated the management and the treatment options adopted for each patient with RFR and the survival in all cases.
2. Materials and methods In the present study, we retrospectively analyzed 733 consecutive patients who underwent open or laparoscopic RN for unilateral T1-T4, N0, M0 RCC between January 2010 and December 2016 at the Urology Department of Hospital Italiano de Buenos Aires, Argentina. Data was collected from our electronic medical record and prospective database for renal mass study (Clinical Research Office of the Endourological Society, CROES). All patients were followed until death (all-cause mortality) or last contact within the first year after RN, at which time they were censored. During follow up, all patients were evaluated with laboratory test, abdominal ultrasound, CT scan or MRI if necessary, as established in the latest EAU Guidelines for RCC [6]. Initial diagnosis of RFR was based on CT scan or MRI findings together with local and/or systemic symptoms. Renal fossa recurrence (RFR) was defined as the appearance of a new tumour in the renal fossa soft tissue, psoas muscle or ipsilateral retroperitoneal/hiliar lymph nodes, excluding ipsilateral adrenal gland. Isolated renal fossa recurrence (iRFR) was defined as the appearance of RFR in the absence of distant metastasis and not isolated RFR as the appearance of RFR in the setting of synchronous distant metastasis.
Statistical analysis: Continuous variables were presented as median and interquartile range and for their comparison, Kruskall-Wallis test with Bonferroni adjustment was used. Categorical variables were summarized as counts (frequency percentages) and they were compared with the chi2 test or Fisher’s exact test when appropriate. Univariate and multivariate analysis was performed by Cox regression. All noncollinear variables with a P value ≤ 0.1 on univariable analysis were included in the multivariable model. For constructing a multivariate model, no more than 4 variables were analyzed in order to avoid overfitting. Regression results were expressed as hazard ratio (HR) with 95% confidence interval (95%). Survival curves were presented as Kaplan−Meier curves, and the log-rank test was used for comparison between groups. All of the analyses were considered significant at a 2-tailed P value of ≤0.05. Relapse free survival (RFS) was defined as time from RN to disease recurrence. Cancer-specific survival (CSS) was defined as time from nephrectomy to death. All statistical tests were performed using statistical software SPSS 23.0 for Microsoft (SPSS Inc; IBM, Chicago, IL) and Graph Pad Prism version 7.0 for Microsoft (GraphPad Software, La Jolla, CA). 3. Results During the mentioned period, of a total of 733 radical nephrectomies (open/laparoscopic), a group of 172 patients was excluded: 52 patients because of benign pathology or urothelial tumour, 115 patients due to metastatic disease, lymph node invasion or positive surgical margins, and 5 patients only underwent exploratory laparotomy (unresectable renal mass). After a median follow-up time of 24 months (12−36) (interquartile range), 21 (3.74%) patients out of 561 included with renal cell carcinoma in the study, developed renal fossa recurrence. Of these, 13 (2.31%) patients were diagnosed with isolated local renal fossa recurrence (Fig. 1). Mean time from RN to diagnosis of any RFR was 29.7 (3−106) months while in iRFR subgroup was 42 (9−106) months. Clinicopathological features of patients who developed iRFR or any RFR are summarized in Table 1. 3.1. Management iRFR after RN poses a therapeutic challenge. Regarding the 13 patients with proven isolated local recurrence, different treatment approaches were adopted; 11 patients underwent open surgical resection, 1 patient laparoscopic surgical resection, and 1 patient percutaneous cryoablation. After surgical resection, tumoral grade was available in 11/12 patients and was grade 2 in 1 (8.3%), grade 3 in 4 (33.3%), and grade 4 with sarcomatoid features in 2 patients (16.6%). Histology was clear cell carcinoma in 8 (66.6%),
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Fig. 1. Consort flow diagram shows patients included in analysis, treatment strategy and disease progression.
papillary II in 3 (25%), and RCC without specified histological subtype in 1 patient (8.3%). There were no histological differences in pathological specimens when comparing initial RN and resected recurrences. Among the 12 patients who underwent surgical resection, 5 (41.6%) had negative resection margins and are free of disease (R0). The other 7 patients (58.3%) developed metastatic disease (lung, bone, or liver dissemination). Five of them had negative resection margins and 2 positive resection margins. All of them underwent salvage target therapy with sunitinib or pazopanib. In case of disease progression, systemic therapy was modified to second-line treatment (axitinib or everolimus). Among the 8 (38%) patients that were diagnosed with RFR in the setting of synchronous metastatic disease (niRFR), 5 (23.8%) were treated with salvage target therapy (sunitinib/pazopanib), and 3 (14.2%) with target therapy and palliative radiation. None of them survived at 4 years. Percutaneous cryoablation was a successful strategy adopted in 1 patient with a left retroperitoneal recurrence 4 years after left RN (Fig. 2). This was the only patient with confirmatory biopsy prior to treatment. After 18 months of follow up, the retroperitoneal mass had no enhancement on CT scan and the size decreased from 22 mm to 15 mm.
3.2. Follow-up and survival In the entire cohort of 561 patients, the estimated 4-year overall RFS rate was 94.9% (IC 91.9−97.8). Estimated 4year RFS for iRFR and niRFR was 90.9% (IC 84.9−96.9) and 97.9% (IC 96.−-99.5), respectively. Regarding CSS, estimated 4-year CSS in patients without RFR, with iRFR and niRFR was 82.7% (confidence interval 95% 70.2−95.2), 69.2% (IC 44.2−94.2), and 0%, respectively (log rank test P < 0.0001), being niRFR group different to others (Fig. 3). Nonisolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. Overall, 51% (IC 26.6−71.2) of patients with any RFR died at 4 years follow-up. Univariable and multivariable models describing prognostic features associated with iRFR are summarized in Table 2. On univariable analysis, lymph node invasion, sex, age, and histological subtype did not result as iRFR predictors. Considering pT1a stage as reference, only pT4 stage resulted as iRFR predictor, with a HR 21.2. ISUP tumoral grade III/IV was nearly significant with P value 0.09. On multivariable analysis, pT4 (adjusted by tumoral grade III/IV), remained as iRFR predictor.
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Table 1 Clinicopathological features of patients with RFR
Age, years. median (IQR) Sex (male %) Right side tumor (%) Approach (%) Open Lap Robotic Pathological grade (%) I II III IV 2010 pTNM (%) T1a T1b T2 T3a T3b T3c T4 Max. tumoral diameter; mm, median (IQR) RCC histological subtype (%) Clear cell Papillary chromophobe Lymph node involvement (%)
No recurrence (N = 540)
Isolated RFR (N = 13)
ni RFR (N = 8)
P value
63.5 (53−72) 377 (69.8) 277 (51.3)
61 (54.5−69) 12 (92.3) 5 (38.5)
58 (47.5−72) 6 (75) 6 (75)
0.914 0.205 0.265 0.006
150 (27.8) 384 (71.1) 6 (1.1)
10 (76.9) 3 (23.1) 0
7 (87.5) 1 (12.5) 0
27 (5) 129 (23.9) 273 (50.6) 111 (20.6)
1 (7.7) 1 (7.7) 6 (46.2) 5 (38.5)
0 0 2 (25) 6 (75)
127 (23.5) 166 (30.7) 75 (13.9) 131 (24.3) 34 (6.3) 2 (0.4) 5 (0.9) 55 (40−77)
2 (15.4) 1 (7.7) 1 (7.7) 6 (46.2) 1 (7.7) 0 2 (15.4) 65 (37.5−84)
0 0 2 (25) 2 (25) 1 (12.5) 2 (25) 1 (12.5) 95 (70−158)
459 (85) 26 (4.8) 55 (10.2) 36 (6.7)
10 (76.9) 3 (23.1) 0 2 (15.4)
8 (100) 0 0 1(12.5)
0.014
0.001
0.004 0.037
0.306
IQR = interquartile range; RCC = renal cell carcinoma; RFR = renal fossa recurrence.
Fig. 2. Cryoablation of retroperitoneal relapse.
4. Discussion Isolated RFR after RN is a rare event and without treatment, it has an unfavorable outcome.
According to previously reported data, when recurrence of RCC occurs within the retroperitoneum, up to 86% of patients die within the first 12 months. Currently, survival rates and response rates have improved with targeted
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Fig. 3. Cancer-specific survival for patients with no recurrence, iRFR and niRFR. RFR = renal fossa recurrence.
therapy for metastatic RCC. However, median overall survival continues to be less than 24 months [10]. Local recurrence after RN represents a therapeutic challenge. In the current study, we report our treatment strategy and prognostic features for this rare event. Itano et al. [7] reported an iRFR incidence of 1.8% (30/ 1737 patients) and Schrodter et al. [2] an incidence of 0.8% (8/1031 patients). These findings are similar to our number of cases identified; 13 patients with iRFR (2.31%) with a mean time from RN to diagnosis of 42 (9−106) months. Only 2 (15.3%) patients in our series who developed an iRFR, had pT1a disease after RN. This is consistent with the majority of reports, such as Psutka et al. [3] (14%) and Margulis et al. [5] (18%). Follow-up in patients after nephrectomy should be more frequent, specifically in patients with T3 or T4 disease, so as to detect local relapses earlier.
5
The present data does not indicate that histological subtype is correlated with RFR or survival, although this might be due to the small sample size. On multivariable analysis, pT4 stage (adjusted by tumoral grade III/IV) was associated with an increased risk of iRFR, similarly to Psutka et al. [3] findings. The analyzed oncological outcomes are in line with data published a few years ago. Median and mean time to development of any RFR was 1 year (12 months) and 2.4 years (29 months) respectively, and this correlates with other previous reports, in which time to recurrence ranged between 1.1 and 3.3 years [8−11]. After surgical treatment, 5 (41.6%) patients out of 12 had negative resection margins and are free of disease (R0). Disease progression after surgery was observed in 7 patients (58.3%), with metastatic disease in lung, bone, or liver. All of them underwent salvage target therapy. Thomas et al. [10] reported a single institutional study of 102 patients with RFR treated with surgical resection. In this group, 42 (41.2%) patients remained with no disease evidence and without any further therapies: 60/102 patients (59%) progressed to metastatic disease after RFR surgery of which 48 (80%) received salvage systemic therapy [12]. In our cohort, among the 8 (38%) patients that were diagnosed with RFR in the setting of synchronous metastatic disease (niRFR), 5 (23.8%) were treated with salvage target therapy (sunitinib/pazopanib), and 3 (14.2%) with target therapy and palliative radiation. In our survival analysis, nonisolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. None of the patients with niRFR survived at 4 years.
Table 2 Univariable and multivariable Cox regression analysis for predictors of development of isolated renal fossa recurrence
Lymph node pTNM pT1a pT1b pT2 pT3a pT3b pT3c pT4 Age Sex (male) ISUP grade I-II III-IV RCC subtype Other RCC Clear cell RCC
iRFR uni HR CI 95%
iRFR P value
2.9 (0.6−13)
0.165
ref. 0.4 (0.1−4.2) 0.7 (0.1−7.4) 2.7 (0.5−14) 1.5 (0.1−17) not measurable 21.2 (2.9−151) 1 (0.9−1.1) 5.7 (0.7−44)
ref. 0.426 0.742 0.228 0.721 0.002 0.668 0.094
ref. 5.9 (0.7−45)
0.09
ref. 0.4 (0.2−2.2)
0.59
iRFR multi HR CI 95%
iRFR P value
ref. 0.3 (0.1−3) 0.4 (0.1−4.3) 1.4 (0.2−7.5) 0.8 (0.1−9.9) not measurable 8.7 (1.1−68)
ref. 0.301 0.433 0.728 0.905
3.7 (0.5−30)
0.212
ref. 3.5 (0.4−31)
0.259
0.041
HR = hazard ratio; ISUP = International Society of Urological Pathology; Multi = multivariable; RCC = renal cell carcinoma; RFR = renal fossa recurrence; TNM = Tumour, Node, Metastasis; Uni = univariable.
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Thomas et al. [10] and Itano et al. [7] reported an estimated 5-year CSS rate in iRFR subgroup of 52% and 51%, respectively. This survival rate is similar in our cohort, in which we observed an estimated 4-year CSS for iRFR of 69.2% (IC 44.2−94.2) [12]. Currently, there is no standardized algorithm for guiding the treatment in RFR and as said previously, surgical treatment of local recurrences is very challenging. While most of the published series have achieved surgical resection through open access, recent case series have suggested that laparoscopic extirpation of RFR can be achieved safely in experienced hands [12,13]. We agree that laparoscopic resection is feasible in selected patients, with the benefit of less morbidity and faster recovery. We performed a laparoscopic transperitoneal resection of a left retroperitoneal recurrence 18 years after RN. The resection was successful, and pathology showed a clear cell carcinoma tumor with negative margins (R0). Alternatively, percutaneous thermal ablation (cryotherapy) has appeared as a minimally invasive strategy for RFR treatment, mainly in selected patients with high morbidity and elevated surgical risk. Suson et al. [14] reported cryoablation of RFR in 3 patients, of whom 1 patient was successfully treated, 1 required repeat treatment for persistent enhancement of the fossa mass, and the third ultimately required surgical excision 9 months after the ablation. To our knowledge, we are the first institution in Latin America to report a case of cryoablation of a left retroperitoneal recurrence 4 years after a left RN. As commented previously, the patient had a 22 mm mass with contrast enhancement on CT scan and MRI. One year after cryoablation, the retroperitoneal mass had no enhancement on CT scan and the size decreased to 15 mm. With respect to systemic therapy, there is not enough evidence to use neoadjuvant target therapy before surgical resection. However, Shuch et al. [15] observed a decrease in retroperitoneal tumor mean size on bevacizumab. Chow et al. [1] suggested early systemic therapy in case of RFR with metastatic disease, tumour size >5 cm, sarcomatoid histology or increase lactate dehydrogenase serum value. We consider that first-line target therapy should be used in these cases and when positive surgical margins are observed after surgical resection (salvage target therapy). This study has some limitations that should be noted. This is a retrospective analysis of a selected patient cohort, who were treated in a single referral institution. Our selected cohort was heterogeneous and included patients with lymph nodes, soft tissue, and psoas muscle recurrence. Although the incidence of RFR was low according to published literature, longer follow-up is necessary to detect potential cases of RFR of very late appearance. 5. Conclusion RFR is a rare condition and in the absence of distant metastatic disease, maximal surgical resection should be our aim to provide a survival advantage.
High pathological tumoral stage (pT) at original nephrectomy and high tumoral grade (ISUP Grade) are independent risk factors for RFR. This group of patients needs closer follow-up to detect earlier recurrences and decide a treatment strategy. Conflict of interest Authors have no conflicts of interest. Acknowledgments We gratefully thank Ignacio Tobia MD for contributing in statistical analysis. References [1] Chow J-J, Ahmed K, Fazili Z, Sheikh M, Sheriff M. Solitary renal fossa recurrence of renal cell carcinoma after nephrectomy. Rev Urol 2014;16:76–82. [2] Schr€odter S, Hakenberg OW, Manseck A, Leike S, Wirth MP. Outcome of surgical treatment of isolated local recurrence after radical nephrectomy for renal cell carcinoma. J Urol 2002;167:1630–3. [3] Psutka SP, et al. Renal fossa recurrence after nephrectomy for renal cell carcinoma: prognostic features and oncological outcomes. BJU Int 2017;119:116–27. [4] Newmark JR, Newmark GM, Epstein JI, Marshall FE. Solitary late recurrence of renal cell carcinoma. Urology 1994;43:725–8. [5] Margulis V, McDonald M, Tamboli P, Swanson DA, Wood CG. Predictors of oncological outcome after resection of locally recurrent renal cell carcinoma. J Urol 2009;181:2044–51. [6] Ljungberg B, et al. EAU guidelines on renal cell carcinoma: 2014 update. European Urol 2015;67:913–24. [7] Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 2000;164:322–5. [8] Master VA, Gottschalk AR, Kane C, Carroll PR. Management of isolated renal fossa recurrence following radical nephrectomy. J Urol 2005;174:473–7. [9] Fayek IS, Habashy HF, Habashy NF. Isolated loco-regional recurrence after radical nephrectomy for renal cell carcinoma: a study of 22 patients. J Egypt Natl Canc Inst 2014;26:161–6. [10] Thomas AZ, Adibi M, Borregales LD, et al. Surgical management of local retroperitoneal recurrence of renal cell carcinoma after radical nephrectomy. J Urol 2015;194:316–22. https://doi.org/10.1016/j. juro.2015.02.2943. [11] Schrodter S, Hakenberg OW, Manseck A, Leike S, Wirth MP. Outcome of surgical treatment of isolated local recurrence after radical nephrectomy for renal cell carcinoma. J Urol 2002:1630–3. https:// doi.org/10.1097/00005392-200204000-00013. [12] Vitagliano G, Ameri C, Castillo O, Rozanec J. Laparoscopic resection of isolated fossa recurrence of renal cell carcinoma after open nephrectomy: report of 6 cases and literature review. Arch Esp Urol 2014;67:277–83. [13] Bandi G, Wen CC, Moon TD, Nakada SY. Single center preliminary experience with hand-assisted laparoscopic resection of isolated renal cell carcinoma fossa recurrences. Urology 2008;71:495–9:discussion 499−500. [14] Suson KD, Richard H, Phelan MW. Cryoablation of renal fossa recurrence after radical nephrectomy. J Endourol 2011;25:559–62. [15] Shuch B, Riggs SB, LaRochelle JC, et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008;102:692–6.
Urologic Oncology: Seminars and Original Investigations 000 (2019) 1−6
Clinical-Kidney cancer
Renal fossa recurrence after radical nephrectomy: Current management, and oncological outcomes Agustin Romeo, MD*, Patricio Garcia Marchi~ nena, MD, Alberto M. Jurado, MD, Guillermo Gueglio, MD, PhD Urology Department, Hospital Italiano de Buenos Aires, Argentina Received 12 May 2019; received in revised form 30 July 2019; accepted 7 October 2019
Abstract Introduction and objectives: Kidney cancers represent 2% of cancers worldwide; the most common type is renal clear cell carcinoma (RCC). Surgical treatment remains the only effective therapy for localized renal cell carcinoma. Approximately 20% to 38% of patients undergoing radical nephrectomy (RN) for localized RCC will have subsequent disease progression, with 0.8% to 3.6% of local recurrences within the ipsilateral retroperitoneum (RFR). The main objective of this study is to evaluate prognostic features, oncological outcomes, and current management for renal fossa recurrence in patients with history of RN for RCC. Materials and methods: We retrospectively analyzed 733 patients who underwent open or laparoscopic RN for unilateral T1-T4 N0 M0 RCC between 2010 and 2016 at the Urology Department of Hospital Italiano de Buenos Aires. Results: During the mentioned period, of a total of 733 RNs (open/laparoscopic), 561 patients with RCC were included in the study. After a median follow-up time of 24 months (12−36) (interquartile range), 21 (3.74%) patients out of 561, developed renal fossa recurrence. Of these, 13 (2.31%) patients were diagnosed with isolated local renal fossa recurrence and different treatment approaches were adopted; 11 patients underwent open surgical resection, 1 patient laparoscopic surgical resection, and 1 case was treated with cryoablation. Regarding cancer-specific survival, estimated 4-year cancer-specific survival in patients without RFR, with isolated RFR (iRFR) and not isolated RFR (niRFR) was 82.7% (CI 95% 70.2−95.2), 69.2% (IC 44.2−94.2) and 0%, respectively (log rank test P < 0.0001 being niRFR group different to others. Non isolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. Overall, 51% (IC 26.6−71.2) of patients with any RFR died at 4 years follow-up. Conclusion: Although RFR is a rare condition, in the absence of distant metastatic disease, aggressive surgical resection should be our aim. High pathological tumoral stage at original nephrectomy and high tumoral grade are independent risk factors for RFR. This group of patients needs closer follow-up to detect earlier recurrences and decide a treatment strategy. Ó 2019 Elsevier Inc. All rights reserved.
Keywords: Renal cell carcinoma; Renal fossa recurrence; Management
1. Introduction Kidney cancers represent 2% of cancers worldwide; the most common type is renal clear cell carcinoma (RCC) [1]. Surgical treatment remains the only effective therapy for localized renal cell carcinoma. In the past, about 25% of patients presented with metastatic disease at diagnosis, while today this proportion has decreased to about 13% due
*Corresponding author. Tel.: (5411) 4959-0200. E-mail address: [email protected] (A. Romeo). https://doi.org/10.1016/j.urolonc.2019.10.004 1078-1439/Ó 2019 Elsevier Inc. All rights reserved.
to increased use of improved imaging techniques leading to an earlier diagnosis. [2] Approximately 20% to 38% of patients undergoing radical nephrectomy (RN) for localized RCC will have subsequent disease progression, with 0.8% to 3.6% of local recurrences within the ipsilateral retroperitoneum including soft tissue recurrences within the renal fossa, ipsilateral psoas muscle, ipsilateral adrenal gland, and regional lymph nodes [3]. The reported incidence of recurrences isolated to the renal fossa alone is 1% to 2% of which 50% to 80% are asymptomatic and discovered on routine follow-up [3].
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Isolated renal fossa recurrence (iRFR) is rare but important to distinguish from local recurrence with synchronous metastasis, which would benefit from surgical resection in selected cases (solitary metastasis). Isolated local recurrence of renal cell carcinoma after RN represents a difficult therapeutic decision because patients with local recurrence must be considered at high risk of developing metastatic disease. On the other hand, the sometimes long course of disease progression in renal cell carcinoma may be considered a reason to treat an isolated local recurrence with the same principles as localized primary renal cell carcinoma [4]. Data on natural history, patient outcomes and prognostic factors associated with RFR are scarce and there is no standardized management strategy. In the era of targeted therapy for locally advanced and metastatic RCC, treatment strategies using combinations of medical and surgical therapies in patients diagnosed with localized recurrence after nephrectomy are paramount in maximizing oncological outcomes [5]. The main objective of this study is to evaluate prognostic features and oncological outcomes for renal fossa recurrence in patients with history of RN for renal cell carcinoma. Also, we evaluated the management and the treatment options adopted for each patient with RFR and the survival in all cases.
2. Materials and methods In the present study, we retrospectively analyzed 733 consecutive patients who underwent open or laparoscopic RN for unilateral T1-T4, N0, M0 RCC between January 2010 and December 2016 at the Urology Department of Hospital Italiano de Buenos Aires, Argentina. Data was collected from our electronic medical record and prospective database for renal mass study (Clinical Research Office of the Endourological Society, CROES). All patients were followed until death (all-cause mortality) or last contact within the first year after RN, at which time they were censored. During follow up, all patients were evaluated with laboratory test, abdominal ultrasound, CT scan or MRI if necessary, as established in the latest EAU Guidelines for RCC [6]. Initial diagnosis of RFR was based on CT scan or MRI findings together with local and/or systemic symptoms. Renal fossa recurrence (RFR) was defined as the appearance of a new tumour in the renal fossa soft tissue, psoas muscle or ipsilateral retroperitoneal/hiliar lymph nodes, excluding ipsilateral adrenal gland. Isolated renal fossa recurrence (iRFR) was defined as the appearance of RFR in the absence of distant metastasis and not isolated RFR as the appearance of RFR in the setting of synchronous distant metastasis.
Statistical analysis: Continuous variables were presented as median and interquartile range and for their comparison, Kruskall-Wallis test with Bonferroni adjustment was used. Categorical variables were summarized as counts (frequency percentages) and they were compared with the chi2 test or Fisher’s exact test when appropriate. Univariate and multivariate analysis was performed by Cox regression. All noncollinear variables with a P value ≤ 0.1 on univariable analysis were included in the multivariable model. For constructing a multivariate model, no more than 4 variables were analyzed in order to avoid overfitting. Regression results were expressed as hazard ratio (HR) with 95% confidence interval (95%). Survival curves were presented as Kaplan−Meier curves, and the log-rank test was used for comparison between groups. All of the analyses were considered significant at a 2-tailed P value of ≤0.05. Relapse free survival (RFS) was defined as time from RN to disease recurrence. Cancer-specific survival (CSS) was defined as time from nephrectomy to death. All statistical tests were performed using statistical software SPSS 23.0 for Microsoft (SPSS Inc; IBM, Chicago, IL) and Graph Pad Prism version 7.0 for Microsoft (GraphPad Software, La Jolla, CA). 3. Results During the mentioned period, of a total of 733 radical nephrectomies (open/laparoscopic), a group of 172 patients was excluded: 52 patients because of benign pathology or urothelial tumour, 115 patients due to metastatic disease, lymph node invasion or positive surgical margins, and 5 patients only underwent exploratory laparotomy (unresectable renal mass). After a median follow-up time of 24 months (12−36) (interquartile range), 21 (3.74%) patients out of 561 included with renal cell carcinoma in the study, developed renal fossa recurrence. Of these, 13 (2.31%) patients were diagnosed with isolated local renal fossa recurrence (Fig. 1). Mean time from RN to diagnosis of any RFR was 29.7 (3−106) months while in iRFR subgroup was 42 (9−106) months. Clinicopathological features of patients who developed iRFR or any RFR are summarized in Table 1. 3.1. Management iRFR after RN poses a therapeutic challenge. Regarding the 13 patients with proven isolated local recurrence, different treatment approaches were adopted; 11 patients underwent open surgical resection, 1 patient laparoscopic surgical resection, and 1 patient percutaneous cryoablation. After surgical resection, tumoral grade was available in 11/12 patients and was grade 2 in 1 (8.3%), grade 3 in 4 (33.3%), and grade 4 with sarcomatoid features in 2 patients (16.6%). Histology was clear cell carcinoma in 8 (66.6%),
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Fig. 1. Consort flow diagram shows patients included in analysis, treatment strategy and disease progression.
papillary II in 3 (25%), and RCC without specified histological subtype in 1 patient (8.3%). There were no histological differences in pathological specimens when comparing initial RN and resected recurrences. Among the 12 patients who underwent surgical resection, 5 (41.6%) had negative resection margins and are free of disease (R0). The other 7 patients (58.3%) developed metastatic disease (lung, bone, or liver dissemination). Five of them had negative resection margins and 2 positive resection margins. All of them underwent salvage target therapy with sunitinib or pazopanib. In case of disease progression, systemic therapy was modified to second-line treatment (axitinib or everolimus). Among the 8 (38%) patients that were diagnosed with RFR in the setting of synchronous metastatic disease (niRFR), 5 (23.8%) were treated with salvage target therapy (sunitinib/pazopanib), and 3 (14.2%) with target therapy and palliative radiation. None of them survived at 4 years. Percutaneous cryoablation was a successful strategy adopted in 1 patient with a left retroperitoneal recurrence 4 years after left RN (Fig. 2). This was the only patient with confirmatory biopsy prior to treatment. After 18 months of follow up, the retroperitoneal mass had no enhancement on CT scan and the size decreased from 22 mm to 15 mm.
3.2. Follow-up and survival In the entire cohort of 561 patients, the estimated 4-year overall RFS rate was 94.9% (IC 91.9−97.8). Estimated 4year RFS for iRFR and niRFR was 90.9% (IC 84.9−96.9) and 97.9% (IC 96.−-99.5), respectively. Regarding CSS, estimated 4-year CSS in patients without RFR, with iRFR and niRFR was 82.7% (confidence interval 95% 70.2−95.2), 69.2% (IC 44.2−94.2), and 0%, respectively (log rank test P < 0.0001), being niRFR group different to others (Fig. 3). Nonisolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. Overall, 51% (IC 26.6−71.2) of patients with any RFR died at 4 years follow-up. Univariable and multivariable models describing prognostic features associated with iRFR are summarized in Table 2. On univariable analysis, lymph node invasion, sex, age, and histological subtype did not result as iRFR predictors. Considering pT1a stage as reference, only pT4 stage resulted as iRFR predictor, with a HR 21.2. ISUP tumoral grade III/IV was nearly significant with P value 0.09. On multivariable analysis, pT4 (adjusted by tumoral grade III/IV), remained as iRFR predictor.
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Table 1 Clinicopathological features of patients with RFR
Age, years. median (IQR) Sex (male %) Right side tumor (%) Approach (%) Open Lap Robotic Pathological grade (%) I II III IV 2010 pTNM (%) T1a T1b T2 T3a T3b T3c T4 Max. tumoral diameter; mm, median (IQR) RCC histological subtype (%) Clear cell Papillary chromophobe Lymph node involvement (%)
No recurrence (N = 540)
Isolated RFR (N = 13)
ni RFR (N = 8)
P value
63.5 (53−72) 377 (69.8) 277 (51.3)
61 (54.5−69) 12 (92.3) 5 (38.5)
58 (47.5−72) 6 (75) 6 (75)
0.914 0.205 0.265 0.006
150 (27.8) 384 (71.1) 6 (1.1)
10 (76.9) 3 (23.1) 0
7 (87.5) 1 (12.5) 0
27 (5) 129 (23.9) 273 (50.6) 111 (20.6)
1 (7.7) 1 (7.7) 6 (46.2) 5 (38.5)
0 0 2 (25) 6 (75)
127 (23.5) 166 (30.7) 75 (13.9) 131 (24.3) 34 (6.3) 2 (0.4) 5 (0.9) 55 (40−77)
2 (15.4) 1 (7.7) 1 (7.7) 6 (46.2) 1 (7.7) 0 2 (15.4) 65 (37.5−84)
0 0 2 (25) 2 (25) 1 (12.5) 2 (25) 1 (12.5) 95 (70−158)
459 (85) 26 (4.8) 55 (10.2) 36 (6.7)
10 (76.9) 3 (23.1) 0 2 (15.4)
8 (100) 0 0 1(12.5)
0.014
0.001
0.004 0.037
0.306
IQR = interquartile range; RCC = renal cell carcinoma; RFR = renal fossa recurrence.
Fig. 2. Cryoablation of retroperitoneal relapse.
4. Discussion Isolated RFR after RN is a rare event and without treatment, it has an unfavorable outcome.
According to previously reported data, when recurrence of RCC occurs within the retroperitoneum, up to 86% of patients die within the first 12 months. Currently, survival rates and response rates have improved with targeted
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Fig. 3. Cancer-specific survival for patients with no recurrence, iRFR and niRFR. RFR = renal fossa recurrence.
therapy for metastatic RCC. However, median overall survival continues to be less than 24 months [10]. Local recurrence after RN represents a therapeutic challenge. In the current study, we report our treatment strategy and prognostic features for this rare event. Itano et al. [7] reported an iRFR incidence of 1.8% (30/ 1737 patients) and Schrodter et al. [2] an incidence of 0.8% (8/1031 patients). These findings are similar to our number of cases identified; 13 patients with iRFR (2.31%) with a mean time from RN to diagnosis of 42 (9−106) months. Only 2 (15.3%) patients in our series who developed an iRFR, had pT1a disease after RN. This is consistent with the majority of reports, such as Psutka et al. [3] (14%) and Margulis et al. [5] (18%). Follow-up in patients after nephrectomy should be more frequent, specifically in patients with T3 or T4 disease, so as to detect local relapses earlier.
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The present data does not indicate that histological subtype is correlated with RFR or survival, although this might be due to the small sample size. On multivariable analysis, pT4 stage (adjusted by tumoral grade III/IV) was associated with an increased risk of iRFR, similarly to Psutka et al. [3] findings. The analyzed oncological outcomes are in line with data published a few years ago. Median and mean time to development of any RFR was 1 year (12 months) and 2.4 years (29 months) respectively, and this correlates with other previous reports, in which time to recurrence ranged between 1.1 and 3.3 years [8−11]. After surgical treatment, 5 (41.6%) patients out of 12 had negative resection margins and are free of disease (R0). Disease progression after surgery was observed in 7 patients (58.3%), with metastatic disease in lung, bone, or liver. All of them underwent salvage target therapy. Thomas et al. [10] reported a single institutional study of 102 patients with RFR treated with surgical resection. In this group, 42 (41.2%) patients remained with no disease evidence and without any further therapies: 60/102 patients (59%) progressed to metastatic disease after RFR surgery of which 48 (80%) received salvage systemic therapy [12]. In our cohort, among the 8 (38%) patients that were diagnosed with RFR in the setting of synchronous metastatic disease (niRFR), 5 (23.8%) were treated with salvage target therapy (sunitinib/pazopanib), and 3 (14.2%) with target therapy and palliative radiation. In our survival analysis, nonisolated RFR was a death risk factor with a HR of 11.4 (4.8−27.2) compared with iRFR or no recurrence. None of the patients with niRFR survived at 4 years.
Table 2 Univariable and multivariable Cox regression analysis for predictors of development of isolated renal fossa recurrence
Lymph node pTNM pT1a pT1b pT2 pT3a pT3b pT3c pT4 Age Sex (male) ISUP grade I-II III-IV RCC subtype Other RCC Clear cell RCC
iRFR uni HR CI 95%
iRFR P value
2.9 (0.6−13)
0.165
ref. 0.4 (0.1−4.2) 0.7 (0.1−7.4) 2.7 (0.5−14) 1.5 (0.1−17) not measurable 21.2 (2.9−151) 1 (0.9−1.1) 5.7 (0.7−44)
ref. 0.426 0.742 0.228 0.721 0.002 0.668 0.094
ref. 5.9 (0.7−45)
0.09
ref. 0.4 (0.2−2.2)
0.59
iRFR multi HR CI 95%
iRFR P value
ref. 0.3 (0.1−3) 0.4 (0.1−4.3) 1.4 (0.2−7.5) 0.8 (0.1−9.9) not measurable 8.7 (1.1−68)
ref. 0.301 0.433 0.728 0.905
3.7 (0.5−30)
0.212
ref. 3.5 (0.4−31)
0.259
0.041
HR = hazard ratio; ISUP = International Society of Urological Pathology; Multi = multivariable; RCC = renal cell carcinoma; RFR = renal fossa recurrence; TNM = Tumour, Node, Metastasis; Uni = univariable.
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Thomas et al. [10] and Itano et al. [7] reported an estimated 5-year CSS rate in iRFR subgroup of 52% and 51%, respectively. This survival rate is similar in our cohort, in which we observed an estimated 4-year CSS for iRFR of 69.2% (IC 44.2−94.2) [12]. Currently, there is no standardized algorithm for guiding the treatment in RFR and as said previously, surgical treatment of local recurrences is very challenging. While most of the published series have achieved surgical resection through open access, recent case series have suggested that laparoscopic extirpation of RFR can be achieved safely in experienced hands [12,13]. We agree that laparoscopic resection is feasible in selected patients, with the benefit of less morbidity and faster recovery. We performed a laparoscopic transperitoneal resection of a left retroperitoneal recurrence 18 years after RN. The resection was successful, and pathology showed a clear cell carcinoma tumor with negative margins (R0). Alternatively, percutaneous thermal ablation (cryotherapy) has appeared as a minimally invasive strategy for RFR treatment, mainly in selected patients with high morbidity and elevated surgical risk. Suson et al. [14] reported cryoablation of RFR in 3 patients, of whom 1 patient was successfully treated, 1 required repeat treatment for persistent enhancement of the fossa mass, and the third ultimately required surgical excision 9 months after the ablation. To our knowledge, we are the first institution in Latin America to report a case of cryoablation of a left retroperitoneal recurrence 4 years after a left RN. As commented previously, the patient had a 22 mm mass with contrast enhancement on CT scan and MRI. One year after cryoablation, the retroperitoneal mass had no enhancement on CT scan and the size decreased to 15 mm. With respect to systemic therapy, there is not enough evidence to use neoadjuvant target therapy before surgical resection. However, Shuch et al. [15] observed a decrease in retroperitoneal tumor mean size on bevacizumab. Chow et al. [1] suggested early systemic therapy in case of RFR with metastatic disease, tumour size >5 cm, sarcomatoid histology or increase lactate dehydrogenase serum value. We consider that first-line target therapy should be used in these cases and when positive surgical margins are observed after surgical resection (salvage target therapy). This study has some limitations that should be noted. This is a retrospective analysis of a selected patient cohort, who were treated in a single referral institution. Our selected cohort was heterogeneous and included patients with lymph nodes, soft tissue, and psoas muscle recurrence. Although the incidence of RFR was low according to published literature, longer follow-up is necessary to detect potential cases of RFR of very late appearance. 5. Conclusion RFR is a rare condition and in the absence of distant metastatic disease, maximal surgical resection should be our aim to provide a survival advantage.
High pathological tumoral stage (pT) at original nephrectomy and high tumoral grade (ISUP Grade) are independent risk factors for RFR. This group of patients needs closer follow-up to detect earlier recurrences and decide a treatment strategy. Conflict of interest Authors have no conflicts of interest. Acknowledgments We gratefully thank Ignacio Tobia MD for contributing in statistical analysis. References [1] Chow J-J, Ahmed K, Fazili Z, Sheikh M, Sheriff M. Solitary renal fossa recurrence of renal cell carcinoma after nephrectomy. Rev Urol 2014;16:76–82. [2] Schr€odter S, Hakenberg OW, Manseck A, Leike S, Wirth MP. Outcome of surgical treatment of isolated local recurrence after radical nephrectomy for renal cell carcinoma. J Urol 2002;167:1630–3. [3] Psutka SP, et al. Renal fossa recurrence after nephrectomy for renal cell carcinoma: prognostic features and oncological outcomes. BJU Int 2017;119:116–27. [4] Newmark JR, Newmark GM, Epstein JI, Marshall FE. Solitary late recurrence of renal cell carcinoma. Urology 1994;43:725–8. [5] Margulis V, McDonald M, Tamboli P, Swanson DA, Wood CG. Predictors of oncological outcome after resection of locally recurrent renal cell carcinoma. J Urol 2009;181:2044–51. [6] Ljungberg B, et al. EAU guidelines on renal cell carcinoma: 2014 update. European Urol 2015;67:913–24. [7] Itano NB, Blute ML, Spotts B, Zincke H. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 2000;164:322–5. [8] Master VA, Gottschalk AR, Kane C, Carroll PR. Management of isolated renal fossa recurrence following radical nephrectomy. J Urol 2005;174:473–7. [9] Fayek IS, Habashy HF, Habashy NF. Isolated loco-regional recurrence after radical nephrectomy for renal cell carcinoma: a study of 22 patients. J Egypt Natl Canc Inst 2014;26:161–6. [10] Thomas AZ, Adibi M, Borregales LD, et al. Surgical management of local retroperitoneal recurrence of renal cell carcinoma after radical nephrectomy. J Urol 2015;194:316–22. https://doi.org/10.1016/j. juro.2015.02.2943. [11] Schrodter S, Hakenberg OW, Manseck A, Leike S, Wirth MP. Outcome of surgical treatment of isolated local recurrence after radical nephrectomy for renal cell carcinoma. J Urol 2002:1630–3. https:// doi.org/10.1097/00005392-200204000-00013. [12] Vitagliano G, Ameri C, Castillo O, Rozanec J. Laparoscopic resection of isolated fossa recurrence of renal cell carcinoma after open nephrectomy: report of 6 cases and literature review. Arch Esp Urol 2014;67:277–83. [13] Bandi G, Wen CC, Moon TD, Nakada SY. Single center preliminary experience with hand-assisted laparoscopic resection of isolated renal cell carcinoma fossa recurrences. Urology 2008;71:495–9:discussion 499−500. [14] Suson KD, Richard H, Phelan MW. Cryoablation of renal fossa recurrence after radical nephrectomy. J Endourol 2011;25:559–62. [15] Shuch B, Riggs SB, LaRochelle JC, et al. Neoadjuvant targeted therapy and advanced kidney cancer: observations and implications for a new treatment paradigm. BJU Int 2008;102:692–6.