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A Review on Follow-Up Strategies for Renal Cell Carcinoma after Nephrectomy
european urology 51 (2007) 1490–1501
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Review – Kidney Cancer
A Review on Follow-Up Strategies for Renal Cell Carcinoma after Nephrectomy Andreas Skolarikos a,*, Gerasimos Alivizatos a, Pilar Laguna b, Jean de la Rosette b a b
AthensMedical School, 2nd Department of Urology, Sismanoglio Hopsital, Athens, Greece Department of Urology, Academic Medical Center, Amsterdam, The Netherlands
Article info
Abstract
Article history: Accepted December 24, 2006 Published online ahead of print on January 9, 2007
Objectives: To provide a comprehensive review of the evidence supporting the necessity for follow-up after nephrectomy for renal cell carcinoma. Methods: We searched the Medline, MeSH, EMBASE, and Cochrane databases using the terms ‘‘renal cell cancer,’’ ‘‘kidney neoplasm,’’ ‘‘followup,’’ ‘‘surveillance,’’ ‘‘prognosis,’’ and ‘‘staging’’ to look for human/ English language/Randomized Controlled Trials/Clinical trials/Review articles/Meta-analysis/Practiced Guidelines, and Editorials. Results: No consensus currently exists on surveillance guidelines after radical or partial nephrectomy for renal cell carcinoma. The rationale for follow-up strategies is to detect local recurrence or metastatic disease and to allow appropriate treatment. Most of the surveillance protocols recommend various follow-up strategies for all tumour stages. The emphasis on follow-up should be during the first 3–5 yr after nephrectomy. There is no consensus about which investigations should be performed and at what intervals. Most surgeons rely on symptom enquiry, physical examination, chest x-ray, and computed tomography scanning. A protocol based on the stage of the initial tumour is adapted by the majority of the investigators. Patients should be followed similarly after radical or partial nephrectomy on the basis of stage-oriented protocols. The combination of various prognostic factors requires further validation over stage-based protocols. There is a paucity of guidelines in the literature regarding follow-up for patients with hereditary forms of renal cell carcinoma. Conclusions: Current guidelines for follow-up are based on observational and case studies. While this fact precludes a high level of evidence-based guidelines, we have to conclude that this is the best available evidence to date.
Keywords: Prognosis Renal cell carcinoma Staging Surveillance
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 2nd Department of Urology, University of Athens, Sismanoglio Hospital, 6 Laskareos st Nea Zoi Peristeri, 12137, Athens, Greece. Tel. +30 210 8039122; Fax: +30 210 5321303. E-mail address: [email protected] (A. Skolarikos). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2006.12.031
european urology 51 (2007) 1490–1501
1.
Introduction
Defining guidelines for follow-up in patients treated for cancer is important from both medical and economic perspectives [1,2]. Currently, however, no consensus exists on surveillance guidelines on renal cell carcinoma (RCC), neither after radical nor after partial nephrectomy. Although some guidelines on follow-up of RCC have been published [3–9], large observational or randomized studies regarding the subject are lacking; therefore, the following questions still demand an answer: 1. What is the rationale for following up patients treated for RCC? 2. Should surveillance protocols be based on tumour staging only? 3. What is the evidence derived from stage-based surveillance protocols after radical nephrectomy? 4. What is the optimal period that follow-up should last? 5. Which follow-up schemes are appropriate? 6. Should patients be followed differently after nephron-sparing surgery or thermoablative techniques compared with patients after radical/ partial nephrectomy? 7. How should patients with hereditary RCC or with end-stage renal disease related to RCC be followed? Our aim was to answer these questions by means of an extensive review of the literature looking for the best available evidence. Consequently findings and recommendations were graded according to the level of evidence based on the criteria for evidencebased medicine [1]. 2.
Methods
Using the MeSH terms ‘‘renal cell cancer,’’ ‘‘kidney neoplasm,’’ ‘‘follow-up,’’ ‘‘surveillance,’’ ‘‘prognosis,’’ and ‘‘staging’’ to looking for human/English language/Randomized Controlled Trials/Clinical trials/Review articles/Meta-analysis/Practiced Guidelines, and Editorials, we searched the Medline, MeSH, EMBASE, and Cochrane databases. To answer the aforementioned questions we specifically addressed several issues: whether detection of local recurrences or distant metastases at the earliest opportunity will allow adjuvant treatment to cure patients after nephrectomy; what investigations should be performed as part of the follow-up to detect the most frequent site of metastases; whether additional information beyond the stage of the tumour adds to better identifying patients at risk for recurrence; whether all patients should undergo follow-up regardless of risk for developing
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metastases; and finally whether the type of initial surgery or patients that belong to specific categories play a role in deciding the follow-up. A grade of evidence was assigned to the different articles and to each one of the conclusions. Finally, on the basis of the most common and appropriate follow-up schemes presented in literature, a recommendation on guidelines for follow-up of RCC after surgery was suggested.
3.
Results
3.1. What is the rationale for following up patients treated for RCC?
The overall incidence of metastatic disease following RCC surgery is approximately 40% [2], the risk being related mostly to high tumour stage and grade [3–13] However, metastases do develop in low- and high-risk patients: in patients with pT1 (0–7%) or pT2 (5.3–26.5%) tumours and in patients with grade 1 (9%) or grade 2 (61%) tumours [3–10]. Five-year survival of patients with untreated metastatic disease is poor (2.7–9%) [14,15]. In contrast, response rates of 5–20% have been reported with systemic immunotherapy or chemotherapy [16]. More recently with the use of antivascular endothelial growth factor antibodies [17] or targeted therapies such as tyrosine kinase inhibitors (sunitinib, sorafenib) [18] and mTOR inhibitors (tensirolimus) [19], preliminary responses in the range of 40% have been described. In addition, 5-yr survival following surgery of isolated solitary or multiple lung metastases ranges from 24% to 60% [1,20], with the highest survival rates among those patients in whom complete surgical resection of the metastases was achieved [21,22]. Surgical resection of isolated brain metastasis resulted in a mean survival of 13.8 mo compared with 7 mo when surgery is not performed [23]. The average survival of patients with head and neck metastasis after surgery, radiation, or combined treatment has been reported to be 32.3 mo, 19.7 mo, and 20.7 mo, respectively [24]. Solitary metastasis of RCC to the liver is reported to occur in 5.4% of all cases with metastasis [25]. It is unclear whether surgical resection improves survival in these patients, although a 5-yr cancer-specific survival of 27% has been reported [26]. In the rare case in which a patient has a solitary bony metastasis, surgical excision of the metastatic site leads to a 5-yr survival of 13–30% [27]. Surgical resection of isolated fossa recurrences with or without adjuvant radiation or immunotherapy can lead to a 5-yr cause-specific survival rate of 30–75% [11–13,28–30]. These rates are superior to the 18% and 13% 5-yr cancer-specific survival of patients with
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solitary local recurrence who are treated with medical therapy or observation, respectively [28]. In general, whether treatment of an asymptomatic recurrence detected on regular follow-up carries a survival advantage over treatment of recurrence detected by symptoms has not been thoroughly studied in the literature [31]. Among patients who are operated for local recurrences, those who present with clinical symptoms have a higher rate of incomplete recurrence resection, positive surgical margins, and poorer survival [5]. The aforementioned data indicate that follow-up after nephrectomy is recommended in all patients to detect local recurrence and distant metastases, and to allow appropriate treatment [5]. The type of evidence supporting these data is obtained from well-designed nonexperimental descriptive studies (level III), but no randomized clinical trials exist (grade B). 3.2. Should surveillance protocols be based on only tumour staging?
Disease relapse and cancer-specific survival are highly related to pathologic tumour stage [3–8,32,33] (Table 1). Although tumour grade [9,32] and various histologic subtypes seem to have a prognostic significance, their inability to accurately predict survival or metastasis for similarly staged tumours underlines the fact that tumour cell differentiation [9,10,31,34,35] and histologic differentiation [31,35–37] are currently less useful tools for prognosis. A few authors have constructed survival and recurrence protocols on the basis of a combination of prognostic factors. Combinations such as tumour stage, Fuhrman nuclear grade and performance
status (University of California at Los Angeles [UCLA] protocol) [38]; patient symptoms; tumour histology, size and pathologic stage (MemorialSloan Kettering Cancer Center [MSKCC] protocol) [39]; tumour stage, size, grade, and necrosis (SSIGN score; Mayo clinic protocol); [40] or patient symptoms at presentation, tumour size, pathologic stage, Fuhrman nuclear grade, tumour necrosis, and microvascular invasion (MSKCC protocol updated) [41] all accurately predicted the 5-yr probability of treatment failure among patients with newly diagnosed RCC [42]. On the basis of their risk group stratification system, the UCLA team recently published an evidence-based postoperative surveillance protocol for patients with localized and locally advanced RCC [43]. In their retrospective study (evidence level III/ B), 559 patients were stratified into low risk (T1, grade 1–2, ECOG PS = 0), high risk (T3, grade >1, ECOG > 0, and/or T4, grade 1–4, ECOG = 0–3), and intermediate risk (all the remaining combinations), according to their probability of survival and tumour recurrence (Table 2). On the basis of their results, the authors recommended for low-risk patients yearly history and physical examination, laboratory tests, and chest computed tomography (CT) for 5 yr and an abdominal CT scan at years 2 and 4, with no further surveillance beyond 5 yr. For intermediate-risk patients, the authors recommended history and physical examination, laboratory tests, and chest CT every 6 mo for the first 3 yr, then yearly for 10 yr of follow-up, with an abdominal CT scan at 1 yr then every 2 yr until 10 yr of follow-up. Finally, for highrisk patients, they recommended more intensive abdominal surveillance, with recommendations identical to those for the intermediate-risk group except with more frequent abdominal CT scans at
Table 1 – Five-year cancer-specific/disease-free survival after radical/partial nephrectomy 5-year cancer-specific (disease-freea) survival pT1a Levy 1998a Ljunberg 1999 Hafez 1997c Fergany 2000c,d Fergany 2000c,e Gofrit 2001a Stephenson 2004a
pT1b 90%b 95%b
93%b
NA = not available. Disease-free survival. b Combined results for different stages are presented. c Results are for partial nephrectomy series. d 5-year cancer-specific survival. e 10-year cancer-specific survival. a
75% 87% 71.4%b 95% 67% 97%
97.6% 94.5% 100%
pT2
100% 100% 87% 81%
pT3a
pT3b 60%
52% 30% 85% 74%
37% 55% 59% 23.5% 73%b
66%
57%
p value 0.001 <0.001 0.04 0.007b NA <0.001
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Table 2 – Data derived by the UCLA-combination-criteria–based surveillance after radical nephrectomy Risk group
Low
Intermediate
High
a
T1
T1
T1
T2
T3
T3
T3
T4
Fuhrman grade
G1–2
G1–2
G3–4
G1–4
G1
G2–4
G2–4
G1–4
0
1
Any
Any
Any
0
1
Any
T stage
ECOG PS No. of patients (%) radical/partial nephrectomy 5-year recurrence-free rate (%) % of recurrence radical/partial nephrectomy Median (mean SD) time to recurrence (mo)b % of chest metastases vs. total metastasesb Frequency (%) of chest metastases at 1, 2, 3, 4, 5, >5 yrb Median ( SD) time to diagnosis of chest metastases (mo)b % of chest metastases diagnosed at 1, 2, 3, 4, 5, >5 yrb % of abdominal metastases vs. total metastasesb % of abdominal metastases at 1, 2, 3, 4, 5, >5 yrb Median (mean SD) time to diagnosis of abdominal metastases (mo)b % of abdominal metastases diagnosed at 1, 2, 3, 4, 5, >5 yrb % of bone metastases Median (range) time to diagnosis of bone metastases (mo)b
% of brain metastases Median time (mean SD) to diagnosis of brain metastases (mo)b
93 (25.5)/103 (66.6)
207 (56.7)/44 (28.8)
65 (17.8)/7 (4.6)
90.4 6.5/2.9
61.8 28.9/6.8
41.9 47.7/28.6
28.9 (26.5 17.1)
17.8 (25.5 23.9)
9.5 (21.9 26.2)
75
77.4
45.5
2.2/1.1/0/3.3/0/0
7.7/4.8/2.4/1.4/0.5/1.9
10.8/3.1/3.1/1.5/0/3.1
23.6 (18.8)
NC
NC
NC
41.7/25/13.5/6.3,2.12/10.4
50/14.3/14.3/7.1/0/7
37.5
58.1
68.2
0/1.1/0/1.1/0/0
7.7/1/2.4/0/0.5/1.9
18.5/4.5/3.1/1.5/0/1.5
32 (NC)
NC
NC
NC
66.6/8.3/16.6/0/2.7/13.8
62/4.3/9.5/4.8/0/5
NC NC
NC NC 44% and 31% of bone metastases were diagnosed within the first and after 5 yr of follow-up, respectively
NC 44 (NC)
NC Brain metastases occurred at 1st and 3rd years of follow-up
9.7 NC Bone recurrences occurred at years 1, 3 and >5 after surgery 6.5 NC Brain metastases occurred in the 1st and 5th years of follow-up
ECOG PS = Eastern Cooperative Oncology Group Performance Status; NC = not clarified. T stage refers to 1997 TNM classification. b Refers to the total number of patients with localized tumours. a
a rate of once every 6 mo for the first 2 yr, then yearly for years 2 to 5, then every 2 yr until 10 yr of follow-up. For both medium- and high-risk groups, a chest x-ray can alternate with a chest CT scan after 3 yr. The main limitation of risk groups’ stratification is heterogeneity within groups. A system that groups patients with respect to recurrence in general may not be optimally tailored to an individual’s risk of recurrence. Although some of these prognostic models have been externally validated in a few institutions [44–46], their advantage over the stage-specific strategy for RCC
surveillance still needs to be more extensively assessed in prospective randomized controlled studies. As literature supports the correlation between tumour stage and the risk of subsequent tumour metastasis, the presented data indicate that a surveillance protocol based on the initial tumour stage is still the most frequently adopted (evidence level III/B). However, in the future, surveillance protocols should be based more frequently on the evidence concerning the risk of recurrence and metastases that has been provided by multivariate survival models.
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3.3. What is the evidence derived from stage-based surveillance protocols after radical nephrectomy?
Staged-based surveillance protocols aim to provide us with the most frequent metastatic sites and the mean time to develop metastasis. Several studies of stage-based surveillance following radical nephrectomy for localized RCC (pT1– 3, N0, Nx, M0) have been published during the last decade [3,5–8]. There have been no prospective randomized controlled trials and all existing evidence is based on case study, mostly observational and retrospective (evidence level III/B) (Table 3). Among 629 patients with pT1 disease treated in these series, 3.2–7% developed metastases at a median time of 35–48 mo [3,5–8]. Pulmonary metastases predominated (0–68.7%), were moderately symptomatic at presentation (16.6–64%), and were mostly diagnosed by the combination of symptoms and chest x-ray (81–100%). Abdominal metastases occurred in fewer than 1.6% of patients, of whom only 0.3% was symptomatic. Bone and brain metastases were diagnosed on the basis of symptoms. Among 301 patients with pT2 disease and 351 patients with pT3 disease, 14–27% and 26–54% developed metastases at a median time of 25–32 mo and 11–22 mo, respectively [3,5–8]. Pulmonary metastases predominated (pT2: 50%; pT3: 41.8– 63.2%), were invariably symptomatic at presentation (pT2: 11–71.4%; pT3: 4.1–75%), but they were always diagnosed with the combination of clinical assessment and chest x-ray. Abdominal metastases succeeded (pT2: 0–38.5%; pT3: 13.9–42.1%) and were highly diagnosed by the combination of physical signs, symptoms, and abnormal liver function tests (pT2: 60–100%; pT3: 73.3–100%). Lymph node involvement was detected in up to one quarter of patients (pT2: 5.8–23%; pT3: 11.6–26.3%). All lymph-node positive patients were asymptomatic, diagnosed via CT scans, and had concomitant metastases at other sites [3,5]. Bone metastases were common (pT2: 17.6–45%; pT3: 16–26.5%), highly symptomatic (pT2: 67–100%; pT3: 57–100%), and always diagnosed by the combination of history, serum alkaline phosphatase, and plain skeletal x-rays. Brain metastases were rare (pT2: 0–15.4%; pT3: 4.4–11.1%), developed at a late stage of the disease, and were all symptomatic at presentation. These data support pulmonary and abdominal sites as being the most prevalent secondary deposition of RCC. The prevalence of metastases is stage dependent. Physical examination, biochemical profile, and radiologic evaluation suffice for making the diagnosis in the majority of these cases (evidence level III/B).
3.4.
What is the optimal period that follow-up should last?
Among all studies regarding RCC surveillance, the latest postnephrectomy pulmonary lesion has been detected at 67 mo for pT1 tumours, at 60–96.6 mo for pT2 tumours and at 59–137.9 mo for pT3 tumours [3,5– 8]. The latest abdominal lesion was detected at 97 mo for pT1 tumours, at 29.1–92 mo for pT2 tumours, and at 18.2–79 mo for pT3 tumours. The latest bone lesion was detected at 42–144 mo, 96.7–144 mo, and 36–65 mo in pT1, pT2, and pT3 tumours, respectively [3,5–8]. In the study by Sandock et al [3], 85% of recurrences occurred within the first 3 yr, while the remaining 15% occurred between 3.4 and 11.4 yr. Ljunberg et al [6] showed that 43% of metastases were observed within 1 yr, 70% within 2 yr, 80% within 3 yr, and 93% within 5 yr of follow-up. Only 7% of metastases occurred after 5 yr and most of them were symptomatic. Stephenson et al [7] detected 25% and 21% of pT1 and pT2 recurrences 5 yr after surgery. Of pT3a and pT3b recurrences, 4.3% and 7.1% were detected 3 yr after surgery in the same study. In addition, while patients with pT3 RCC have a higher risk of metastasis than those with pTl–T2 disease, all three groups are at risk for the same duration [5]. These findings suggest that the emphasis of follow-up should be during the first 3–5 yr after nephrectomy (evidence level III/B). Similarly, surveillance frequency can be relaxed after an appropriate interval (3 yr) (evidence level III/B). However, the data also support that the follow-up of patients after radical nephrectomy may be longer than 5 yr, maybe even lifelong [8,47]. 3.5. Which follow-up schemes proposed in the literature are appropriate?
Guidelines for surveillance of patients undergoing nephrectomy have been published from several authors during the last decade (evidence level III/B, IV/C) (Table 4) [3–8,47,48]. First assessment is recommended at 4–6 wk and includes physical examination to exclude surgical complications, serum creatinine to assess the remaining kidney function, and hemoglobin to assess recovery of peroperative blood loss. If alkaline phosphatase is abnormal preoperatively, repeat measurements are recommended to exclude residual tumor or distant metastasis [47]. Throughout follow-up, radionuclide scans are restricted to positive symptom enquiry or raised alkaline phosphatase. Less than half of the published series propose that patients with pT1–T2 tumours should be evaluated with clinical assessment and chest x-ray every 6 mo during the first 3 yr and yearly thereafter [3,6,47].
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Table 3 – Data derived from stage-based surveillance after radical nephrectomy
No. of patients
% of recurrence
Median (range) time to recurrence (mo) % of pulmonary metastases (total/symptomatic) Median (range) time to diagnosis of pulmonary metastases (mo) % of abdominal metastases (total/symptomatic)c Median (range) time to diagnosis of abdominal metastases (mo) % of bone metastases (total/symptomatic) Median (range) time to diagnosis of bone metastases (mo) % of brain metastases (total/symptomatic) Median (range) time to diagnosis of brain metastases (mo)
pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 PT3 PT1 PT2 PT3
Sandocka 1995
Levy 1998
Ljunberg 1999
Gofrit 2001
19 82 36 0 14.6 52.8 — 29.5 (3.5–97) 22 (3–138) 0 (–) 53.8 (71.4) 63.2 (75) — 39.6 (6.9–96.6) 26.4 (3–138) 0 (–) 38.5 (92.3) 42.1 (92.3) — 12 (3.5–29) 7.6 (3–18.2) 0 (–) 38.5 (100) 26.5 (100) — 37 (3.8–97) 19.8 (3.8–40.5) 0 (–) 15.4 (100) 11.1 (100) — NA 4
113 64 109 7 27 39 38 (18–67) 32 (3–115) 17 (2–88) 50 (0) 52.9 (11) 41.8 (11) 53 (30–67) 31 (4–67) 14 (5–59) 0 (–) 29.4 (60) 34.8 (73.3) — 68 (53–83) 23.5 (5–67) 25 (100) 17.6 (67) 16.27 (57) 38.5 (35–42) 24 (3–115) 7 (3–65) 12.5 (100) 5.8 (100) 9.3 (100) 18 11 17 (9–22)
70 43 48 7 14 54 43 (27–60) 29.5 (3–144) 17 (2–62) 54.5b (16.6) 54.5 (16.6) 53.3 (4.1) 8.5 (3–60)b 8.5 (3–60)b 17 (2–62) 0 (–) 0 (–) 20 (100) — — 13 (3–20) 45 (100)b 45 (100)b 22.2 (100) 40 (8–144)b 40 (8–144)b 14.5 (6–36) 0 (–) 0 (–) 4.4 (100) — — 9.5 (9–10)
124 26 50 3.2 23 26 48 (22–64) 28.2 (6–64) 19.8 (4–55) NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Stephenson 2004 303 84 108 5 16.6 34.25 35 (2–93) 25 (3–95) 11 (1–102) 68.7 (64) NA NA NA NA NA 1.6 (0.3) 1.8 (100) 13.9 (73.3) NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
NA = not available. T category was based on 1992 TNM classification. b Results for pT1 and pT2 stages were combined in the study of Ljunberg et al 1999 [6]. c In parentheses and under the term symptomatic, cases are presented that were diagnosed due to positive physical examination, symptom history, or abnormal serum studies. a
The remaining studies have recommended a yearly follow-up for these patients [4,5,7,48]. All studies agreed that for pT3 tumours, clinical assessment and chest x-ray should be performed every 6 mo for the first 3 yr and yearly thereafter. Three of 8 studies have recommended routine abdominal CT in patients with pT2 disease [4,5,48], and 7 of 8 recommended routine abdominal imaging for pT3a–b disease [4–8,47,48]. Sandock et al [3] showed that only 0.73% of patients benefited from routine follow-up CT; therefore, they recommended CT at suspicion of recurrence based on symptoms or abnormal serum tests. In an other study, Levy et al [5] showed that 9% of patients with metastases were diagnosed only on the basis of surveillance CT in the absence of symptoms, abnormal serum chemistry, or disease recurrence at another site. Surveillance CT detected no metastases prior to a 29-mo period postoperatively, regardless of pathologic stage.
Therefore, these authors advocated surveillance CT of the abdomen and pelvis at 24 and 60 mo. Contrary to the above conclusion, Ljunberg et al [6] reported in their series that one of the nine intraabdominal/retroperitoneal metastases was detected by scheduled CT, and they recommended routine CT scans for high-risk patients (eg, pT3 tumours) at 6 and 12 mo. The rest of the studies recommended abdominal CT for pT3a–b tumours every 6 mo [4,47], or yearly [6,48] up to the second [4,48] or third year [6,7] postoperatively and then annually [47] or biannually [4,7,48]. Despite these recommendations two topics need further discussion and prospective evaluation in the future. No laboratory test is able to detect lung metastases or lymph node metastases, which represent the large majority of metastases in these patients. Laboratory tests mainly detect symptomatic metastases, such as bone or liver metastases. Since these
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Table 4 – Stage-based surveillance guidelines after nephrectomy proposed during the decade 1995–2005 Clinical assessment (history, physical examination, laboratory studies) pT1 Sandock 1995a Hafez 1997b Levy 1998 Ljunberg 1999 Gofrit 2001b
Mickish 2001c
pT2 Sandock 1995 Hafez 1997b Levy 1998 Ljunberg 1999 Gofrit 2001b Mickish 2001c Stephenson 2004b Uzzo 2003 Novick 2005b pT3 Sandock 1995 Hafez 1996b Levy 1998 Ljunberg 1999 Gofrit 2001b Mickish 2001c Stephenson 2004b Uzzo 2003 Novick 2005b
Abdominal CT
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Not recommended for pT1a tumours
Not recommended Every 2 yr for tumours >2.5 cm Not recommended Not recommended Not recommended for pT1a tumours
III/B III/B III/B III/B III/B
Every 6 mo for 3 yr, then every year from 3 to 5 yr Yearly Every year or 2 yr Yearly
Periodic for pT1b Every 6 mo for 3 yr, then every year from 3 to 5 yr Yearly Not recommended Not recommended
Periodic for pT1b Not recommended
IV/C
Not recommended Not recommended Not recommended
III/B III/B IV/C
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–5 yr Yearly Every year Yearly
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–5 yr Yearly Every year Annually
Not recommended Every 2 yr for tumours >2.5 cm At 24 and 60 mo Not recommended Meticulous periodic follow-up Not recommended
III/B III/B III/B III/B III/B IV/C
Not recommended At year 2, then every 2 yr Every 2 yr
III/B III/B IV/C
Every 6 mo until 3 yr, then yearly Yearly Every 6 mo until 3 yr, then yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr Every 6 mo until 3 yr, then yearly Every 6 mo Yearly
Every 6 mo until 3 yr, then yearly Yearly Every 6 mo until 3 yr, then yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr Every 6 mo until 3 yr, then yearly Every 6 mo Annually
Not recommended Every 6 mo until 2 yr, then every 2 yr At 24 and 60 mo At 6 and 12 mo Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr
III/B III/B III/B III/B III/B IV/C
At 6, 12, 24, and 36 mo, then every 2 yr At year 1, then every 2 yr Similar to radical nephrectomy
III/B III/B IV/C
CT = computed tomography. T category was based on 1992 TNM classification. b Partial nephrectomy was performed in 100% (Hafez et al, Novick et al), 22.5% (Gofrit et al [8]), and 21% (Stephenson et al [7]) of the patients. c European Association of Urology (EAU) proposed guidelines based on literature data. a
Level of evidence
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Stephenson 2004b Uzzo 2003 Novick 2005b
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Not recommended for pT1a tumours; periodic for pT1b
Chest x-ray
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metastases are manifested through clinical symptoms, it is very difficult to establish that repetitive measurements are necessary for follow-up. In addition, chest CT scan may be more useful than plain x-rays in earlier detection of lung and thoracic lymph node metastases. A prospective comparison between these two modalities may clarify whether the chest CT scan should be incorporated in the surveillance of RCC patients postnephrectomy. Without being a result of high-level evidencebased urology, Fig. 1 depicts an algorithm for RCC follow-up after radical or partial nephrectomy based on the most frequently proposed surveillance protocols in the literature. 3.6. Should patients after nephron-sparing surgery or thermoablative techniques be followed differently compared with patients after radical nephrectomy?
Stage-specific survival rates following nephronsparing surgery are similar to those following radical nephrectomy [8,49–51].
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Recently, Fergany et al [52] reinforced the surveillance guidelines on nephron-sparing surgery proposed by one of his colleagues a decade ago [4], as well as by other authors [53] (Table 4). During a 10-yr follow-up of 117 nephron-sparing renal operations, no recurrence developed in pTla, pT1b, and pT2 tumours. The incidence of local tumour recurrence was 10% and 12% at a mean interval of 105 and 79.5 mo for T3a and T3b disease, respectively. Distant metastases occurred in 2%, 29%, 0%, 33%, and 53% at a median follow-up of 20, 51, 41, and 25 mo in patients with pTla, pT1b, pT2, pT3a, and pT3b disease, respectively. Combined local recurrence and distant metastases occurred in 2%, 5%, 20%, 10%, and 12% of patients, respectively. In the above study, recurrence in general was noted in a followup period longer than 5 and 10 yr after surgery in 41% and 8.8% of patients, respectively. This finding illustrates the unpredictable nature of RCC and the need for long-term follow-up [52,53]. The aforementioned data indicate that patients undergoing nephron-sparing surgery should be followed similarly to those submitted to radical
Fig. 1 – Algorithm for renal cell carcinoma (RCC) surveillance following radical or partial nephrectomy based on the most common stage-based surveillance protocols proposed in the literature. CT = computed tomography.
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nephrectomy, on the basis of stage-derived surveillance protocols (evidence level III/B). Cryoablation, radiofrequency ablation, highintensity focused ultrasound, interstitial laser, microwave thermotherapy, and photon irradiation, were recently being advocated as nephron-sparing minimally invasive treatment for carefully selected patients. At present the clinical data are limited and the follow-up is short. The assessment of effectiveness of therapy by diligent follow-up imaging and/or biopsy of the tumour lesions is still controversial. No specific guidelines on how we should follow-up these patients exist at this moment [54]. No firm evidence has been proposed for a differential surveillance on the basis of the type of surgery. However, studies incorporating posttreatment biopsy have shown a high proportion of local failure following the use of different ablative techniques [54]. This fact may indicate that these patients should be followed intensively after treatment. 3.7. How should patients with hereditary RCC or RCC related to end-stage renal disease be followed?
There is a paucity of guidelines in the literature regarding follow-up of patients with RCC developed in von Hippel-Lindau disease (VHL), tuberous sclerosis (TS) complex, or hereditary papillary renal cell carcinoma (HPRCC) [55]. In contrast to sporadic RCCs, hereditary RCCs often are discovered at a younger age in a multicentric and bilateral fashion, and affected individuals face a high and lifelong risk of recurrence [56]. Most hereditary RCCs seem to have a minimal metastatic potential when tumour measures less than 3 cm in diameter. Nephrectomy in these cases is not performed until the largest tumour reaches 3 cm. As a consequence, surveillance of these patients is mainly based on tumour size rather than on tumour histology, location, or multifocality [55,57]. In addition, patients who exhibit an aggressive phenotype should undergo imaging relatively frequently (every 3–6 mo), whereas patients with a mild phenotype may safely undergo imaging at 2- to 3-yr intervals [55,57]. The benefit of following up patients with RCC related to end-stage renal disease with routine imaging has been a subject of debate. The argument is similar to the one for the necessity for screening these patients. Since overall survival in patients on dialysis is dictated mostly by comorbidity risk factors, the costs of follow-up may outweigh the benefits of detecting local recurrences or distant metastases [58]. However, for those patients who are candidates for renal transplantation, follow-up is warranted. It is generally suggested to delay trans-
plantation for at least 2 yr after treatment for most cancers [59], especially if the patients are symptomatic at presentation [60]. However, patients with incidentally discovered renal tumours may be eligible for transplantation soon after cancer treatment [60]. CT scan may be more sensitive than ultrasound in following up patients with end-stage renal disease, especially those with multiple renal cysts. However it has limitations such as the cost and the inability to perform a contrast-enhanced study [58]. Contrastenhanced ultrasound or magnetic resonance imaging testing may constitute better alternatives for these patients.
4.
Conclusions
Renal cell carcinomas often behave aggressively and are associated with a poor prognosis. The whole body of literature on follow-up after surgical treatment of RCC is based on observational studies with a lack of randomized trials (evidence level III/B). On the basis of our nonstructured review, we can affirm that, among patients who develop metastases, a subset will benefit from salvage surgery or immunotherapy, a fact that underscores the need for surveillance following primary surgical treatment. Clinical assessment including history recording, physical examination, and laboratory studies, as well as chest x-ray, should be performed twice a year for the first 3 yr and then annually, irrespective of the tumour pathologic stage. Abdominal CT scan may not be recommended for pathologic stages T1 and T2, while most studies support scanning to be performed every 6 mo for the first 2–3 yr and then every 2–3 yr for patients with pT3 tumours. Although surveillance may be more intense during the first 3 yr after surgery, patients who have been operated for RCC should be followed lifelong. Patients should be followed similarly after radical or partial nephrectomy on the basis of stage-oriented protocols. The combination of various prognostic factors requires further validation over stage-based protocols. They may eventually provide a rational approach to identify treatable recurrences, while minimizing unnecessary examinations and patient anxiety. Finally, there is an emerging need to prospectively apply and study follow-up protocols by implying a global or European network. A global network analyzing the time to relapse and site of relapse by ‘‘risk,’’ as estimated by validated multivariate survival and surveillance models, will develop in the future more ‘‘individualized’’ and cost-effective surveillance guidelines.
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Conflicts of interest The authors have nothing to disclose.
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[17] Yang JC, Haworth L, Sherry RM, et al. A randomized trial of bevacizumab, an anti-vascular endothelial growth factor antibody, for metastatic renal cancer. N Engl J Med 2003;349:427–34. [18] Motzer RJ, Rini BI, Bukowski RM, et al. Sunitinib in patients with metastatic renal cell carcinoma. JAMA 2006;295: 2516–24. [19] Hudes G, Carducci M, Tomczak P, et al. A phase 3, randomized, 3-arm study of temsirolimus (TEMSR) or interferonalpha (IFN) or the combination of TEMSR + IFN in the treatment of first-line, poor-risk patients with advanced renal cell carcinoma (adv RCC). 2006 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2006;24(18S):LBA4. [20] Piltz S, Meimarakis G, Wichmann MW, et al. Long-term results after pulmonary resection of renal cell carcinoma metastases. Ann Thorac Surg 2002;73:1082–7. [21] Hofmann HS, Neef H, Krobe K, et al. Prognostic factors and survival after pulmonary resection of metastatic renal cell carcinoma. Eur Urol 2005;48:77–81, discussion 81–2. [22] Murthy SC, Kim K, Rice TW, et al. Can we predict longterm survival after pulmonary metastasectomy for renal cell carcinoma? Ann Thorac Surg 2005;79:996–1003. [23] Decker DA, Decker VL, Herskovic A, et al. Brain metastases in patients with renal cell carcinoma: prognosis and treatment. J Clin Oncol 1984;2:169–73. [24] Kent SE, Majumdar B. Metastatic tumours in the maxillary sinus. A report of two cases and a review of the literature. J Laryngol Otol 1985;99:459–62. [25] Saitoh H, Nakayama M, Nakamura K, et al. Distant metastasis of renal adenocarcinoma in nephrectomized cases. J Urol 1982;127:1092–5. [26] Fujisaki S, Takayama T, Shimada K, et al. Hepatectomy for metastatic renal cell carcinoma. Hepatogastroenterology 1997;44:817–9. [27] Baloch KG, Grimer RJ, Carter SR, et al. Radical surgery for the solitary bony metastasis from renal-cell carcinoma. J Bone Joint Surg Br 2000;82:62–7. [28] Itano NB, Blute ML, Spotts B, et al. Outcome of isolated renal cell carcinoma fossa recurrence after nephrectomy. J Urol 2000;164:322–5. [29] Sandhu SS, Symes A, A’Hern R, et al. Surgical excision of isolated renal-bed recurrence after radical nephrectomy for renal cell carcinoma. BJU Int 2005;95:522–5. [30] Master VA, Gottschalk AR, Kane C, et al. Management of isolated renal fossa recurrence following radical nephrectomy. J Urol 2005;174:473–7, discussion 477. [31] Jansen NK, Kim HL, Figlin RA, et al. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin N Am 2003;30:843–52. [32] Tsui KH, Shvarts O, Smith RB, et al. Prognostic indicators for renal cell carcinoma: a multivariate analysis of 643 patients using the revised 1997 TNM staging criteria. J Urol 2000;163:1090–5. [33] Ficarra V, Novara G, Iafrate M, et al. Proposal for reclassification of the TNM staging system in patients with locally advanced (pT3–4) renal cell carcinoma according to the cancer-related outcome. Eur Urol 2007;51:722–31.
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[34] Goldstein NS. The current state of renal cell carcinoma grading. Union Internationale Contre le Cancer (UICC) and the American Joint Committee on Cancer (AJCC). Cancer 1997;80:977–80. [35] Ficarra V, Martignoni G, Galfano A, et al. Prognostic role of the histologic subtypes of renal cell carcinoma after slide revision. Eur Urol 2006;50:786–94. [36] Amin MB, Tamboli P, Javidan Stricker H, et al. Prognostic impact of histological subtyping of adult renal epithelial neoplasms: an experience of 405 cases. Am J Surg Pathol 2002;26:281–91. [37] Motzer RJ, Bacik J, Mariani T, et al. Treatment outcome and survival associated with metastatic renal cell carcinoma of non-clear-cell histology. J Clin Oncol 2002;20:2376–81. [38] Zisman A, Pantuck AJ, Wieder J, et al. Risk group assessment and clinical outcome algorithm to predict the natural history of patients with surgically resected renal cell carcinoma. J Clin Oncol 2002;20:4559–66. [39] Kattan MW, Reuter V, Motzer RJ, et al. A postoperative prognostic nomogram for renal cell carcinoma. J Urol 2001;166:63–7. [40] Frank I, Blute ML, Cheville JC, et al. An outcome prediction model for patients with clear cell carcinoma treated with radical nephrectomy based on tumor stage, size, grade, and necrosis: the SSIGN Score. J Urol 2002;168: 2395–400. [41] Sorbellini M, Kattan MW, Snyder ME, et al. A postoperative prognostic nomogram predicting recurrence for patients with conventional clear cell renal cell carcinoma. J Urol 2005;173:48–51. [42] Cindolo L, Patard JJ, Chiodini P, et al. Comparison of predictive accuracy of four models for nonmetastatic renal cell carcinoma after nephrectomy: a multicenter European study. Cancer 2005;104:1362–71. [43] Lam JS, Shvarts O, Leppert JT, et al. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005;174:466–72. [44] Ficarra V, Matrignoni G, Lohse C, et al. External validation of the Mayo Clinic Stage, Size, Grade and Necrosis (SSIGN) score to predict cancer specific survival using a European series of conventional renal cell carcinoma. J Urol 2006;175:1235–9. [45] Han KR, Bleumer I, Pantuck AJ, et al. Validation of an integrated staging system toward improved prognostication of patients with localized renal cell carcinoma in an international population. J Urol 2003;170:2221–4.
[46] Patard JJ, Kim HL, Lam JS, et al. Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma an international multicenter study. J Clin Oncol 2004;22:3316–22. [47] Mickisch G, Carballido J, Hellsten S, et al., for the European Association of Urology. Guidelines on renal cell cancer. Eur Urol 2001;40:252–5. [48] Uzzo RG, Novick AC. Surveillance strategies following surgery for renal cell carcinoma. In: Belldegrun A, Ritchie AWS, Figlin RA, editors. Renal and adrenal tumors: biology and management. New York: Oxford University Press; 2003. p. 324–30. [49] Belldegrun A, Tsui KH, deKernion JB, et al. Efficacy of nephron-sparing surgery for renal cell carcinoma: analysis based on the new 1997 tumor-node-metastasis staging system. J Clin Oncol 1999;17:2868–75. [50] Becker F, Siemer S, Hack M, et al. Excellent long-term cancer control with elective nephron-sparing surgery for selected renal cell carcinomas measuring more than 4 cm. Eur Urol 2006;49:1058–64. [51] Carini M, Minervini A, Lapini A, et al. Simple enucleation for the treatment of renal cell carcinoma between 4 and 7 cm in greatest dimension: progression and long-term survival. J Urol 2006;175:2022–6. [52] Fergany AF, Hafez KS, Novick A. Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol 2000;163:442–5. [53] Novick AC, Derweesh I. Open partial nephrectomy for renal tumours: current status. BJU Int 2005;95(Suppl 2): 35–40. [54] Ankem MK, Nakada SY. Needle-ablative nephron-sparing surgery. BJU Int 2005;95(Suppl 2):46–51. [55] Duffey BG, Choyke PL, Glenn G, et al. The relationship between renal tumor size and metastases in patients with von Hippel-Lindau disease. J Urol 2004;172:63–5. [56] Hwang JJ, Uchio EM, Linehan WM, et al. Hereditary kidney cancer. Urol Clin N Am 2003;30:831–42. [57] Walther MM, Choyke PL, Glenn G, et al. Renal cancer in families with hereditary renal cancer: prospective analysis of a tumor size threshold for renal parenchymal sparing surgery. J Urol 1999;161:1475–9. [58] Farivar-Mohseni H, Perlmutter AE, Wilson S, et al. Renal cell carcinoma and end stage renal disease. J Urol 2006;175:2018–21. [59] Kasiske BL, Ramos EL, Gaston RS, et al. The evaluation of renal transplant candidates: clinical practice guidelines. J Am Soc Nephrol 1995;6:1–34. [60] Penn I. Tumors after renal and cardiac transplantation. Hematol Oncol Clin North Am 1993;7:431–5.
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Editorial Comment on: A Review on Follow-Up Strategies for Renal Cell Carcinoma after Nephrectomy Tobias Klatte, Allan J. Pantuck Department of Urology, University of California Los Angeles, Los Angeles, CA [email protected] In this timely review article, Skolarikos et al [1] provide an in-depth summary of issues pertaining to surveillance for disease recurrence following nephrectomy for patients with localized renal cell carcinoma (RCC). The reviewed topic is of paramount importance for the urologic community because it is estimated that 30% of patients undergoing nephrectomy for presumed localized disease eventually experience recurrence. Furthermore, there is still uncertainty regarding the optimum approach to detect recurrence early. Based on a comprehensive analysis of the relevant literature, the authors discuss the rationale for surveillance and the timing, intensity, duration, and methods of surveillance appropriate for various patient groupings. The authors emphasize that, at the present time, no prospective or randomized studies have been conducted to address these important questions. All currently available recommendations on surveillance are based on retrospective, mostly single-center studies achieving a maximum evidence level of only III/B. However, until the time that high-level evidence becomes available (and there are currently no plans for prospective studies to evaluate this question of which we are aware), patients must be followed using the best data available. In the distant past, the majority of clinicians followed all patients according to the same general plan, regardless of tumor histology, tumor stage, tumor grade, or other factors of tumor biology that drive the risk of tumor recurrence. At the present time, the most widespread surveillance strategies are based on stage-based protocols [2] because tumor stage is the most important predictor for recurrence after nephrectomy, allowing the intensity and duration of surveillance strategies to be tailored according to the tumor’s stage. However, in the last few years, integrated staging systems that combine multiple clinical and pathologic variables have
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become the favored tool for postoperative risk group assessment. These nomograms, which place patients into groups having high, intermediate, and low risk of disease recurrence, are beginning to be applied to the surveillance arena [3]. As the authors note, however, it is evident that, even using sophisticated nomograms, each patient risk group still is a heterogeneous mix of patients having different risks for recurrence. In the future, it is quite probable that molecular markers such as p53 [4] will further improve the predictive ability of clinical and pathologic nomograms, which may permit further smoothing of this heterogeneity and allow for a surveillance protocol that is better tailored to the individual patient. As a final note, it should be emphasized that surveillance strategies at present should be applied only to tumors managed by extirpative surgeries. The lack of long-term data on outcomes for tumor ablative therapies, such as cryotherapy or radiofrequency ablation, dictates that patients undergoing these still experimental therapies will require more intensive follow-up for distant as well as local recurrence than one might recommend based on tumor biology alone.
References [1] Skolarikos A, Alivizatos G, Laguna P, de la Rosette J. A review on follow-up strategies for renal cell carcinoma after nephrectomy. Eur Urol 2007;51:1490–501. [2] Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003;30:843–52. [3] Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005;174: 466–72. [4] Shvarts O, Seligson D, Lam J, et al. p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma. J Urol 2005;173:725–8. DOI: 10.1016/j.eururo.2006.12.032 DOI of original article: 10.1016/j.eururo.2006.12.031
available at www.sciencedirect.com journal homepage: www.europeanurology.com
Review – Kidney Cancer
A Review on Follow-Up Strategies for Renal Cell Carcinoma after Nephrectomy Andreas Skolarikos a,*, Gerasimos Alivizatos a, Pilar Laguna b, Jean de la Rosette b a b
AthensMedical School, 2nd Department of Urology, Sismanoglio Hopsital, Athens, Greece Department of Urology, Academic Medical Center, Amsterdam, The Netherlands
Article info
Abstract
Article history: Accepted December 24, 2006 Published online ahead of print on January 9, 2007
Objectives: To provide a comprehensive review of the evidence supporting the necessity for follow-up after nephrectomy for renal cell carcinoma. Methods: We searched the Medline, MeSH, EMBASE, and Cochrane databases using the terms ‘‘renal cell cancer,’’ ‘‘kidney neoplasm,’’ ‘‘followup,’’ ‘‘surveillance,’’ ‘‘prognosis,’’ and ‘‘staging’’ to look for human/ English language/Randomized Controlled Trials/Clinical trials/Review articles/Meta-analysis/Practiced Guidelines, and Editorials. Results: No consensus currently exists on surveillance guidelines after radical or partial nephrectomy for renal cell carcinoma. The rationale for follow-up strategies is to detect local recurrence or metastatic disease and to allow appropriate treatment. Most of the surveillance protocols recommend various follow-up strategies for all tumour stages. The emphasis on follow-up should be during the first 3–5 yr after nephrectomy. There is no consensus about which investigations should be performed and at what intervals. Most surgeons rely on symptom enquiry, physical examination, chest x-ray, and computed tomography scanning. A protocol based on the stage of the initial tumour is adapted by the majority of the investigators. Patients should be followed similarly after radical or partial nephrectomy on the basis of stage-oriented protocols. The combination of various prognostic factors requires further validation over stage-based protocols. There is a paucity of guidelines in the literature regarding follow-up for patients with hereditary forms of renal cell carcinoma. Conclusions: Current guidelines for follow-up are based on observational and case studies. While this fact precludes a high level of evidence-based guidelines, we have to conclude that this is the best available evidence to date.
Keywords: Prognosis Renal cell carcinoma Staging Surveillance
# 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved. * Corresponding author. 2nd Department of Urology, University of Athens, Sismanoglio Hospital, 6 Laskareos st Nea Zoi Peristeri, 12137, Athens, Greece. Tel. +30 210 8039122; Fax: +30 210 5321303. E-mail address: [email protected] (A. Skolarikos). 0302-2838/$ – see back matter # 2007 European Association of Urology. Published by Elsevier B.V. All rights reserved.
doi:10.1016/j.eururo.2006.12.031
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1.
Introduction
Defining guidelines for follow-up in patients treated for cancer is important from both medical and economic perspectives [1,2]. Currently, however, no consensus exists on surveillance guidelines on renal cell carcinoma (RCC), neither after radical nor after partial nephrectomy. Although some guidelines on follow-up of RCC have been published [3–9], large observational or randomized studies regarding the subject are lacking; therefore, the following questions still demand an answer: 1. What is the rationale for following up patients treated for RCC? 2. Should surveillance protocols be based on tumour staging only? 3. What is the evidence derived from stage-based surveillance protocols after radical nephrectomy? 4. What is the optimal period that follow-up should last? 5. Which follow-up schemes are appropriate? 6. Should patients be followed differently after nephron-sparing surgery or thermoablative techniques compared with patients after radical/ partial nephrectomy? 7. How should patients with hereditary RCC or with end-stage renal disease related to RCC be followed? Our aim was to answer these questions by means of an extensive review of the literature looking for the best available evidence. Consequently findings and recommendations were graded according to the level of evidence based on the criteria for evidencebased medicine [1]. 2.
Methods
Using the MeSH terms ‘‘renal cell cancer,’’ ‘‘kidney neoplasm,’’ ‘‘follow-up,’’ ‘‘surveillance,’’ ‘‘prognosis,’’ and ‘‘staging’’ to looking for human/English language/Randomized Controlled Trials/Clinical trials/Review articles/Meta-analysis/Practiced Guidelines, and Editorials, we searched the Medline, MeSH, EMBASE, and Cochrane databases. To answer the aforementioned questions we specifically addressed several issues: whether detection of local recurrences or distant metastases at the earliest opportunity will allow adjuvant treatment to cure patients after nephrectomy; what investigations should be performed as part of the follow-up to detect the most frequent site of metastases; whether additional information beyond the stage of the tumour adds to better identifying patients at risk for recurrence; whether all patients should undergo follow-up regardless of risk for developing
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metastases; and finally whether the type of initial surgery or patients that belong to specific categories play a role in deciding the follow-up. A grade of evidence was assigned to the different articles and to each one of the conclusions. Finally, on the basis of the most common and appropriate follow-up schemes presented in literature, a recommendation on guidelines for follow-up of RCC after surgery was suggested.
3.
Results
3.1. What is the rationale for following up patients treated for RCC?
The overall incidence of metastatic disease following RCC surgery is approximately 40% [2], the risk being related mostly to high tumour stage and grade [3–13] However, metastases do develop in low- and high-risk patients: in patients with pT1 (0–7%) or pT2 (5.3–26.5%) tumours and in patients with grade 1 (9%) or grade 2 (61%) tumours [3–10]. Five-year survival of patients with untreated metastatic disease is poor (2.7–9%) [14,15]. In contrast, response rates of 5–20% have been reported with systemic immunotherapy or chemotherapy [16]. More recently with the use of antivascular endothelial growth factor antibodies [17] or targeted therapies such as tyrosine kinase inhibitors (sunitinib, sorafenib) [18] and mTOR inhibitors (tensirolimus) [19], preliminary responses in the range of 40% have been described. In addition, 5-yr survival following surgery of isolated solitary or multiple lung metastases ranges from 24% to 60% [1,20], with the highest survival rates among those patients in whom complete surgical resection of the metastases was achieved [21,22]. Surgical resection of isolated brain metastasis resulted in a mean survival of 13.8 mo compared with 7 mo when surgery is not performed [23]. The average survival of patients with head and neck metastasis after surgery, radiation, or combined treatment has been reported to be 32.3 mo, 19.7 mo, and 20.7 mo, respectively [24]. Solitary metastasis of RCC to the liver is reported to occur in 5.4% of all cases with metastasis [25]. It is unclear whether surgical resection improves survival in these patients, although a 5-yr cancer-specific survival of 27% has been reported [26]. In the rare case in which a patient has a solitary bony metastasis, surgical excision of the metastatic site leads to a 5-yr survival of 13–30% [27]. Surgical resection of isolated fossa recurrences with or without adjuvant radiation or immunotherapy can lead to a 5-yr cause-specific survival rate of 30–75% [11–13,28–30]. These rates are superior to the 18% and 13% 5-yr cancer-specific survival of patients with
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solitary local recurrence who are treated with medical therapy or observation, respectively [28]. In general, whether treatment of an asymptomatic recurrence detected on regular follow-up carries a survival advantage over treatment of recurrence detected by symptoms has not been thoroughly studied in the literature [31]. Among patients who are operated for local recurrences, those who present with clinical symptoms have a higher rate of incomplete recurrence resection, positive surgical margins, and poorer survival [5]. The aforementioned data indicate that follow-up after nephrectomy is recommended in all patients to detect local recurrence and distant metastases, and to allow appropriate treatment [5]. The type of evidence supporting these data is obtained from well-designed nonexperimental descriptive studies (level III), but no randomized clinical trials exist (grade B). 3.2. Should surveillance protocols be based on only tumour staging?
Disease relapse and cancer-specific survival are highly related to pathologic tumour stage [3–8,32,33] (Table 1). Although tumour grade [9,32] and various histologic subtypes seem to have a prognostic significance, their inability to accurately predict survival or metastasis for similarly staged tumours underlines the fact that tumour cell differentiation [9,10,31,34,35] and histologic differentiation [31,35–37] are currently less useful tools for prognosis. A few authors have constructed survival and recurrence protocols on the basis of a combination of prognostic factors. Combinations such as tumour stage, Fuhrman nuclear grade and performance
status (University of California at Los Angeles [UCLA] protocol) [38]; patient symptoms; tumour histology, size and pathologic stage (MemorialSloan Kettering Cancer Center [MSKCC] protocol) [39]; tumour stage, size, grade, and necrosis (SSIGN score; Mayo clinic protocol); [40] or patient symptoms at presentation, tumour size, pathologic stage, Fuhrman nuclear grade, tumour necrosis, and microvascular invasion (MSKCC protocol updated) [41] all accurately predicted the 5-yr probability of treatment failure among patients with newly diagnosed RCC [42]. On the basis of their risk group stratification system, the UCLA team recently published an evidence-based postoperative surveillance protocol for patients with localized and locally advanced RCC [43]. In their retrospective study (evidence level III/ B), 559 patients were stratified into low risk (T1, grade 1–2, ECOG PS = 0), high risk (T3, grade >1, ECOG > 0, and/or T4, grade 1–4, ECOG = 0–3), and intermediate risk (all the remaining combinations), according to their probability of survival and tumour recurrence (Table 2). On the basis of their results, the authors recommended for low-risk patients yearly history and physical examination, laboratory tests, and chest computed tomography (CT) for 5 yr and an abdominal CT scan at years 2 and 4, with no further surveillance beyond 5 yr. For intermediate-risk patients, the authors recommended history and physical examination, laboratory tests, and chest CT every 6 mo for the first 3 yr, then yearly for 10 yr of follow-up, with an abdominal CT scan at 1 yr then every 2 yr until 10 yr of follow-up. Finally, for highrisk patients, they recommended more intensive abdominal surveillance, with recommendations identical to those for the intermediate-risk group except with more frequent abdominal CT scans at
Table 1 – Five-year cancer-specific/disease-free survival after radical/partial nephrectomy 5-year cancer-specific (disease-freea) survival pT1a Levy 1998a Ljunberg 1999 Hafez 1997c Fergany 2000c,d Fergany 2000c,e Gofrit 2001a Stephenson 2004a
pT1b 90%b 95%b
93%b
NA = not available. Disease-free survival. b Combined results for different stages are presented. c Results are for partial nephrectomy series. d 5-year cancer-specific survival. e 10-year cancer-specific survival. a
75% 87% 71.4%b 95% 67% 97%
97.6% 94.5% 100%
pT2
100% 100% 87% 81%
pT3a
pT3b 60%
52% 30% 85% 74%
37% 55% 59% 23.5% 73%b
66%
57%
p value 0.001 <0.001 0.04 0.007b NA <0.001
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Table 2 – Data derived by the UCLA-combination-criteria–based surveillance after radical nephrectomy Risk group
Low
Intermediate
High
a
T1
T1
T1
T2
T3
T3
T3
T4
Fuhrman grade
G1–2
G1–2
G3–4
G1–4
G1
G2–4
G2–4
G1–4
0
1
Any
Any
Any
0
1
Any
T stage
ECOG PS No. of patients (%) radical/partial nephrectomy 5-year recurrence-free rate (%) % of recurrence radical/partial nephrectomy Median (mean SD) time to recurrence (mo)b % of chest metastases vs. total metastasesb Frequency (%) of chest metastases at 1, 2, 3, 4, 5, >5 yrb Median ( SD) time to diagnosis of chest metastases (mo)b % of chest metastases diagnosed at 1, 2, 3, 4, 5, >5 yrb % of abdominal metastases vs. total metastasesb % of abdominal metastases at 1, 2, 3, 4, 5, >5 yrb Median (mean SD) time to diagnosis of abdominal metastases (mo)b % of abdominal metastases diagnosed at 1, 2, 3, 4, 5, >5 yrb % of bone metastases Median (range) time to diagnosis of bone metastases (mo)b
% of brain metastases Median time (mean SD) to diagnosis of brain metastases (mo)b
93 (25.5)/103 (66.6)
207 (56.7)/44 (28.8)
65 (17.8)/7 (4.6)
90.4 6.5/2.9
61.8 28.9/6.8
41.9 47.7/28.6
28.9 (26.5 17.1)
17.8 (25.5 23.9)
9.5 (21.9 26.2)
75
77.4
45.5
2.2/1.1/0/3.3/0/0
7.7/4.8/2.4/1.4/0.5/1.9
10.8/3.1/3.1/1.5/0/3.1
23.6 (18.8)
NC
NC
NC
41.7/25/13.5/6.3,2.12/10.4
50/14.3/14.3/7.1/0/7
37.5
58.1
68.2
0/1.1/0/1.1/0/0
7.7/1/2.4/0/0.5/1.9
18.5/4.5/3.1/1.5/0/1.5
32 (NC)
NC
NC
NC
66.6/8.3/16.6/0/2.7/13.8
62/4.3/9.5/4.8/0/5
NC NC
NC NC 44% and 31% of bone metastases were diagnosed within the first and after 5 yr of follow-up, respectively
NC 44 (NC)
NC Brain metastases occurred at 1st and 3rd years of follow-up
9.7 NC Bone recurrences occurred at years 1, 3 and >5 after surgery 6.5 NC Brain metastases occurred in the 1st and 5th years of follow-up
ECOG PS = Eastern Cooperative Oncology Group Performance Status; NC = not clarified. T stage refers to 1997 TNM classification. b Refers to the total number of patients with localized tumours. a
a rate of once every 6 mo for the first 2 yr, then yearly for years 2 to 5, then every 2 yr until 10 yr of follow-up. For both medium- and high-risk groups, a chest x-ray can alternate with a chest CT scan after 3 yr. The main limitation of risk groups’ stratification is heterogeneity within groups. A system that groups patients with respect to recurrence in general may not be optimally tailored to an individual’s risk of recurrence. Although some of these prognostic models have been externally validated in a few institutions [44–46], their advantage over the stage-specific strategy for RCC
surveillance still needs to be more extensively assessed in prospective randomized controlled studies. As literature supports the correlation between tumour stage and the risk of subsequent tumour metastasis, the presented data indicate that a surveillance protocol based on the initial tumour stage is still the most frequently adopted (evidence level III/B). However, in the future, surveillance protocols should be based more frequently on the evidence concerning the risk of recurrence and metastases that has been provided by multivariate survival models.
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3.3. What is the evidence derived from stage-based surveillance protocols after radical nephrectomy?
Staged-based surveillance protocols aim to provide us with the most frequent metastatic sites and the mean time to develop metastasis. Several studies of stage-based surveillance following radical nephrectomy for localized RCC (pT1– 3, N0, Nx, M0) have been published during the last decade [3,5–8]. There have been no prospective randomized controlled trials and all existing evidence is based on case study, mostly observational and retrospective (evidence level III/B) (Table 3). Among 629 patients with pT1 disease treated in these series, 3.2–7% developed metastases at a median time of 35–48 mo [3,5–8]. Pulmonary metastases predominated (0–68.7%), were moderately symptomatic at presentation (16.6–64%), and were mostly diagnosed by the combination of symptoms and chest x-ray (81–100%). Abdominal metastases occurred in fewer than 1.6% of patients, of whom only 0.3% was symptomatic. Bone and brain metastases were diagnosed on the basis of symptoms. Among 301 patients with pT2 disease and 351 patients with pT3 disease, 14–27% and 26–54% developed metastases at a median time of 25–32 mo and 11–22 mo, respectively [3,5–8]. Pulmonary metastases predominated (pT2: 50%; pT3: 41.8– 63.2%), were invariably symptomatic at presentation (pT2: 11–71.4%; pT3: 4.1–75%), but they were always diagnosed with the combination of clinical assessment and chest x-ray. Abdominal metastases succeeded (pT2: 0–38.5%; pT3: 13.9–42.1%) and were highly diagnosed by the combination of physical signs, symptoms, and abnormal liver function tests (pT2: 60–100%; pT3: 73.3–100%). Lymph node involvement was detected in up to one quarter of patients (pT2: 5.8–23%; pT3: 11.6–26.3%). All lymph-node positive patients were asymptomatic, diagnosed via CT scans, and had concomitant metastases at other sites [3,5]. Bone metastases were common (pT2: 17.6–45%; pT3: 16–26.5%), highly symptomatic (pT2: 67–100%; pT3: 57–100%), and always diagnosed by the combination of history, serum alkaline phosphatase, and plain skeletal x-rays. Brain metastases were rare (pT2: 0–15.4%; pT3: 4.4–11.1%), developed at a late stage of the disease, and were all symptomatic at presentation. These data support pulmonary and abdominal sites as being the most prevalent secondary deposition of RCC. The prevalence of metastases is stage dependent. Physical examination, biochemical profile, and radiologic evaluation suffice for making the diagnosis in the majority of these cases (evidence level III/B).
3.4.
What is the optimal period that follow-up should last?
Among all studies regarding RCC surveillance, the latest postnephrectomy pulmonary lesion has been detected at 67 mo for pT1 tumours, at 60–96.6 mo for pT2 tumours and at 59–137.9 mo for pT3 tumours [3,5– 8]. The latest abdominal lesion was detected at 97 mo for pT1 tumours, at 29.1–92 mo for pT2 tumours, and at 18.2–79 mo for pT3 tumours. The latest bone lesion was detected at 42–144 mo, 96.7–144 mo, and 36–65 mo in pT1, pT2, and pT3 tumours, respectively [3,5–8]. In the study by Sandock et al [3], 85% of recurrences occurred within the first 3 yr, while the remaining 15% occurred between 3.4 and 11.4 yr. Ljunberg et al [6] showed that 43% of metastases were observed within 1 yr, 70% within 2 yr, 80% within 3 yr, and 93% within 5 yr of follow-up. Only 7% of metastases occurred after 5 yr and most of them were symptomatic. Stephenson et al [7] detected 25% and 21% of pT1 and pT2 recurrences 5 yr after surgery. Of pT3a and pT3b recurrences, 4.3% and 7.1% were detected 3 yr after surgery in the same study. In addition, while patients with pT3 RCC have a higher risk of metastasis than those with pTl–T2 disease, all three groups are at risk for the same duration [5]. These findings suggest that the emphasis of follow-up should be during the first 3–5 yr after nephrectomy (evidence level III/B). Similarly, surveillance frequency can be relaxed after an appropriate interval (3 yr) (evidence level III/B). However, the data also support that the follow-up of patients after radical nephrectomy may be longer than 5 yr, maybe even lifelong [8,47]. 3.5. Which follow-up schemes proposed in the literature are appropriate?
Guidelines for surveillance of patients undergoing nephrectomy have been published from several authors during the last decade (evidence level III/B, IV/C) (Table 4) [3–8,47,48]. First assessment is recommended at 4–6 wk and includes physical examination to exclude surgical complications, serum creatinine to assess the remaining kidney function, and hemoglobin to assess recovery of peroperative blood loss. If alkaline phosphatase is abnormal preoperatively, repeat measurements are recommended to exclude residual tumor or distant metastasis [47]. Throughout follow-up, radionuclide scans are restricted to positive symptom enquiry or raised alkaline phosphatase. Less than half of the published series propose that patients with pT1–T2 tumours should be evaluated with clinical assessment and chest x-ray every 6 mo during the first 3 yr and yearly thereafter [3,6,47].
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Table 3 – Data derived from stage-based surveillance after radical nephrectomy
No. of patients
% of recurrence
Median (range) time to recurrence (mo) % of pulmonary metastases (total/symptomatic) Median (range) time to diagnosis of pulmonary metastases (mo) % of abdominal metastases (total/symptomatic)c Median (range) time to diagnosis of abdominal metastases (mo) % of bone metastases (total/symptomatic) Median (range) time to diagnosis of bone metastases (mo) % of brain metastases (total/symptomatic) Median (range) time to diagnosis of brain metastases (mo)
pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 pT3 pT1 pT2 PT3 PT1 PT2 PT3
Sandocka 1995
Levy 1998
Ljunberg 1999
Gofrit 2001
19 82 36 0 14.6 52.8 — 29.5 (3.5–97) 22 (3–138) 0 (–) 53.8 (71.4) 63.2 (75) — 39.6 (6.9–96.6) 26.4 (3–138) 0 (–) 38.5 (92.3) 42.1 (92.3) — 12 (3.5–29) 7.6 (3–18.2) 0 (–) 38.5 (100) 26.5 (100) — 37 (3.8–97) 19.8 (3.8–40.5) 0 (–) 15.4 (100) 11.1 (100) — NA 4
113 64 109 7 27 39 38 (18–67) 32 (3–115) 17 (2–88) 50 (0) 52.9 (11) 41.8 (11) 53 (30–67) 31 (4–67) 14 (5–59) 0 (–) 29.4 (60) 34.8 (73.3) — 68 (53–83) 23.5 (5–67) 25 (100) 17.6 (67) 16.27 (57) 38.5 (35–42) 24 (3–115) 7 (3–65) 12.5 (100) 5.8 (100) 9.3 (100) 18 11 17 (9–22)
70 43 48 7 14 54 43 (27–60) 29.5 (3–144) 17 (2–62) 54.5b (16.6) 54.5 (16.6) 53.3 (4.1) 8.5 (3–60)b 8.5 (3–60)b 17 (2–62) 0 (–) 0 (–) 20 (100) — — 13 (3–20) 45 (100)b 45 (100)b 22.2 (100) 40 (8–144)b 40 (8–144)b 14.5 (6–36) 0 (–) 0 (–) 4.4 (100) — — 9.5 (9–10)
124 26 50 3.2 23 26 48 (22–64) 28.2 (6–64) 19.8 (4–55) NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
Stephenson 2004 303 84 108 5 16.6 34.25 35 (2–93) 25 (3–95) 11 (1–102) 68.7 (64) NA NA NA NA NA 1.6 (0.3) 1.8 (100) 13.9 (73.3) NA NA NA NA NA NA NA NA NA NA NA NA NA NA NA
NA = not available. T category was based on 1992 TNM classification. b Results for pT1 and pT2 stages were combined in the study of Ljunberg et al 1999 [6]. c In parentheses and under the term symptomatic, cases are presented that were diagnosed due to positive physical examination, symptom history, or abnormal serum studies. a
The remaining studies have recommended a yearly follow-up for these patients [4,5,7,48]. All studies agreed that for pT3 tumours, clinical assessment and chest x-ray should be performed every 6 mo for the first 3 yr and yearly thereafter. Three of 8 studies have recommended routine abdominal CT in patients with pT2 disease [4,5,48], and 7 of 8 recommended routine abdominal imaging for pT3a–b disease [4–8,47,48]. Sandock et al [3] showed that only 0.73% of patients benefited from routine follow-up CT; therefore, they recommended CT at suspicion of recurrence based on symptoms or abnormal serum tests. In an other study, Levy et al [5] showed that 9% of patients with metastases were diagnosed only on the basis of surveillance CT in the absence of symptoms, abnormal serum chemistry, or disease recurrence at another site. Surveillance CT detected no metastases prior to a 29-mo period postoperatively, regardless of pathologic stage.
Therefore, these authors advocated surveillance CT of the abdomen and pelvis at 24 and 60 mo. Contrary to the above conclusion, Ljunberg et al [6] reported in their series that one of the nine intraabdominal/retroperitoneal metastases was detected by scheduled CT, and they recommended routine CT scans for high-risk patients (eg, pT3 tumours) at 6 and 12 mo. The rest of the studies recommended abdominal CT for pT3a–b tumours every 6 mo [4,47], or yearly [6,48] up to the second [4,48] or third year [6,7] postoperatively and then annually [47] or biannually [4,7,48]. Despite these recommendations two topics need further discussion and prospective evaluation in the future. No laboratory test is able to detect lung metastases or lymph node metastases, which represent the large majority of metastases in these patients. Laboratory tests mainly detect symptomatic metastases, such as bone or liver metastases. Since these
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Table 4 – Stage-based surveillance guidelines after nephrectomy proposed during the decade 1995–2005 Clinical assessment (history, physical examination, laboratory studies) pT1 Sandock 1995a Hafez 1997b Levy 1998 Ljunberg 1999 Gofrit 2001b
Mickish 2001c
pT2 Sandock 1995 Hafez 1997b Levy 1998 Ljunberg 1999 Gofrit 2001b Mickish 2001c Stephenson 2004b Uzzo 2003 Novick 2005b pT3 Sandock 1995 Hafez 1996b Levy 1998 Ljunberg 1999 Gofrit 2001b Mickish 2001c Stephenson 2004b Uzzo 2003 Novick 2005b
Abdominal CT
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Not recommended for pT1a tumours
Not recommended Every 2 yr for tumours >2.5 cm Not recommended Not recommended Not recommended for pT1a tumours
III/B III/B III/B III/B III/B
Every 6 mo for 3 yr, then every year from 3 to 5 yr Yearly Every year or 2 yr Yearly
Periodic for pT1b Every 6 mo for 3 yr, then every year from 3 to 5 yr Yearly Not recommended Not recommended
Periodic for pT1b Not recommended
IV/C
Not recommended Not recommended Not recommended
III/B III/B IV/C
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–5 yr Yearly Every year Yearly
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–5 yr Yearly Every year Annually
Not recommended Every 2 yr for tumours >2.5 cm At 24 and 60 mo Not recommended Meticulous periodic follow-up Not recommended
III/B III/B III/B III/B III/B IV/C
Not recommended At year 2, then every 2 yr Every 2 yr
III/B III/B IV/C
Every 6 mo until 3 yr, then yearly Yearly Every 6 mo until 3 yr, then yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr Every 6 mo until 3 yr, then yearly Every 6 mo Yearly
Every 6 mo until 3 yr, then yearly Yearly Every 6 mo until 3 yr, then yearly Every 6 mo until 3 yr, then yearly Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr Every 6 mo until 3 yr, then yearly Every 6 mo Annually
Not recommended Every 6 mo until 2 yr, then every 2 yr At 24 and 60 mo At 6 and 12 mo Meticulous periodic follow-up Every 6 mo for 3 yr, then every year from 3–10 yr
III/B III/B III/B III/B III/B IV/C
At 6, 12, 24, and 36 mo, then every 2 yr At year 1, then every 2 yr Similar to radical nephrectomy
III/B III/B IV/C
CT = computed tomography. T category was based on 1992 TNM classification. b Partial nephrectomy was performed in 100% (Hafez et al, Novick et al), 22.5% (Gofrit et al [8]), and 21% (Stephenson et al [7]) of the patients. c European Association of Urology (EAU) proposed guidelines based on literature data. a
Level of evidence
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Stephenson 2004b Uzzo 2003 Novick 2005b
Every 6 mo until 3 yr, then yearly Yearly Yearly Every 6 mo until 3 yr, then yearly Not recommended for pT1a tumours; periodic for pT1b
Chest x-ray
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metastases are manifested through clinical symptoms, it is very difficult to establish that repetitive measurements are necessary for follow-up. In addition, chest CT scan may be more useful than plain x-rays in earlier detection of lung and thoracic lymph node metastases. A prospective comparison between these two modalities may clarify whether the chest CT scan should be incorporated in the surveillance of RCC patients postnephrectomy. Without being a result of high-level evidencebased urology, Fig. 1 depicts an algorithm for RCC follow-up after radical or partial nephrectomy based on the most frequently proposed surveillance protocols in the literature. 3.6. Should patients after nephron-sparing surgery or thermoablative techniques be followed differently compared with patients after radical nephrectomy?
Stage-specific survival rates following nephronsparing surgery are similar to those following radical nephrectomy [8,49–51].
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Recently, Fergany et al [52] reinforced the surveillance guidelines on nephron-sparing surgery proposed by one of his colleagues a decade ago [4], as well as by other authors [53] (Table 4). During a 10-yr follow-up of 117 nephron-sparing renal operations, no recurrence developed in pTla, pT1b, and pT2 tumours. The incidence of local tumour recurrence was 10% and 12% at a mean interval of 105 and 79.5 mo for T3a and T3b disease, respectively. Distant metastases occurred in 2%, 29%, 0%, 33%, and 53% at a median follow-up of 20, 51, 41, and 25 mo in patients with pTla, pT1b, pT2, pT3a, and pT3b disease, respectively. Combined local recurrence and distant metastases occurred in 2%, 5%, 20%, 10%, and 12% of patients, respectively. In the above study, recurrence in general was noted in a followup period longer than 5 and 10 yr after surgery in 41% and 8.8% of patients, respectively. This finding illustrates the unpredictable nature of RCC and the need for long-term follow-up [52,53]. The aforementioned data indicate that patients undergoing nephron-sparing surgery should be followed similarly to those submitted to radical
Fig. 1 – Algorithm for renal cell carcinoma (RCC) surveillance following radical or partial nephrectomy based on the most common stage-based surveillance protocols proposed in the literature. CT = computed tomography.
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nephrectomy, on the basis of stage-derived surveillance protocols (evidence level III/B). Cryoablation, radiofrequency ablation, highintensity focused ultrasound, interstitial laser, microwave thermotherapy, and photon irradiation, were recently being advocated as nephron-sparing minimally invasive treatment for carefully selected patients. At present the clinical data are limited and the follow-up is short. The assessment of effectiveness of therapy by diligent follow-up imaging and/or biopsy of the tumour lesions is still controversial. No specific guidelines on how we should follow-up these patients exist at this moment [54]. No firm evidence has been proposed for a differential surveillance on the basis of the type of surgery. However, studies incorporating posttreatment biopsy have shown a high proportion of local failure following the use of different ablative techniques [54]. This fact may indicate that these patients should be followed intensively after treatment. 3.7. How should patients with hereditary RCC or RCC related to end-stage renal disease be followed?
There is a paucity of guidelines in the literature regarding follow-up of patients with RCC developed in von Hippel-Lindau disease (VHL), tuberous sclerosis (TS) complex, or hereditary papillary renal cell carcinoma (HPRCC) [55]. In contrast to sporadic RCCs, hereditary RCCs often are discovered at a younger age in a multicentric and bilateral fashion, and affected individuals face a high and lifelong risk of recurrence [56]. Most hereditary RCCs seem to have a minimal metastatic potential when tumour measures less than 3 cm in diameter. Nephrectomy in these cases is not performed until the largest tumour reaches 3 cm. As a consequence, surveillance of these patients is mainly based on tumour size rather than on tumour histology, location, or multifocality [55,57]. In addition, patients who exhibit an aggressive phenotype should undergo imaging relatively frequently (every 3–6 mo), whereas patients with a mild phenotype may safely undergo imaging at 2- to 3-yr intervals [55,57]. The benefit of following up patients with RCC related to end-stage renal disease with routine imaging has been a subject of debate. The argument is similar to the one for the necessity for screening these patients. Since overall survival in patients on dialysis is dictated mostly by comorbidity risk factors, the costs of follow-up may outweigh the benefits of detecting local recurrences or distant metastases [58]. However, for those patients who are candidates for renal transplantation, follow-up is warranted. It is generally suggested to delay trans-
plantation for at least 2 yr after treatment for most cancers [59], especially if the patients are symptomatic at presentation [60]. However, patients with incidentally discovered renal tumours may be eligible for transplantation soon after cancer treatment [60]. CT scan may be more sensitive than ultrasound in following up patients with end-stage renal disease, especially those with multiple renal cysts. However it has limitations such as the cost and the inability to perform a contrast-enhanced study [58]. Contrastenhanced ultrasound or magnetic resonance imaging testing may constitute better alternatives for these patients.
4.
Conclusions
Renal cell carcinomas often behave aggressively and are associated with a poor prognosis. The whole body of literature on follow-up after surgical treatment of RCC is based on observational studies with a lack of randomized trials (evidence level III/B). On the basis of our nonstructured review, we can affirm that, among patients who develop metastases, a subset will benefit from salvage surgery or immunotherapy, a fact that underscores the need for surveillance following primary surgical treatment. Clinical assessment including history recording, physical examination, and laboratory studies, as well as chest x-ray, should be performed twice a year for the first 3 yr and then annually, irrespective of the tumour pathologic stage. Abdominal CT scan may not be recommended for pathologic stages T1 and T2, while most studies support scanning to be performed every 6 mo for the first 2–3 yr and then every 2–3 yr for patients with pT3 tumours. Although surveillance may be more intense during the first 3 yr after surgery, patients who have been operated for RCC should be followed lifelong. Patients should be followed similarly after radical or partial nephrectomy on the basis of stage-oriented protocols. The combination of various prognostic factors requires further validation over stage-based protocols. They may eventually provide a rational approach to identify treatable recurrences, while minimizing unnecessary examinations and patient anxiety. Finally, there is an emerging need to prospectively apply and study follow-up protocols by implying a global or European network. A global network analyzing the time to relapse and site of relapse by ‘‘risk,’’ as estimated by validated multivariate survival and surveillance models, will develop in the future more ‘‘individualized’’ and cost-effective surveillance guidelines.
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Conflicts of interest The authors have nothing to disclose.
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Editorial Comment on: A Review on Follow-Up Strategies for Renal Cell Carcinoma after Nephrectomy Tobias Klatte, Allan J. Pantuck Department of Urology, University of California Los Angeles, Los Angeles, CA [email protected] In this timely review article, Skolarikos et al [1] provide an in-depth summary of issues pertaining to surveillance for disease recurrence following nephrectomy for patients with localized renal cell carcinoma (RCC). The reviewed topic is of paramount importance for the urologic community because it is estimated that 30% of patients undergoing nephrectomy for presumed localized disease eventually experience recurrence. Furthermore, there is still uncertainty regarding the optimum approach to detect recurrence early. Based on a comprehensive analysis of the relevant literature, the authors discuss the rationale for surveillance and the timing, intensity, duration, and methods of surveillance appropriate for various patient groupings. The authors emphasize that, at the present time, no prospective or randomized studies have been conducted to address these important questions. All currently available recommendations on surveillance are based on retrospective, mostly single-center studies achieving a maximum evidence level of only III/B. However, until the time that high-level evidence becomes available (and there are currently no plans for prospective studies to evaluate this question of which we are aware), patients must be followed using the best data available. In the distant past, the majority of clinicians followed all patients according to the same general plan, regardless of tumor histology, tumor stage, tumor grade, or other factors of tumor biology that drive the risk of tumor recurrence. At the present time, the most widespread surveillance strategies are based on stage-based protocols [2] because tumor stage is the most important predictor for recurrence after nephrectomy, allowing the intensity and duration of surveillance strategies to be tailored according to the tumor’s stage. However, in the last few years, integrated staging systems that combine multiple clinical and pathologic variables have
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become the favored tool for postoperative risk group assessment. These nomograms, which place patients into groups having high, intermediate, and low risk of disease recurrence, are beginning to be applied to the surveillance arena [3]. As the authors note, however, it is evident that, even using sophisticated nomograms, each patient risk group still is a heterogeneous mix of patients having different risks for recurrence. In the future, it is quite probable that molecular markers such as p53 [4] will further improve the predictive ability of clinical and pathologic nomograms, which may permit further smoothing of this heterogeneity and allow for a surveillance protocol that is better tailored to the individual patient. As a final note, it should be emphasized that surveillance strategies at present should be applied only to tumors managed by extirpative surgeries. The lack of long-term data on outcomes for tumor ablative therapies, such as cryotherapy or radiofrequency ablation, dictates that patients undergoing these still experimental therapies will require more intensive follow-up for distant as well as local recurrence than one might recommend based on tumor biology alone.
References [1] Skolarikos A, Alivizatos G, Laguna P, de la Rosette J. A review on follow-up strategies for renal cell carcinoma after nephrectomy. Eur Urol 2007;51:1490–501. [2] Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am 2003;30:843–52. [3] Lam JS, Shvarts O, Leppert JT, Pantuck AJ, Figlin RA, Belldegrun AS. Postoperative surveillance protocol for patients with localized and locally advanced renal cell carcinoma based on a validated prognostic nomogram and risk group stratification system. J Urol 2005;174: 466–72. [4] Shvarts O, Seligson D, Lam J, et al. p53 is an independent predictor of tumor recurrence and progression after nephrectomy in patients with localized renal cell carcinoma. J Urol 2005;173:725–8. DOI: 10.1016/j.eururo.2006.12.032 DOI of original article: 10.1016/j.eururo.2006.12.031