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Patterns of Tumor Recurrence and Guidelines for Followup After Nephron Sparing Surgery for Sporadic Renal Cell Carcinoma
@322-5347/97/1576-2067$03.00/0 THE JOURNAL OF UROLOGY
Val. 157,2067-2070, June 1997 Printed in U S A .
Copyright 0 1997 by AMERICAN UROUXICAL ASS~CIATION, INC.
PATTERNS OF TUMOR RECURRENCE AND GUIDELINES FOR FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CARCINOMA KHALED S. HAFEZ, ANDREW C. NOVICK* AND STEVEN C. CAMPBELL From the Department of Urology, The Cleveland Clinic Foundation, Cleveland, Ohio
ABSTRACT
Purpose: We delineated patterns of tumor recurrence and developed guidelines for followup aRer nephron sparing surgery for sporadic renal cell carcinoma. Materials and Methods: Before December 1994, 327 patients underwent nephron sparing surgery for sporadic localized renal cell carcinoma at our clinic. Mean postoperative followup was 55.6 months. The course and outcome for patients with postoperative recurrent renal cell carcinoma were reviewed in detail. Results: Renal cell carcinoma recurred after nephron sparing surgery in 38 patients (11.6%), including 13 (4.0%)who had local tumor recurrence with (7) or without (6) metastatic disease and 25 (7.6%) who had metastatic disease without local tumor recurrence. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by a followup chest x-ray or abdominal computerized tomography (CT) in 13. The respective incidences of postoperative local tumor recurrence and metastatic disease according to initial pathological tumor stage were 0 and 4.4%for stage T1,2.0 and 5.3%for stage T2,8.2 and 11.5%for stage T3a, and 10.6 and 14.9%for stage T3b disease. The peak postoperative intervals until local tumor recurrence were 6 to 24 months (7 of 10 patients with stage T3 renal cell carcinoma) and longer than 48 months (all 3 with stage T2 disease). Patients with isolated local tumor recurrence had better survival compared to those with local tumor recurrence and metastatic disease or metastases only. Conclusions: Followup for recurrent malignancy after nephron sparing surgery for renal cell carcinoma can be tailored according to the initial pathological tumor stage. All patients should be evaluated yearly with a medical history, physical examination and select laboratory studies. Patients with stage T1 renal cell carcinoma require no additional monitoring, while those with stage T2 disease should also undergo a yearly chest x-ray and abdominal CT every 2 years. The same recommendations are offered for patients with stage T3 renal cell carcinoma except that abdominal CT should be done every 6 months for the first 2 years postoperatively. KEYWORDS:kidney neoplasms; carcinoma, renal cell; neoplasm metastasis
Nephron sparing surgery provides effective therapy for patients with localized renal cell carcinoma in whom preservation of renal function is a relevant clinical consideration. The technical success rate with this approach is excellent and long-term patient survival free of cancer is comparable to that obtained after radical nephrectomy, particularly for low stage renal cell carcinoma.' The major disadvantage of nephron sparing surgery is the risk of postoperative local tumor recurrence, which in the aggregate is greater than that occurring after radical nephrectomy. For this reason patients treated with nephron sparing surgery for renal cell carcinoma have undergone more frequent followup with abdominal imaging studies postoperatively to enable prompt detection of local tumor recurrence.13 Nevertheless, the timing, presentation and prognosis for patients with local or metastatic recurrence after nephron sparing surgery for renal cell carcinoma have not been well defined. We performed a detailed analysis of tumor recurrence patterns after nephron sparing surgery for sporadic localized renal cell carcinoma in the hope of developing appropriate guidelines for postoperative followup in these patients.
MATERIALS AND METHODS
All 327 cases of nephron sparing surgery for sporadic lo-
calized renal cell carcinoma at our clinic up to December 1994 were reviewed to identify those with recurrence postoperatively. Patients with von Hippel-Lindau disease or known metastatic tumor preoperatively were excluded from this review. Complete followup information was available on all 327 patients through a departmental registry. Throughout the study period our recommendation for postoperative followup was to obtain liver and renal function studies, chest radiography and abdominal computerized tomography (CT) every 6 months for 4 years and yearly thereafter. Patients with recurrent renal cell carcinoma postoperatively were identified for this study, and classified according to whether recurrent malignancy was initially detected locally in the remnant kidney with or without concomitant metastasis or whether the initial manifestation of recurrence was at a metastatic site. Information collected on these patients included initial pathological tumor stage, sit&) of recurrence, interval to recurrence, associated symptoms, method of detection of recurrence, treatment and outcome. Pathological tumor staging was determined according to the TNM system proposed by the International Union Against Cancer: stage T1-tumors 2.5 cm. or smaller with no peneAccepted for publication November 15, 1996. * Re uests for reprints: De artment of Umlo The Cleveland tration through the renal capsule, stage "2-tumorS larger clinic $oundation, 9500 Euclii Ave. (A1001, Clev%nd, Ohio 44195. than 2.5 cm. with no penetration through the renal capsule, 2067
2068
FOLLOR" AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
stage T3a-invasion
of the perinephric fat but without extension beyond &rota's fascia and stage T3b-microscopic or gross involvement of the renal venous system.4 The Kaplan-Meier method was used to perform all survival data analyses. The Wilcoxon test was used to compare survival results in patient subgroups. RESULTS
TABLE1. Local and metastatic tumor recurrence afler nephron sparing surgery according to pathological tumor stage Local Recurrence Metastatic Ca Tumor No. Stage Pts. No. h. Mean Mos. to No. Pts. Mean Mos. to (%) Recurrence (5%) Recurrence T2 T3a
-
6 8 0 151 3 12.0) 61 5 (8.2)
62.0 36.4
5(10.6)
30.4
13 (4.0)
40.0
T3b 47 Totals
Mos. Postop.
3 (4.4) 8 (5.3) 7 (11.5) 7t14.9) 25 (7.6)
44.8 40.0
5.0
2~.6 27.6
No. Detection of Local Recurrence (initial pathological tumor stage)
Less than 6 6-24
0
24-48
2 4(3T2andlT3)
More than 48
Among all 327 patients treated with nephron sparing surgery for renal cell carcinoma the initial pathological tumor stage was T1 in 68 patients, T2 in 151, T3a in 61 and T3b in 47. Mean postoperative followup was 55.6 months. The 5-year cancer specific survival rate for the overall series was 92%. The corresponding rates according to pathological tumor stage were 95,85 and 82% for stages T1 to 2, T3a and T3b renal cell carcinoma, respectively. Renal cell carcinoma recurred following nephron sparing surgery in 38 patients (11.6%). including 27 men and 11 women 48 to 82 years old (mean age 63.8). Recurrent malignancy was initially detected in the remaining portion of the operated kidney in 13 patients (4.0%), including 7 who also had metastatic disease at detection of the local recurrence. In 25 patients (7.6%)1or more metastatic lesions were detected without local recurrence. Mean postoperative followup for these 38 patients was 54.4 months. Local tumor recurrence. A total of 13 patients (4.0%) had local tumor recurrence after nephron sparing surgery, including 6 with isolated lesions and 7 who also had metastatic disease at the time the local tumor was detected. The incidence of local tumor recurrence according to pathological tumor stage was 0,2.0,8.2 and 10.6% for stages T1, T2, T3a and T3b renal cell carcinoma, respectively (table 1).Mean interval to recurrence according to stage for patients with local tumor recurrence was 62.0, 36.4 and 30.4 months for stages "2, T3a and T3b renal cell carcinoma. Local tumor recurrence was detected greater than 48 months postoperatively in all 3 patients with stage T2 disease. Of 10 patients with local recurrence after nephron sparing surgery for stage T3 disease the interval to detection of local cancer was 6 to 24, 24 to 48 and longer than 48 months in 7, 2 and 1 case, respectively (table 2). Five patients with local tumor recurrence were asymptomatic and the recurrent malignancy was detected on followup CT of the abdomen. Local disease was detected in 8 patients due to gross hematuria, flank pain or a recent decrease in kidney function. All 6 patients who had isolated local disease in the remnant kidney (mean interval to recurrence 46.7 months) underwent secondary surgical excision of locally recurrent malignancy via another partial (2) or total (4) nephrectomy. Of these patients 3 are disease-free (mean survival 52.4 months), 2 died of unrelated causes (mean survival 86.7 months) and 1died of metastasis 33 months postoperatively. Seven patients also had metastatic disease at the time local tumor recurrence was detected (mean interval to recurrence 34.3 months). The primary site of metastasis in these patients was bone (3), liver (3) or lung (1). Two patients underwent total nephrectomy and resection of a solitary met-
TI
TABLE2. Interval to detection of local recurrence and ?m?tastatic disease after nephron sparing surgery
I
(all T3) (all T3)
no^^^^^
Of
7 8
5 5
astatic lesion, while 5 received systemic therapy, radiotherapy or symptomatic management. Of the 13 patients with local tumor recurrence 6 are currently alive, 5 died of malignancy and 2 died of unrelated causes. The 4-year cancer specific survival rate from detection of local tumor recurrence was 66.7% for patients with isolated local disease and 31.2% for those with local cancer and concomitant metastasis. Metastatic disease. A total of 25 patients (7.6%) had metastatic disease without local tumor recurrence following nephron sparing surgery for renal cell carcinoma. The incidence of metastatic recurrence according to pathological tumor stage was 4.4,5.3, 11.5and 14.9%for stages T1, T2, T3a and T3b renal cell carcinoma, respectively. This information is shown in table 1along with the mean interval to recurrence in each category. Metastatic recurrences were detected at less than 6 months postoperatively in 7 patients, 6 to 24 months in 8,24 to 48 months in 5 and greater than 48 months in 5 (table 2). Table 3 shows the initial site of metastatic disease in these patients according to the original pathological tumor stage. A total of 11 patients had pulmonary metastatic disease aRer nephron sparing surgery within a mean of 24.6 months postoperatively. Metastatic disease was detected by followup chest radiography in 3 patients, and by cough, hemoptysis, shortness of breath or weight loss in 8. Eight patients had a solitary pulmonary metastasis, while 3 had multiple lung lesions. Of these 11patients 5 underwent surgical excision of a solitary pulmonary metastasis, while the remaining 6 received systemic therapy (3), radiotherapy (1)or symptomatic treatment (2). All 11 patients died, with a mean survival of 27.3 months after detection of metastatic disease. All 6 patients who had solitary (3) or multiple (3) bone metastases after nephron sparing surgery within a mean of 51.4 months postoperatively presented with symptomatic bone pain. Two patients underwent surgical excision of an isolated rib metastasis and 4 received systemic therapy (11, radiotherapy (2) or symptomatic management (1).All 6 patients died, with a mean survival of 10.4 months after detection of metastatic disease. All 3 patients with symptomatic brain metastasis at a mean of 10.3 months after nephron sparing surgery underwent surgical excision of the metastatic lesions, with l each also receiving systemic therapy and radiotherapy. All 3 patients died, with a mean survival of 26.7 months after detection of metastasis. Three patients had isolated liver metastasis on followup CT at a mean of 15.4 months aRer nephron sparing surgery. Two patients who underwent surgical resection of a liver metastasis were alive at 51 and 52 months after detection of the metastasis, while 1 was treated with systemic therapy and died at 19 months. One patient had pancreatic metastases a t 30 months and 1 had malignant retroperitoneal lymphadenopathy at 14 months after nephron sparing surgery, all detected on followup abdominal CT. Both patients received systemic therapy, and they died 30 and 7 months, respectively, after detection of the metastases. For all 25 patients with metastatic disease the cancer specific survival rate from detection of metastasis was 31.4% at 2 years and 7.9% at 5 years. Patient survival after nephron sparing surgery. The 3-year
FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
2069
TABLE3. Site of metastatic disease after nephron sparing surgery according to pathological tumor stuge No. Metastases (mean mos. to recurrence)
Tumor Stage
Lug
TI T2 T3a T3b
0 6 (37.2) 3 (3.1) 2 (18.9)
Totals
Bone
Brain
2 (57.5) l(64.4) 1 (3.4) 2 (61.4)
0 0 1 (3.0) 2 (14.5)
-
-
6 (51.4)
3 (10.3)
-
11 (24.6)
Liver
PtUlcreaS
l(19.6)
Lymph Nodes
Totals
0
1 (5.0) l(21.8)
0 l(30.0) 0 0
-
0
3 (44.8) 8 (40.0) 7 (6.01 7 (28.6)
3 (15.4)
l(30.0)
l(14.0)
0
and 5-year cancer specific survival rates after nephron sparing surgery for the overall group of 38 patients who had postoperative recurrence were 63.4 and 54.8%, respectively (part A of figure). The 5-year cancer specific survival rates after nephron sparing surgery for patients with stages T1 to 2, T3a and T3b renal cell carcinoma and postoperative recurrence were 71.4,30.0 and 55.0%, respedively (p = 0.04, part B of figure). The 5-year cancer specific sunrival rates for patients with isolated local tumor recurrence, local recurrence and concomitant metastasis, and metastatic disease only were 80.0,60.0and 48.0%, respectively (p = 0.12, part C of figure).
0 l(14.0)
-
25 (27.6)
metastatic disease, and 25 (7.6%)who had metastatic disease without local cancer. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by followup chest x-ray or abdominal CT in 13. Patients who had an isolated local tumor recurrence had significantly better extended survival compared to those with local disease and metastasis or metastasis only (p = 0.04). This finding supports a policy of secondary surgical excision with partial or total nephrectomy for patients who have isolated local tumor recurrence after nephron sparing surgery for renal cell carcinoma. For patients with metastatic disease postoperatively, resection of a solitary metastasis may be Considered but more effective systemic therapy for renal cell carcinoma is needed to improve substantially the outcome in this group. An important finding in our study was the difference in the incidence of local and metastatic disease after nephron sparing surgery according to the initial pathological tumor (pT) stage. In patients who underwent nephron sparing surgery for stage pT1 renal cell carcinoma there were no postoperative local tumor recurrences and only 3 (4.4%) had metastatic disease. Of the latter cases 2 comprised bone metastases that were detected due to symptomatic bone pain. These data strongly suggest that patients treated with nephron sparing surgery for stage pT1 renal cell carcinoma require only limited monitoring postoperatively. In evaluating tumor recurrence after nephron sparing surgery for stage pT2 renal cell carcinoma only 3 of 151patients (2.0%) had local disease, which was detected longer than 4 years postoperatively. This information suggests that early frequent radiographic monitoring for local tumor recurrence is unnecessary in these patients. Eight patients (5.3%) had metastases afier nephron sparing surgery for stage pT2 renal cell carcinoma, and the lung was the initial site of metastasis in 6. Therefore, periodic postoperative chest radiography appears to be a reasonable practice in this group. A greater incidence of local and metastatic recurrence was observed in patients with stage pT3 renal cell carcinoma who underwent nephron sparing surgery (9.3and 13.0%,respectively). These rates were similar in patients with stages pT3a and pT3b disease. Of 10 patients in this category who had local tumor recurrence 7 were diagnosed within the first 2 years postoperatively, which suggests that more frequent early radiographic monitoring for local tumor recurrence is appropriate after nephron sparing surgery for stage pT3 renal cell carcinoma. The initial site of metastasis was abdominal or retroperitoneal in only 3 of 14 patients with stage
DISCUSSION
Several recent studies have confirmed that nephron sparing surgery can provide effective long-term therapy for patients with localized renal cell carcin0rna.b-8 Nevertheless, the followup schedule for monitoring patients after nephron sparing surgery for renal cell carcinoma has received relatively little attention in the literature. It is acknowledged that there is a greater risk of local tumor recurrence after nephron sparing surgery compared to radical nephrectomy, with larger studies suggesting an incidence of up to 10%for the former procedure.9 Specific data concerning metastatic disease after nephron sparing surgery for renal cell carcinoma have also been lacking, although it is assumed that these are not markedly M e r e n t from those observed after radical nephrectomy. We performed a detailed analysis of tumor recurrence patterns after nephron sparing surgery for sporadic localized renal cell carcinoma in the hope of developing appropriate guidelines for postoperative followup in these patients. Patients with renal cell carcinoma and von Hippel-Lindau disease were excluded from this study, since they represent a distinct group in terms of these issues.10 We analyzed our experience with nephron sparing surgery in 327 patients with sporadic localized renal cell carcinoma up to the end of 1994. As in previous reports? the 5-year cancer specific survival rate for the overall series was excellent (92%). Mean postoperative followup in these patients was 55.6 months. Throughout the study period our practice for postoperative followup was to obtain liver and renal function studies, chest radiography and abdominal CT every 6 months for 4 years and yearly thereafter. A total of 38 patients (11.6%) had recurrent renal cell carcinoma following nephron sparing surgery, including 13 (4.0%) with local tumor recurrence with (7) or without (6)
Fen
FBO
.. . . . . .., . . . ... . . .. .... . ..
c
A
o0
B
(2
18
24
SO
34
hmh. POsl-OP.ratl..I"
<2
48
Y
M
B
Monrnm
P O ~ B - ~ ~ V ~ I N ~ I Y
C
Months PosllOperalirely
h n c e r specific survival from nephron sparing surgery. A, 38 patients with post0 rative recurrent malignancy.B, patients with atages PT1 to 2 (14). pT3a (12) and pT3b (12) renal cell carcinoma. C, atients with isolate8ocal tumor recurrence (6), local tumor recurrence and concomitant metastasis (71, and metastatic disease only (25). &st, distant.
2070
FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
pT3 renal cell carcinoma, suggesting a limited role for abdominal CT to detect metastatic disease in this group. CONCLUSIONS
When designing an appropriate strategy for postoperative followup after nephron sparing surgery for renal cell carcinoma a balance must be established between reasonable evaluations aimed at detecting treatable disease and overly aggressive followup that may provide more specific information but does not impact on the quality or length of survival. The cost of postoperative monitoring studies is an additional related issue. Our results confirm the excellent outcome after nephron sparing surgery for most patients with sporadic localized renal cell carcinoma. The risk of postoperative local recurrence or metastasis is directly related to the initial pathological tumor stage. This finding and the more detailed analysis of recurrence data within each tumor stage group indicate that followup after nephron sparing surgery can be tailored according to the initial pathological tumor stage and can perhaps be more limited than the current practice at many centers, including ours. Our findings and recommendations are similar to those of a recent study of the followup of patients with renal cell carcinoma treated with radical nephrectomy.' We recommend a postoperative followup scheme after nephron sparing surgery for sporadic localized renal cell carcinoma. All patients should be evaluated with a medical history, physical examination and select blood studies on a yearly basis, including serum calcium, alkaline phosphatase, liver function tests, blood urea nitrogen, serum creatinine and electrolytes. A 24-hour urinary protein measurement should also be obtained in patients with a solitary remnant kidney to screen for hyperfiltration nephropathy.12 The need for postoperative radiographic followup varies according to the initial pT stage. Patients who undergo nephron sparing surgery for stage pT1 renal cell carcinoma do not require radiographic imaging postoperatively in view of the low risk of recurrence. A yearly chest x-ray is recommended after nephron sparing surgery for stages pT2 and pT3 renal cell carcinoma, since the lung is the most common site of postoperative metastasis in both groups. Abdominal or retroperitoneal recurrence is uncommon in patients with stage pT2 cancer, particularly early after nephron sparing surgery, and these patients require only occasional followup abdominal CT. We recommend that CT be done every 2 years in this
category. Patients with stage pT3 disease are a t greater risk for local tumor recurrence, particularly during the first 2 years after nephron sparing surgery, and they may benefit from more frequent followup abdominal CT initially. We recommend that CT be done every 6 months for 2 years and every 2 years thereafter. We prefer CT for detection of abdominal and retroperitoneal tumor recurrence in this followup scheme. However, some centers may elect to substitute ultrasonography due to the decreased cost. REFERENCES
1. Licht, M. R. and Novick, A. C.: Nephron sparing surgery for renal cell carcinoma. J. Urol., 149 1, 1993. 2. Van Poppel, H., Cleas, H., Willemen, P., Oyen, R. and Baert, L.: Is there a place for conservative surgery in t h e treatment of renal carcinoma? Brit. J. Urol., 67: 129, 1991. 3. Montie, J. E.: Follow-up after partial or total nephrectomy for renal cell carcinoma. Urol. Clin. N. Amer., 21: 589, 1994. 4. Hermanek, P. and Schrott, K. M.: Evaluation of the new tumor, nodes and metastasis classification of renal cell carcinoma. J. Urol., 144: 238, 1990. 5. Licht, M. R., Novick, A. C. and Goormastic, M.: Nephron sparing surgery in incidental versus suspected renal cell carcinoma. J. Urol., 152: 39, 1994. 6. Morgan, W. R. and Zincke, H.: Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. J. Urol., 144: 852, 1990. 7. Moll, V., Becht, E. and Ziegler, M.: Kidney preserving surgery in renal cell tumors: indications, techniques and results in 152 patients. J. Urol., 150: 319, 1993. 8. Steinbach, F., Stockle, M., Muller, S. C., Thuroff, J. W., Melchoir, S. W., Stein, R. and Hohenfellner, R.: Conservative surgery of renal cell tumors in 140 patients: 2 1 years of experience. J. Urol., 148: 24, 1992. 9. Campbell, S. C. and Novick, A. C.: Management of local recurrence following radical nephrectomy or partial nephrectomy. Urol. Clin. N. Amer., 21: 593, 1994. 10. Steinbach, F., Novick, A. C., Zincke, H., Miller, D. P., Williams, R. D., Lund, G., Skinner, D. G., Esrig, D., Richie, J. P., de Kernion, J. B., Marshall, F. and Marsh, C. L.: Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J. Urol., 153: 1812, 1995. 11. Sandock, D. S., Seftel, A. D. and Resnick, M. I.: A new protocol for the followup of renal cell carcinoma based on pathological stage. J. Urol., 154 28, 1995. 12. Novick, A. C., Gephardt, G., Guz, B., Steinmuller, D. and Tubbs, R. R.: Long-term follow-up after partial removal of a solitary kidney. New Engl. J. Med., 325: i058, 1991.
Val. 157,2067-2070, June 1997 Printed in U S A .
Copyright 0 1997 by AMERICAN UROUXICAL ASS~CIATION, INC.
PATTERNS OF TUMOR RECURRENCE AND GUIDELINES FOR FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CARCINOMA KHALED S. HAFEZ, ANDREW C. NOVICK* AND STEVEN C. CAMPBELL From the Department of Urology, The Cleveland Clinic Foundation, Cleveland, Ohio
ABSTRACT
Purpose: We delineated patterns of tumor recurrence and developed guidelines for followup aRer nephron sparing surgery for sporadic renal cell carcinoma. Materials and Methods: Before December 1994, 327 patients underwent nephron sparing surgery for sporadic localized renal cell carcinoma at our clinic. Mean postoperative followup was 55.6 months. The course and outcome for patients with postoperative recurrent renal cell carcinoma were reviewed in detail. Results: Renal cell carcinoma recurred after nephron sparing surgery in 38 patients (11.6%), including 13 (4.0%)who had local tumor recurrence with (7) or without (6) metastatic disease and 25 (7.6%) who had metastatic disease without local tumor recurrence. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by a followup chest x-ray or abdominal computerized tomography (CT) in 13. The respective incidences of postoperative local tumor recurrence and metastatic disease according to initial pathological tumor stage were 0 and 4.4%for stage T1,2.0 and 5.3%for stage T2,8.2 and 11.5%for stage T3a, and 10.6 and 14.9%for stage T3b disease. The peak postoperative intervals until local tumor recurrence were 6 to 24 months (7 of 10 patients with stage T3 renal cell carcinoma) and longer than 48 months (all 3 with stage T2 disease). Patients with isolated local tumor recurrence had better survival compared to those with local tumor recurrence and metastatic disease or metastases only. Conclusions: Followup for recurrent malignancy after nephron sparing surgery for renal cell carcinoma can be tailored according to the initial pathological tumor stage. All patients should be evaluated yearly with a medical history, physical examination and select laboratory studies. Patients with stage T1 renal cell carcinoma require no additional monitoring, while those with stage T2 disease should also undergo a yearly chest x-ray and abdominal CT every 2 years. The same recommendations are offered for patients with stage T3 renal cell carcinoma except that abdominal CT should be done every 6 months for the first 2 years postoperatively. KEYWORDS:kidney neoplasms; carcinoma, renal cell; neoplasm metastasis
Nephron sparing surgery provides effective therapy for patients with localized renal cell carcinoma in whom preservation of renal function is a relevant clinical consideration. The technical success rate with this approach is excellent and long-term patient survival free of cancer is comparable to that obtained after radical nephrectomy, particularly for low stage renal cell carcinoma.' The major disadvantage of nephron sparing surgery is the risk of postoperative local tumor recurrence, which in the aggregate is greater than that occurring after radical nephrectomy. For this reason patients treated with nephron sparing surgery for renal cell carcinoma have undergone more frequent followup with abdominal imaging studies postoperatively to enable prompt detection of local tumor recurrence.13 Nevertheless, the timing, presentation and prognosis for patients with local or metastatic recurrence after nephron sparing surgery for renal cell carcinoma have not been well defined. We performed a detailed analysis of tumor recurrence patterns after nephron sparing surgery for sporadic localized renal cell carcinoma in the hope of developing appropriate guidelines for postoperative followup in these patients.
MATERIALS AND METHODS
All 327 cases of nephron sparing surgery for sporadic lo-
calized renal cell carcinoma at our clinic up to December 1994 were reviewed to identify those with recurrence postoperatively. Patients with von Hippel-Lindau disease or known metastatic tumor preoperatively were excluded from this review. Complete followup information was available on all 327 patients through a departmental registry. Throughout the study period our recommendation for postoperative followup was to obtain liver and renal function studies, chest radiography and abdominal computerized tomography (CT) every 6 months for 4 years and yearly thereafter. Patients with recurrent renal cell carcinoma postoperatively were identified for this study, and classified according to whether recurrent malignancy was initially detected locally in the remnant kidney with or without concomitant metastasis or whether the initial manifestation of recurrence was at a metastatic site. Information collected on these patients included initial pathological tumor stage, sit&) of recurrence, interval to recurrence, associated symptoms, method of detection of recurrence, treatment and outcome. Pathological tumor staging was determined according to the TNM system proposed by the International Union Against Cancer: stage T1-tumors 2.5 cm. or smaller with no peneAccepted for publication November 15, 1996. * Re uests for reprints: De artment of Umlo The Cleveland tration through the renal capsule, stage "2-tumorS larger clinic $oundation, 9500 Euclii Ave. (A1001, Clev%nd, Ohio 44195. than 2.5 cm. with no penetration through the renal capsule, 2067
2068
FOLLOR" AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
stage T3a-invasion
of the perinephric fat but without extension beyond &rota's fascia and stage T3b-microscopic or gross involvement of the renal venous system.4 The Kaplan-Meier method was used to perform all survival data analyses. The Wilcoxon test was used to compare survival results in patient subgroups. RESULTS
TABLE1. Local and metastatic tumor recurrence afler nephron sparing surgery according to pathological tumor stage Local Recurrence Metastatic Ca Tumor No. Stage Pts. No. h. Mean Mos. to No. Pts. Mean Mos. to (%) Recurrence (5%) Recurrence T2 T3a
-
6 8 0 151 3 12.0) 61 5 (8.2)
62.0 36.4
5(10.6)
30.4
13 (4.0)
40.0
T3b 47 Totals
Mos. Postop.
3 (4.4) 8 (5.3) 7 (11.5) 7t14.9) 25 (7.6)
44.8 40.0
5.0
2~.6 27.6
No. Detection of Local Recurrence (initial pathological tumor stage)
Less than 6 6-24
0
24-48
2 4(3T2andlT3)
More than 48
Among all 327 patients treated with nephron sparing surgery for renal cell carcinoma the initial pathological tumor stage was T1 in 68 patients, T2 in 151, T3a in 61 and T3b in 47. Mean postoperative followup was 55.6 months. The 5-year cancer specific survival rate for the overall series was 92%. The corresponding rates according to pathological tumor stage were 95,85 and 82% for stages T1 to 2, T3a and T3b renal cell carcinoma, respectively. Renal cell carcinoma recurred following nephron sparing surgery in 38 patients (11.6%). including 27 men and 11 women 48 to 82 years old (mean age 63.8). Recurrent malignancy was initially detected in the remaining portion of the operated kidney in 13 patients (4.0%), including 7 who also had metastatic disease at detection of the local recurrence. In 25 patients (7.6%)1or more metastatic lesions were detected without local recurrence. Mean postoperative followup for these 38 patients was 54.4 months. Local tumor recurrence. A total of 13 patients (4.0%) had local tumor recurrence after nephron sparing surgery, including 6 with isolated lesions and 7 who also had metastatic disease at the time the local tumor was detected. The incidence of local tumor recurrence according to pathological tumor stage was 0,2.0,8.2 and 10.6% for stages T1, T2, T3a and T3b renal cell carcinoma, respectively (table 1).Mean interval to recurrence according to stage for patients with local tumor recurrence was 62.0, 36.4 and 30.4 months for stages "2, T3a and T3b renal cell carcinoma. Local tumor recurrence was detected greater than 48 months postoperatively in all 3 patients with stage T2 disease. Of 10 patients with local recurrence after nephron sparing surgery for stage T3 disease the interval to detection of local cancer was 6 to 24, 24 to 48 and longer than 48 months in 7, 2 and 1 case, respectively (table 2). Five patients with local tumor recurrence were asymptomatic and the recurrent malignancy was detected on followup CT of the abdomen. Local disease was detected in 8 patients due to gross hematuria, flank pain or a recent decrease in kidney function. All 6 patients who had isolated local disease in the remnant kidney (mean interval to recurrence 46.7 months) underwent secondary surgical excision of locally recurrent malignancy via another partial (2) or total (4) nephrectomy. Of these patients 3 are disease-free (mean survival 52.4 months), 2 died of unrelated causes (mean survival 86.7 months) and 1died of metastasis 33 months postoperatively. Seven patients also had metastatic disease at the time local tumor recurrence was detected (mean interval to recurrence 34.3 months). The primary site of metastasis in these patients was bone (3), liver (3) or lung (1). Two patients underwent total nephrectomy and resection of a solitary met-
TI
TABLE2. Interval to detection of local recurrence and ?m?tastatic disease after nephron sparing surgery
I
(all T3) (all T3)
no^^^^^
Of
7 8
5 5
astatic lesion, while 5 received systemic therapy, radiotherapy or symptomatic management. Of the 13 patients with local tumor recurrence 6 are currently alive, 5 died of malignancy and 2 died of unrelated causes. The 4-year cancer specific survival rate from detection of local tumor recurrence was 66.7% for patients with isolated local disease and 31.2% for those with local cancer and concomitant metastasis. Metastatic disease. A total of 25 patients (7.6%) had metastatic disease without local tumor recurrence following nephron sparing surgery for renal cell carcinoma. The incidence of metastatic recurrence according to pathological tumor stage was 4.4,5.3, 11.5and 14.9%for stages T1, T2, T3a and T3b renal cell carcinoma, respectively. This information is shown in table 1along with the mean interval to recurrence in each category. Metastatic recurrences were detected at less than 6 months postoperatively in 7 patients, 6 to 24 months in 8,24 to 48 months in 5 and greater than 48 months in 5 (table 2). Table 3 shows the initial site of metastatic disease in these patients according to the original pathological tumor stage. A total of 11 patients had pulmonary metastatic disease aRer nephron sparing surgery within a mean of 24.6 months postoperatively. Metastatic disease was detected by followup chest radiography in 3 patients, and by cough, hemoptysis, shortness of breath or weight loss in 8. Eight patients had a solitary pulmonary metastasis, while 3 had multiple lung lesions. Of these 11patients 5 underwent surgical excision of a solitary pulmonary metastasis, while the remaining 6 received systemic therapy (3), radiotherapy (1)or symptomatic treatment (2). All 11 patients died, with a mean survival of 27.3 months after detection of metastatic disease. All 6 patients who had solitary (3) or multiple (3) bone metastases after nephron sparing surgery within a mean of 51.4 months postoperatively presented with symptomatic bone pain. Two patients underwent surgical excision of an isolated rib metastasis and 4 received systemic therapy (11, radiotherapy (2) or symptomatic management (1).All 6 patients died, with a mean survival of 10.4 months after detection of metastatic disease. All 3 patients with symptomatic brain metastasis at a mean of 10.3 months after nephron sparing surgery underwent surgical excision of the metastatic lesions, with l each also receiving systemic therapy and radiotherapy. All 3 patients died, with a mean survival of 26.7 months after detection of metastasis. Three patients had isolated liver metastasis on followup CT at a mean of 15.4 months aRer nephron sparing surgery. Two patients who underwent surgical resection of a liver metastasis were alive at 51 and 52 months after detection of the metastasis, while 1 was treated with systemic therapy and died at 19 months. One patient had pancreatic metastases a t 30 months and 1 had malignant retroperitoneal lymphadenopathy at 14 months after nephron sparing surgery, all detected on followup abdominal CT. Both patients received systemic therapy, and they died 30 and 7 months, respectively, after detection of the metastases. For all 25 patients with metastatic disease the cancer specific survival rate from detection of metastasis was 31.4% at 2 years and 7.9% at 5 years. Patient survival after nephron sparing surgery. The 3-year
FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
2069
TABLE3. Site of metastatic disease after nephron sparing surgery according to pathological tumor stuge No. Metastases (mean mos. to recurrence)
Tumor Stage
Lug
TI T2 T3a T3b
0 6 (37.2) 3 (3.1) 2 (18.9)
Totals
Bone
Brain
2 (57.5) l(64.4) 1 (3.4) 2 (61.4)
0 0 1 (3.0) 2 (14.5)
-
-
6 (51.4)
3 (10.3)
-
11 (24.6)
Liver
PtUlcreaS
l(19.6)
Lymph Nodes
Totals
0
1 (5.0) l(21.8)
0 l(30.0) 0 0
-
0
3 (44.8) 8 (40.0) 7 (6.01 7 (28.6)
3 (15.4)
l(30.0)
l(14.0)
0
and 5-year cancer specific survival rates after nephron sparing surgery for the overall group of 38 patients who had postoperative recurrence were 63.4 and 54.8%, respectively (part A of figure). The 5-year cancer specific survival rates after nephron sparing surgery for patients with stages T1 to 2, T3a and T3b renal cell carcinoma and postoperative recurrence were 71.4,30.0 and 55.0%, respedively (p = 0.04, part B of figure). The 5-year cancer specific sunrival rates for patients with isolated local tumor recurrence, local recurrence and concomitant metastasis, and metastatic disease only were 80.0,60.0and 48.0%, respectively (p = 0.12, part C of figure).
0 l(14.0)
-
25 (27.6)
metastatic disease, and 25 (7.6%)who had metastatic disease without local cancer. Recurrent renal cell carcinoma was detected by associated symptoms in 25 patients and by followup chest x-ray or abdominal CT in 13. Patients who had an isolated local tumor recurrence had significantly better extended survival compared to those with local disease and metastasis or metastasis only (p = 0.04). This finding supports a policy of secondary surgical excision with partial or total nephrectomy for patients who have isolated local tumor recurrence after nephron sparing surgery for renal cell carcinoma. For patients with metastatic disease postoperatively, resection of a solitary metastasis may be Considered but more effective systemic therapy for renal cell carcinoma is needed to improve substantially the outcome in this group. An important finding in our study was the difference in the incidence of local and metastatic disease after nephron sparing surgery according to the initial pathological tumor (pT) stage. In patients who underwent nephron sparing surgery for stage pT1 renal cell carcinoma there were no postoperative local tumor recurrences and only 3 (4.4%) had metastatic disease. Of the latter cases 2 comprised bone metastases that were detected due to symptomatic bone pain. These data strongly suggest that patients treated with nephron sparing surgery for stage pT1 renal cell carcinoma require only limited monitoring postoperatively. In evaluating tumor recurrence after nephron sparing surgery for stage pT2 renal cell carcinoma only 3 of 151patients (2.0%) had local disease, which was detected longer than 4 years postoperatively. This information suggests that early frequent radiographic monitoring for local tumor recurrence is unnecessary in these patients. Eight patients (5.3%) had metastases afier nephron sparing surgery for stage pT2 renal cell carcinoma, and the lung was the initial site of metastasis in 6. Therefore, periodic postoperative chest radiography appears to be a reasonable practice in this group. A greater incidence of local and metastatic recurrence was observed in patients with stage pT3 renal cell carcinoma who underwent nephron sparing surgery (9.3and 13.0%,respectively). These rates were similar in patients with stages pT3a and pT3b disease. Of 10 patients in this category who had local tumor recurrence 7 were diagnosed within the first 2 years postoperatively, which suggests that more frequent early radiographic monitoring for local tumor recurrence is appropriate after nephron sparing surgery for stage pT3 renal cell carcinoma. The initial site of metastasis was abdominal or retroperitoneal in only 3 of 14 patients with stage
DISCUSSION
Several recent studies have confirmed that nephron sparing surgery can provide effective long-term therapy for patients with localized renal cell carcin0rna.b-8 Nevertheless, the followup schedule for monitoring patients after nephron sparing surgery for renal cell carcinoma has received relatively little attention in the literature. It is acknowledged that there is a greater risk of local tumor recurrence after nephron sparing surgery compared to radical nephrectomy, with larger studies suggesting an incidence of up to 10%for the former procedure.9 Specific data concerning metastatic disease after nephron sparing surgery for renal cell carcinoma have also been lacking, although it is assumed that these are not markedly M e r e n t from those observed after radical nephrectomy. We performed a detailed analysis of tumor recurrence patterns after nephron sparing surgery for sporadic localized renal cell carcinoma in the hope of developing appropriate guidelines for postoperative followup in these patients. Patients with renal cell carcinoma and von Hippel-Lindau disease were excluded from this study, since they represent a distinct group in terms of these issues.10 We analyzed our experience with nephron sparing surgery in 327 patients with sporadic localized renal cell carcinoma up to the end of 1994. As in previous reports? the 5-year cancer specific survival rate for the overall series was excellent (92%). Mean postoperative followup in these patients was 55.6 months. Throughout the study period our practice for postoperative followup was to obtain liver and renal function studies, chest radiography and abdominal CT every 6 months for 4 years and yearly thereafter. A total of 38 patients (11.6%) had recurrent renal cell carcinoma following nephron sparing surgery, including 13 (4.0%) with local tumor recurrence with (7) or without (6)
Fen
FBO
.. . . . . .., . . . ... . . .. .... . ..
c
A
o0
B
(2
18
24
SO
34
hmh. POsl-OP.ratl..I"
<2
48
Y
M
B
Monrnm
P O ~ B - ~ ~ V ~ I N ~ I Y
C
Months PosllOperalirely
h n c e r specific survival from nephron sparing surgery. A, 38 patients with post0 rative recurrent malignancy.B, patients with atages PT1 to 2 (14). pT3a (12) and pT3b (12) renal cell carcinoma. C, atients with isolate8ocal tumor recurrence (6), local tumor recurrence and concomitant metastasis (71, and metastatic disease only (25). &st, distant.
2070
FOLLOWUP AFTER NEPHRON SPARING SURGERY FOR SPORADIC RENAL CELL CANCER
pT3 renal cell carcinoma, suggesting a limited role for abdominal CT to detect metastatic disease in this group. CONCLUSIONS
When designing an appropriate strategy for postoperative followup after nephron sparing surgery for renal cell carcinoma a balance must be established between reasonable evaluations aimed at detecting treatable disease and overly aggressive followup that may provide more specific information but does not impact on the quality or length of survival. The cost of postoperative monitoring studies is an additional related issue. Our results confirm the excellent outcome after nephron sparing surgery for most patients with sporadic localized renal cell carcinoma. The risk of postoperative local recurrence or metastasis is directly related to the initial pathological tumor stage. This finding and the more detailed analysis of recurrence data within each tumor stage group indicate that followup after nephron sparing surgery can be tailored according to the initial pathological tumor stage and can perhaps be more limited than the current practice at many centers, including ours. Our findings and recommendations are similar to those of a recent study of the followup of patients with renal cell carcinoma treated with radical nephrectomy.' We recommend a postoperative followup scheme after nephron sparing surgery for sporadic localized renal cell carcinoma. All patients should be evaluated with a medical history, physical examination and select blood studies on a yearly basis, including serum calcium, alkaline phosphatase, liver function tests, blood urea nitrogen, serum creatinine and electrolytes. A 24-hour urinary protein measurement should also be obtained in patients with a solitary remnant kidney to screen for hyperfiltration nephropathy.12 The need for postoperative radiographic followup varies according to the initial pT stage. Patients who undergo nephron sparing surgery for stage pT1 renal cell carcinoma do not require radiographic imaging postoperatively in view of the low risk of recurrence. A yearly chest x-ray is recommended after nephron sparing surgery for stages pT2 and pT3 renal cell carcinoma, since the lung is the most common site of postoperative metastasis in both groups. Abdominal or retroperitoneal recurrence is uncommon in patients with stage pT2 cancer, particularly early after nephron sparing surgery, and these patients require only occasional followup abdominal CT. We recommend that CT be done every 2 years in this
category. Patients with stage pT3 disease are a t greater risk for local tumor recurrence, particularly during the first 2 years after nephron sparing surgery, and they may benefit from more frequent followup abdominal CT initially. We recommend that CT be done every 6 months for 2 years and every 2 years thereafter. We prefer CT for detection of abdominal and retroperitoneal tumor recurrence in this followup scheme. However, some centers may elect to substitute ultrasonography due to the decreased cost. REFERENCES
1. Licht, M. R. and Novick, A. C.: Nephron sparing surgery for renal cell carcinoma. J. Urol., 149 1, 1993. 2. Van Poppel, H., Cleas, H., Willemen, P., Oyen, R. and Baert, L.: Is there a place for conservative surgery in t h e treatment of renal carcinoma? Brit. J. Urol., 67: 129, 1991. 3. Montie, J. E.: Follow-up after partial or total nephrectomy for renal cell carcinoma. Urol. Clin. N. Amer., 21: 589, 1994. 4. Hermanek, P. and Schrott, K. M.: Evaluation of the new tumor, nodes and metastasis classification of renal cell carcinoma. J. Urol., 144: 238, 1990. 5. Licht, M. R., Novick, A. C. and Goormastic, M.: Nephron sparing surgery in incidental versus suspected renal cell carcinoma. J. Urol., 152: 39, 1994. 6. Morgan, W. R. and Zincke, H.: Progression and survival after renal-conserving surgery for renal cell carcinoma: experience in 104 patients and extended followup. J. Urol., 144: 852, 1990. 7. Moll, V., Becht, E. and Ziegler, M.: Kidney preserving surgery in renal cell tumors: indications, techniques and results in 152 patients. J. Urol., 150: 319, 1993. 8. Steinbach, F., Stockle, M., Muller, S. C., Thuroff, J. W., Melchoir, S. W., Stein, R. and Hohenfellner, R.: Conservative surgery of renal cell tumors in 140 patients: 2 1 years of experience. J. Urol., 148: 24, 1992. 9. Campbell, S. C. and Novick, A. C.: Management of local recurrence following radical nephrectomy or partial nephrectomy. Urol. Clin. N. Amer., 21: 593, 1994. 10. Steinbach, F., Novick, A. C., Zincke, H., Miller, D. P., Williams, R. D., Lund, G., Skinner, D. G., Esrig, D., Richie, J. P., de Kernion, J. B., Marshall, F. and Marsh, C. L.: Treatment of renal cell carcinoma in von Hippel-Lindau disease: a multicenter study. J. Urol., 153: 1812, 1995. 11. Sandock, D. S., Seftel, A. D. and Resnick, M. I.: A new protocol for the followup of renal cell carcinoma based on pathological stage. J. Urol., 154 28, 1995. 12. Novick, A. C., Gephardt, G., Guz, B., Steinmuller, D. and Tubbs, R. R.: Long-term follow-up after partial removal of a solitary kidney. New Engl. J. Med., 325: i058, 1991.