0022-5347/00/1642-0322~0 lk JOURNAL OF U R O L O G ~ Copyright 0 2000 by h r u c m UROLOCICAL ASSOCIATION, I N C . ~

Vol. 164, 322-325, August 2000 Printed in U.S.A.

OUTCOME OF ISOLATED RENAL CELL CARCINOMA FOSSA RECURRENCE AFTER NEPHRECTOMY

NANCY B. ITANO, MICHAEL L. BLUTE, BRUCE SPOTTS AND HORST ZINCKE From the Departments of Urology and Biostatistics, Mayo Clinic and Foundation, Rochester, Minnesota

ABSTRACT

Purpose: Local recurrence of renal cell carcinoma in the renal fossa after complete radical nephrectomy is uncommon. We characterize and determine outcome in a small subset of patients.

Materials and Methods: From 1970 to 1998 the incidence of isolated renal bed recurrence among 1,737 T1-3NOMO unilateral nephrectomy cases was 1.8% (standard error [SEI 0.4) at 5 years. There were 30 patients in whom isolated local fossa carcinoma recurred after complete radical nephrectomy without evidence of metastatic disease. Patients with any nodal involve- ment at radical nephrectomy were excluded from study as were those who had undergone any form of partial nephrectomy. Patient charts were reviewed for clinical presentation, stage, treatment, development of metastatic disease and survival. Pathological stage was assigned according to the 1997 TNM staging system. Recurrence was identified in 12 (40%) patients during routine followup and the remaining 18 (60%) presented with symptoms related to the recurrent tumor. Patients were divided into 3 treatment groups of observation (9), therapy excluding surgical extirpation (11) and complete surgical resection alone or in conjunction with additional therapy (10). Mean time from local recurrence to development of metastatic disease was calculated. Survival from local recurrence to overall death and disease specific death was estimated using the Kaplan-Meier method. Survival curves for the different treatment groups were then compared.

Results: There were 30 patients identified with an ipsilateral renal fossa recurrence of renal cell carcinoma after complete nephrectomy in the absence of disseminated disease. Mean fol- lowup was 3.3 years (range 0.006 to 14.8) and no patient was lost to followup. The T stage of the primary tumor was TlPT2 in 13 cases, T3a in 4, T3b in 12, and T3c in 1, and all were node negative. Mean time to metastasis was 1.6 years (range 0.006 to 7.3) in the 19 patients who had documented interval metastatic disease after local recurrence. There were 26 deaths, of which 25 were disease specific. Estimated overall crude and cause specific survival at 1 and 5 years was 66% and 28%, respectively. Calculating survival among symptomatic and asymptomatic patients revealed no discernible difference in outcome (p = 0.94). The 5-year survival rate with surgical resection was 51% (SE 18) compared to 18% (12) treated with adjuvant medical therapy and only 13% (12) with observation alone. The differences in cause specific survival were significant (p 50.02).

Conclusions: Isolated local recurrence is rare with less than a 2% incidence at 5-year followup. Presently long-term survival with locally recurrent renal cell carcinoma is poor with a 28% survival rate at 5 years. However, patients who underwent surgical resection had an improved 5-year cause specific survival rate of 51% compared to 18% treated with adjuvant medical therapy and 13% with observation alone. This finding suggests that select patients may benefit from an aggressive surgical approach.

KEY WORDS: carcinoma, renal cell; neoplasm recurrence, local; surgery

PATIENTS AND METHODS Locally recurrent renal cell carcinoma of the renal fossa without identifiable distant metastasis is ra1e.l-3 There is limited information in the literature regarding patient pre- sentation, treatment and Outcome. Reports of renal fossa recurrences have included reported series with widely meta- static disease and anecdotal case reports of isolated renal cell carcinoma recurrences.4-10 Historically the incidence of met- astatic disease at diagnosis is 25% to 50% and after nephrec- tomy metastatic disease will develop in approximately 50% of cases.l.11 However, only 2% to 4% of patients will have soli- tary metastasis.11,12 Renal cell carcinoma fossa recurrence with surgical excision alone122 13 and in combination with

Patientpopulation. F~~~ 1970 to 1998,1,737 patients were identified with localized unilateral renal cell carcinoma (TI- 3NOMO) at the time of complete nephrectomy. Ipsilateral renal fossa disease recurred in 30 (1.8%) patients without evidence of metastatic disease. F~~~~ recuITence was deter- mined by angiography early in the series and then by abdom- inal computerized tomography (cT). Additional pathological tissue diagnosis was made in 22 of the 30 patients. In all patients a history was obtained and physical examination was performed at the time of recurrence, and patients were divided into symptomatic and asymptomatic groups. Patient

postoperative immunotherapy14 has been described. charts were specifically reviewed to identify concurrent med- We report Our experience with 30 patients, and the outcomes ical problems at the time offossa recurrence. Co-morbidities were evaluated p i n g the Charlson index and survival com- parisons were made according to the Charlson score.15 All

of surgical and nonsurgical management.

Accepted for publication March 10, 2000. 322

ISOLATED RENAL CELL CARCINOMA RECURRENCE 323

chest radiographs or CT and bone scans were negative for metastases. Patients were then routinely followed at 6 to 12-month intervals with physical examinations, laboratory evaluation and radiological studies.

Treatment groups. The 30 patients were retrospectively categorized into 3 treatment groups of observation (91, med- ical therapy (radiation, chemotherapy or immunotherapy, 11) and complete surgical resection alone or in conjunction with additional therapy (10). Patients who underwent oper- ative exploration and biopsy without en bloc resection were categorized according to whether they received subsequent treatment. Of the 11 patients treated medically 9 received external beam radiation, 1 was given a-interferon immuno- therapy and 1 chemotherapy (mithramycin). Of the 10 sur- gical group patients 4 received additional radiation and 2 postoperative immunotherapy. These treatment groups are outlined in table 1.

RESULTS

Patient characteristics. There were 18 men and 12 women with a mean age of 67 years (range 35 to 85). The recurrence involved the left side in 16 patients and the right side in 14. Mean followup was 3.3 years (range 0.0006 to 14.8) with a median of 1.6. Mean time from nephrectomy to development of renal fossa disease was 2.8 years (range 0.11 to 13.13) with a median of 1.5. Of the 19 patients with documented interval metastatic disease (development of known metastases after fossa recurrence and before death) mean time to metastases was 1.6 years (range 0.005 to 7.34). Diagnosis was made in 12 (40%) asymptomatic patients at the time of routine followup. Of the remaining 18 (60%) patients 12 had flank or abdom- inal pain, 2 gross hematuria, 2 abdominal bulging, 1 weight loss and 1 dyspnea.

Pathology. The primary kidney cancer was staged accord- ing to the 1997 TNM classification.16 The T stage of the primary tumor was TliT2 in 13 cases, T3a in 4, T3b in 12, and T3c in 1, and all cases were NO. None of the specimens showed evidence of microvascular invasion. Histological sub- types were conventional clear cell in 23 cases, papillary in 4, chromophobe in 2 and sarcomatoid in 1.

Statistical analysis. The calculated incidence of isolated renal fossa recurrence among unilateral T1-3NOMO nephrec- tomy cases was 1.8% 5 0.4% at 5-year followup and 2.3% 5 0.5% at 10-year followup. There were 26 deaths, of which 25 were from renal cell carcinoma. Overall and cause specific 1-year survival was 66% (standard error [SE] 6.4) and 28% (8.7) at 5 years. There was no survival advantage for patients who were asymptomatic versus those with symptoms (p = 0.94). Other univariate factors that were without statistical significance included original T stage, grade and size of the renal tumor. Although patients with a longer disease-free interval after nephrectomy tended to demonstrate improved survival (RR = 0.74, 95% confidence interval 0.54 to 1.011,

TABLE 1. Renal cell carcinoma fossa recurrence treatment categories

No, No.Primary No. Surgical En

Observation TE:fitnt Bloc Resection

No additional treatment Radiotherapy:

Preop. external beam ra- diotherapy + intraoper- ative radiotherapy

Postop. external beam radiotherapy

Mithramycin chemotherapy: Immunotherapy:

u-Interferon Interleukin-2

Total No.

9 3

3 9

1

1

1 2 1

9 11 10 - - -

this did not meet the criteria for statistical significance (p 50.06).

Surgery. Retroperitoneal exploration was performed in 14 patients and 10 had complete en bloc excision of the renal cell carcinoma fossa mass. Operative and hospital records were available for 13 patients. A variety of surgical approaches were used including chevrodsubcostal in 4 cases, flank in 2, midline in 2 and thoracoabdominal in 1. All gross disease was excised. Uniform identification and inking of specific surgical margins were not performed consistently. En bloc excision required extirpation of contiguous organs in 5 cases, includ- ing partial hepatectomy, splenectomy, bowel resection, psoas or quadratus lumborum muscles, and diaphragm. Mean op- erative estimated blood loss was 2,800 cc (range 200 to 9,700) and hospital stay averaged 12 days (range 5 to 19). Blood product transfusions were required in 6 (67%) cases either intraoperatively or postoperatively.

There were 3 (33%) postoperative complications and no perioperative deaths. Complications included prolonged ileus which responded to conservative management in 1 case, pneumonia in 1 and hydropneumothorax which resolved with chest tube drainage in 1. Recurrent disease in the fossa was documented in 50% (5/10) of surgically treated patients. Of the remaining 5 surgically treated patients 3 died of widely metastatic disease, and 2 are disease-free 15 and 2.5 years, respectively, after surgical resection and are being followed with routine CT.

Treatment group analysis. The 5-year cause specific sur- vival with surgical resection was 51% (SE 18) compared to 18% (12) with adjuvant medical therapy and only 13% (12) with observation (p = 0.02, see figure). The surgical group was analyzed to determine if there were additional charac- teristics that could account for the apparent survival benefit. There was no statistical difference in original T stage (p = 0.83), grade (0.24) or maximum tumor size (0.37) between those who did and did not have surgery. However, patients who had undergone surgical intervention did have a younger median age (63.7 versus 69.4 years) and longer median disease-free interval between nephrectomy and ipsilateral fossa recurrence (3.1 versus 0.9 years, p 10.03) than those who did not undergo surgery. However, the multivariate proportional hazards regression analysis evaluating surgical treatment and disease-free interval simultaneously showed that neither alone accounted for the apparent survival ben- efit (p = 0.12 and p = 0.31, respectively).

To determine whether there was an objective difference in overall health between those who underwent surgery and those who did not Charlson co-morbidity indexes were ap- plied to both groups a t the time of renal fossa recurrence diagnosis. Mean co-morbidity index score was 3.27 (median 3.0) for patients who did and 3.05 (median 3.0) for those who did not undergo surgical resection (not significant p = 0.64). A higher co-morbidity index was associated with a higher likelihood of death from co-morbid disease.

DISCUSSION

There is limited information on the incidence, presentation and therapy of isolated local renal cell carcinoma fossa re- currences. It is controversial whether this entity is consid- ered a remnant of microscopic disease or a form of metastatic disease. Historically patients with metastatic renal carci- noma have a poor prognosis, with the majority dying within 2 years of diagnosis and a 5-year survival rate of approxi- mately 10%.1~11.13 O’Dea et a1 identified a 2.5% incidence of solitary metastatic lesions, and those with metachronous solitary metastases who were aggressively treated with sur- gical resection had a 5-year survival rate of 23%.3 Middleton reported a 5-year survival rate of 34% for patients who un- derwent surgical resection of an isolated metastasis but did not report the site of recurrences.17 Skinner et a1 had a 5-year

324 ISOLATED RENAL CELL CARCINOMA RECURRENCE

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survival rate of 29% after surgical treatment of metastatic foci in 41 patients, including 7 (17%) with retroperitoneal disease.18 Local ipsilateral fossa recurrence may behave sim- ilarly to other isolated soft tissue metastases.

Esrig et a1 reported a 3-year survival rate of 36% among patients with isolated fossa recurrence but all 11 patients had undergone surgical extirpation.13 Tanguay et a1 noted that 12 of their 16 patients who underwent surgical extirpa- tion for local recurrence were alive a median of 23.5 months since diagnosis.14 However, half of those patients also received biological therapy (a-interferon, y-interferon, 5-fluorouracil, interleukin-2, mitomycin C and tumor necro- sis factor) preoperatively and postoperatively. deKernion et a1 reported on 86 patients with metastatic renal cell carci- noma and determined that local fossa recurrence in the face of widely metastatic disease was a poor prognostic factor.' Patients with local recurrence and disseminated disease had a 1-year survival rate of only 14% compared to a 1-year survival rate of 40% among those without local recurrence. However, 9 of their 11 patients with TNM stage disease had positive regional lymph node metastasis a t radical nephrec- tomy.

Our patients had an overall cause specific survival at 3 and 5 years of 40% and 28%, respectively. Our patients under- went observation, medical therapy or surgical intervention. None of them had metastasis at the time of local recurrence or regional lymph node involvement at the time of nephrec- tomy. Table 2 compares the outcomes from these studies. Interestingly, almost half of our patients (40%) were asymp- tomatic when they were diagnosed with isolated renal cell

TABLE 2. Review of literature: renal fossa renal cell carcinoma recurrences

~

References

No. pts. No. no evidence of metastasis (%) Mean age Mean followup (mos.) Median followup (mos.) No. symptomatic (%) Mos. to recurrence % Overall 5-yr. survival % Overall 3-yr. survival % Overall 1-yr. survival No. surgical resection (%) % Periop. deaths (No.) % Reported complications (No.) Av. hospital stay (days) Av. blood loss (cc)

11 10 (91) 59

- -

9 (82)

Not reported 31

36 55 11 (100) 18 (2) 18 (2)

16 15 (94) 53

17

16.5

-

6 (38)

- - -

15 (94) 0 (0)

31 (5) 10

950

30 30 (100) 67 40 18 18 (60) 34 28 40 66 10 (33) 0 (0)

33 (3) 12

2,800

carcinoma recurrence, which correlates with the study of Tanguay et a1 in which 10 of 16 (38%) patients were asymp- tomatic.14 We found no significant benefit among those who were asymptomatic. Additionally, there was no correlation among original T stage, grade or tumor size and survival. Similar to Esrig et al, we were unable to document a statis- tical correlation between the disease-free interval and out- come.13 We did find a positive correlation between the me- dian time from nephrectomy to development of local recurrence and survival that was highly suggestive (RR = 0.74), but did not achieve statistical significance.

Our data suggest a significant benefit among those pa- tients who underwent complete en bloc surgical resection compared to medical therapy or observation, with a 5-year survival rate of 51%, compared to 18% treated with medical therapy and 13% with observation. However, additional ad- juvant medical therapy was similar as both groups of pa- tients primarily underwent radiotherapy (table l). The 2 significant prognostic factors determined in this study were surgical resection and a greater time to development of fossa recurrence. Among operative candidates median disease-free interval was greater than for those not offered surgery, which may have imparted a selection bias. However, multivariate analysis directly comparing the 2 variables showed that the longer disease-free interval did not solely account for the difference in survival. Additionally, there did not appear to be a significant difference in co-morbidities as evidenced by the Charlson indexes. These weighted indexes factor in med- ical conditions that portend prognostic estimations of long- term survival.

CONCLUSIONS

The primary treatment of renal cell carcinoma is surgical. Chemotherapy for metastatic disease has been disappoint- ing, although newer studies on immunotherapy appear promising.19 We believe that the isolated recurrence of renal cell carcinoma in the renal bed may behave as a solitary metastasis and that select patients may benefit from surgical resection. Surgioal resection of isolated renal cell carcinoma fossa recurrence with or without radiation should be consid- ered in a patient with an acceptable co-morbidity index and when it has been more than 1 year since nephrectomy. We reported no p,erioperative deaths and, while our complication rate was significant, earlier recognition of fossa recurrence may prove to be more responsive to aggressive treatment.

ISOLATED RENAL CELL CARCINOMA RECURRENCE 325 REFERENCES

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