- Email: [email protected]
The Role of Nephron Sparing Surgery for Metastatic (pM1) Renal Cell Carcinoma
The Role of Nephron Sparing Surgery for Metastatic (pM1) Renal Cell Carcinoma Amy E. Krambeck,* Bradley C. Leibovich, Christine M. Lohse, Eugene D. Kwon, Horst Zincke† and Michael L. Blute‡ From the Departments of Urology (AEK, BCL, EDK, HZ, MLB) and Health Sciences Research (CML), Mayo Medical School and Mayo Clinic, Rochester, Minnesota
Purpose: Studies have demonstrated increased time to progression when cytoreductive nephrectomy is performed for metastatic renal cell carcinoma. We evaluated the role of nephron sparing surgery in these patients. Materials and Methods: We selected all patients with pM1 renal cell carcinoma treated with nephron sparing surgery or radical nephrectomy, and all patients with pM0 renal cell carcinoma undergoing nephron sparing surgery for solitary kidney from 1970 to 2002 from the Mayo Clinic Nephrectomy Registry. Results: We identified 16 patients who underwent nephron sparing surgery for pM1 renal cell carcinoma. Solitary kidney was present in 12, 3 had bilateral synchronous disease and 1 had elective nephron sparing surgery. Cancer specific survival rates at 1, 3 and 5 years were 81%, 49% and 49%, respectively. We identified 404 patients who underwent radical nephrectomy for pM1 renal cell carcinoma. Cancer specific survival rates at 1, 3 and 5 years were 51%, 21% and 13%, respectively. The pM1 nephron sparing surgery for solitary kidney cases were more likely to have early (33% vs 10%, p ⫽ 0.009) or late (50% vs 19%, p ⫽ 0.018) complications compared with pM1 radical nephrectomy cases. There were no significant differences in early (p ⫽ 0.475) or late (p ⫽ 0.350) complications between pM1 nephron sparing surgery cases and 139 pM0 nephron sparing surgery cases. Conclusions: Cancer specific survival rates in pM1 nephron sparing surgery cases were comparable to pM1 radical nephrectomy cases. Although there were differences in early and late complications between the pM1 nephron sparing surgery and pM1 radical nephrectomy groups, there were no differences when compared with imperative pM0 nephron sparing surgery cases. This study demonstrates that nephron sparing surgery can achieve adequate cytoreductive therapy while preserving renal function, with postoperative complication rates similar to those of pM0 nephron sparing surgery cases. Key Words: carcinoma, renal cell; neoplasm metastasis
lthough renal cell carcinoma accounts for only 3% of all adult malignancies, it is a highly lethal disease even in the face of aggressive treatment.1 Recent studies indicate an increase in the incidence of RCC of 2.5% per year across all population groups.2,3 While advancements in imaging techniques have improved tumor detection rates, up to a third will present with metastatic (pM1) RCC.2– 4 Currently the only curative treatment for RCC is surgical resection.5 For patients with pM1 disease, surgical resection of the primary and occasionally the metastases has a role in treatment of symptoms and for cytoreduction before immunotherapy. At present, the only accepted indications for NSS are imperative, such as tumor in a functionally or anatomically solitary kidney or bilateral renal masses. Patients with impaired renal function are also considered candidates for NSS. However, during the last decade the role of NSS has
A
Submitted for publication November 1, 2005. Study received Institutional Review Board approval. * Correspondence: Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (telephone: 507-5360044; FAX: 507-284-4987; e-mail: [email protected]). ‡ Requests for reprints: Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (telephone: 507284-2511; FAX: 507-284-4951; e-mail: [email protected]).
0022-5347/06/1765-1990/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
expanded to encompass small renal masses in patients with normal contralateral kidneys. Some urologists now believe NSS is the standard of care for renal tumors less than 4 cm regardless of the contralateral kidney status.6 –9 Our institution recently reported no difference in cancer specific and metastases-free survival in patients with 4 to 7 cm RCC tumors treated with open NSS vs RN.10 To our knowledge no investigators have addressed the role of NSS in patients presenting with pM1 RCC. The goal of our study was to identify indications for NSS in patients with pM1 RCC and to determine if cancer specific survival with and without complete metastasectomy is affected by NSS. To assess quality of life, early and late postoperative complications were compared between patients with pM1 disease treated with NSS vs RN. We also compared early and late complications in patients with pM1 disease undergoing NSS to those with organ confined disease (pM0) treated with NSS for a solitary kidney.
MATERIALS AND METHODS Patient Selection Upon approval from the Institutional Review Board, we identified 16 patients who underwent open NSS and 404 patients who underwent open RN with pM1 RCC between
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Vol. 176, 1990-1995, November 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.07.015
NEPHRON SPARING SURGERY FOR METASTATIC RENAL CELL CARCINOMA 1970 and 2002 using the Mayo Clinic Nephrectomy Registry. Complications in the pM1 NSS group were also compared to 139 patients with pM0 RCC treated with NSS for a solitary kidney during the same time. Overall patients with metastatic RCC who were considered candidates for NSS were those with anatomically or functionally solitary kidneys, chronic renal insufficiency, or bilateral tumors with potentially surgically resectable metastatic disease. Complete resection was defined as no evidence of disease following nephrectomy and metastasectomy. Complications Early surgical complications (within 30 days of surgery) included intraoperative death, perioperative (during hospitalization) death, hemorrhage, deep vein thrombosis, pulmonary embolism, myocardial infarction, wound infection, abscess, urine leak (for NSS cases only), sepsis, need for additional surgery, acute renal failure, dialysis, kidney loss, ileus, pneumothorax, duration of hospitalization, blood loss during surgery (cc), and units of blood transfused during surgery and hospitalization. Late complications (30 days to 1 year following surgery) included chronic renal insufficiency or chronic renal failure (postoperative creatinine greater than 2), proteinuria (protein osmolality ratio greater than 0.12), wound hernia and hemodialysis. Statistical Methods Cancer specific survival was estimated using the KaplanMeier method and compared between groups using the log rank test. Early and late complications were compared using chi-square and Wilcoxon rank sum tests. Statistical analyses were performed using the SAS® software package. All p values were 2-sided and those less than 0.05 were considered statistically significant. RESULTS Table 1 contains a summary of the patient characteristics for the 16 who underwent NSS. Solitary metastases were present in 11 patients, 3 were pulmonary, 3 ipsilateral adrenal gland, 1 bone, 1 brain, 1 nonregional lymph node and 1 thyroid. Five patients had distant metastases to multiple locations, including 1 patient with metastases in 9 sites. Of the 5 patients with multiple metastases 4 had at least 1 occurrence of pulmonary metastases. During followup 12 patients with pM1 NSS died, including 11 who died of RCC at a median of 1.5 years following
TABLE 1. Patient and tumor characteristics for pM1 RCC treated with NSS No. sex (%): Male Female No. indication for NSS (%): Solitary kidney Bilateral disease Elective No. histology (%): Clear cell Ca Papillary Ca No. metastasis (%): Solitary Multiple Mean pt age at NSS (range) Mean cm tumor size (range)
11 5
(68.8) (31.2)
12 3 1
(75.0) (18.8) (6.2)
15 1
(93.8) (6.2)
11 (68.8) 5 (31.2) 59 (46–74) 4.6 (1.0–12.0)
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NSS (range 0 to 11). One patient with clear cell RCC had a local recurrence in the same kidney 28 months following NSS. Cancer specific survival rates at 1, 3 and 5 years for the 16 patients with pM1 treated with NSS were 81.3%, 49.2% and 49.2%, respectively. Cancer specific survival rates at 1, 3 and 5 years for the 404 patients treated with RN for pM1 RCC were 50.5%, 21.1% and 12.8%, respectively. Cancer specific survival for the patients with pM1 treated with NSS and RN is shown in figure 1. There was a significant difference in survival between the pM1 NSS cases and the pM1 RN cases (p ⫽ 0.013). Our registry indicated that none of the pM1 NSS cases received adjuvant immunotherapy at our institution. Of the patients with pM1 disease who underwent NSS, complete resection of all metastatic sites was performed in 14 (87.5%) patients compared with 91 (22.6%) of the pM1 RN patients (p ⬍0.001). Of the 2 patients in the pM1 NSS group who did not undergo complete resection, 1 died of RCC 1 month following NSS and the other died of RCC 1.8 years following NSS. The cancer specific survival rates at 1, 3 and 5 years for the pM1 NSS complete resection group were 85.7%, 56.3% and 56.3%, respectively, compared with 64.6%, 29.0% and 20.1%, respectively, for the pM1 RN complete resection group, and 46.0%, 18.4% and 10.5%, respectively, for the pM1 RN incomplete resection group. A comparison of cancer specific survival for pM1 NSS complete resection, pM1 RN complete resection, and pM1 RN incomplete resection patients is illustrated in figure 2. Although the pM1 NSS cases with complete resection appeared to have improved cancer specific survival compared with the pM1 RN cases with complete resection, this difference was not statistically significant (p ⫽ 0.097). For the comparison of early and late complications, only those patients with a solitary kidney in the pM1 NSS group were analyzed (table 2). A significant difference in early postoperative complications was noted between the RN and NSS groups (p ⫽ 0.009), with an overall complication rate in the RN group of 9.9% (40) compared with 33.3% (4) in the NSS group. There were no statistically significant differences between the 2 groups with regards to duration of hospitalization, blood loss, or units of blood transfused during surgery or hospitalization. Early complications in the pM1 NSS group were also compared to the pM0 NSS solitary kidney group. There was no significant difference between the 2 groups (p ⫽ 0.475), with an overall early complication rate in the pM0 NSS of 22.3% (31). There were no statistically significant differences between the pM1 and pM0 NSS groups with regards to duration of hospitalization, blood loss, or units of blood transfused during surgery or hospitalization. A significant difference was noted between the pM1 NSS and pM1 RN groups with regards to late complications (p ⫽ 0.018), with a higher incidence of chronic renal insufficiency, proteinuria, and dialysis in the NSS group (table 3). Dialysis was required in 2 (16.7%) patients in the pM1 NSS group compared with 7 (1.7%) patients in the pM1 RN group. When comparing the pM1 NSS group to the pM0 solitary kidney NSS group, there was no difference in late complications (p ⫽ 0.350). Dialysis was required in 13 (9.4%) patients in the pM0 solitary kidney NSS group. The 3 patients in the pM1 NSS group with bilateral synchronous disease underwent contralateral RN at the time of NSS. These patients were not included in the pM1 NSS group or pM1 RN group when analyzing postoperative
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FIG. 1. Kaplan-Meier curve comparing cancer specific survival for 16 patients with pM1 RCC treated with NSS and 404 patients with pM1 RCC treated with RN. Cancer specific survival rates (standard error, number still at risk) at 1, 3 and 5 years were 81.3% (9.8%, 13), 49.2% (12.7%, 7) and 49.2% (12.7%, 6), respectively, for patients treated with NSS compared with 50.5% (2.5%, 194), 21.1% (2.1%, 73) and 12.8% (1.8%, 40), respectively, for patients treated with RN (p ⫽ 0.013).
complications. Only 1 of these patients had an early complication consisting of a wound infection. The other 2 patients were free of postoperative complications. DISCUSSION Approximately 20% to 30% of patients with RCC present with metastatic disease.4 Overall patients with metastatic RCC have a poor prognosis with a median survival of 6 to 10 months and a 2-year survival of 10% to 20%.11 However, a subset of patients with advanced disease will experience improvements in survival with aggressive therapy.12 Controversy surrounds the role of surgery in the management of pM1 RCC. Previously surgical resection of the primary tumor or metastases was reserved for palliation of symptoms when angioinfarction could not provide adequate symptomatic control. Recently studies demonstrated that complete resection of the primary tumor and all clinically evident metastatic disease improves survival.13 Furthermore, nephrectomy before immunotherapy has been shown to result in a survival benefit in phase III clinical trials.14 –16 The theoretic rationale for surgical resection of the primary tumor includes improved performance status, reduction of tumor burden, prevention of complications during immunotherapy, elimination of paraneoplastic symptoms and eradication of additional metastases source.1,4 Nephrectomy is thought to improve survival in patients receiving immunotherapy by removing the primary tumor as an immunologic sink.17,18 Opponents to cytoreductive surgery question the benefits of surgical intervention in the metastatic setting with concerns over the delay in receiving systemic therapy secondary to surgical mortality, significant morbidity, complications or disease progression. To decrease postoperative morbidity in patients with metastatic RCC who are candidates for surgical intervention, NSS has been instituted in certain circumstances at our institution. This includes those patients with anatomically or functionally solitary kidneys, chronic renal insufficiency, or bilateral tumors who are otherwise good candidates for debulking sur-
gery as defined in the literature.19 This represents a highly select patient population consisting of patients with high preoperative performance status, surgically resectable metastatic disease, and who are potential candidates for postoperative immunotherapy. To our knowledge the outcome of pM1 RCC cases managed with NSS has not been previously evaluated. The 16 patients with pM1 RCC treated with NSS at our institution did not demonstrate inferior cancer specific survival rates compared to those patients with pM1 RCC treated with RN. These patients actually appeared to have improved cancer specific survival compared with the RN group. However, due to the small number of patients in the NSS group, we cannot conclude that NSS improves cancer specific survival compared to RN, but it is reasonable to state that survival is not worsened. The cancer specific survival rate at 1 year in the NSS group was impressive at 81%, however this decreased to 49% by 3 years, which is consistent with the natural history of this disease. Local recurrence was limited to 1 patient in the pM1 NSS group, which occurred more than 2 years after treatment of the primary tumor. This study also confirms an improved cancer specific survival in those patients treated with complete metastasectomy regardless of whether the primary tumor was treated with NSS or RN. When comparing postoperative complications between the pM1 RN and pM1 NSS groups, there was a significant difference when evaluating early events. However, NSS did not significantly increase the duration of hospitalization when compared to the RN group, nor did it affect postoperative blood replacement requirements. Close comparison of the early postoperative complications between the pM1 NSS and pM1 RN groups demonstrated major differences limited only to renal failure and dialysis. One would expect a higher rate of such
FIG. 2. Kaplan-Meier curve comparing cancer specific survival for 14 patients with pM1 RCC treated with NSS and complete resection of metastases, 91 patients with pM1 RCC treated with RN and complete resection of metastases, and 312 patients with pM1 RCC treated with RN and incomplete resection of metastases. Cancer specific survival rates (standard error, number still at risk) at 1, 3 and 5 years were 85.7% (9.4%, 12), 56.3% (13.5%, 7) and 56.3% (13.5%, 6), respectively for pM1 NSS complete resection group; 64.6% (5.0%, 58), 29.0% (4.9%, 23) and 20.1% (4.4%, 15), respectively for pM1 RN complete resection group; and 46.0% (2.9%, 135), 18.4% (2.3%, 50) and 10.5% (1.8%, 25), respectively for pM1RN incomplete resection group. Although patients with pM1 treated with NSS with complete resection appeared to have improved cancer specific survival compared to patients with pM1 treated with RN with complete resection, this difference was not statistically significant (p ⫽ 0.097).
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TABLE 2. Early surgical complications by nephrectomy type for pM1 and pM0 RCC
No. pts No. early complications (%): Intraop death Periop death Hemorrhage Deep vein thrombosis Pulmonary embolism Myocardial infarction Wound infection Abscess Urine leak Sepsis Acute renal failure Dialysis Kidney loss Additional surgery Ileus Pneumothorax Any early complication* Days of hospitalization:† Mean Median (range) Blood loss during surgery:† Mean Median (range) Blood units during surgery:‡ Mean Median (range) Blood units during hospitalization:§ Mean Median (range)
pM1 RN
pM1 Solitary NSS
pM0 Solitary NSS
404
12
139
2 (0.5) 5 (1.2) 6 (1.5) 1 (0.3) 4 (1.0) 1 (0.3) 7 (1.7) 3 (0.7) NA 2 (0.5) 2 (0.5) 1 (0.3) 1 (0.3) 17 (4.2) 5 (1.2) 0 (0.0) 40 (9.9)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (25.0) 2 (16.7) 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) 4 (33.3)
8.6 7 (1–46)
9.3 9 (4–26)
1,088 633 (3–12,000)
1,184 1,000 (150–3,700)
0 (0.0) 2 (1.4) 2 (1.4) 0 (0.0) 0 (0.0) 2 (1.4) 2 (1.4) 3 (2.2) 6 (4.3) 1 (0.7) 11 (7.9) 3 (2.2) 0 (0.0) 14 (10.1) 5 (3.6) 0 (0.0) 31 (22.3) 9.8 7 (1–60) 996 650 (50–5,400)
2.1 1 (0–21)
1.8 1 (0–9)
1.0 0 (0–8)
3.1 2 (0–26)
2.2 1 (0–9)
1.7 0 (0–10)
* p ⫽ 0.009 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.475 for pM1 solitary NSS vs pM0 solitary NSS. † p Value not significant. ‡ p ⫽ 0.917 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.160 for pM1 solitary NSS vs pM0 solitary NSS. § p ⫽ 0.656 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.494 for pM1 solitary NSS vs pM0 solitary NSS.
complications in patients with an imperative indication for NSS as in this series. This point is illustrated by the comparison of postoperative complications between the pM1 NSS group and pM0 solitary kidney NSS group, which demonstrated no significant difference in early complications. Differences in late surgical complications between the pM1 NSS and RN groups were also significant, however, the majority of these complications such as chronic renal insufficiency, proteinuria and dialysis are again considered a function of the imperative indication for NSS. Furthermore, comparisons of late complications in the pM1 NSS group and the pM0 solitary kidney NSS group demonstrated no statistically significant differences. The patients with pM1 RCC in our series may have benefited from NSS compared to RN. NSS allowed cytoreduction as well as palliation of symptoms while preserving renal function in the majority of patients. Standard RN in this cohort would have rendered 93.8% of the patients
anephric, thus affecting quality of life and contributing to significant morbidity. Certain studies have suggested that cytoreductive nephrectomy for metastatic RCC before systemic treatment is beneficial.4 However, postoperative morbidity and worsening performance status result in some patients being unable to receive systemic therapy. Thus, appropriate patient selection is mandatory to recognize beneficial results.19 In patients with pM1 with imperative indications for NSS the usefulness of surgery for the primary tumor is unknown. Our data would indicate that in patients where surgical NSS is technically feasible, oncological outcome is not inferior. Furthermore, in the small subset of patients who can be rendered clinically free of disease with NSS and metastasectomy, complete surgical resection may confer a better prognosis.13 Although data on subsequent immunotherapy are not available in this series, the ability to deliver optimal dosing immunotherapy is reduced for patients in renal failure.5 Based on renal function and histological clear
TABLE 3. Late surgical complications by nephrectomy type for pM1 and pM0 RCC
No. pts No. late complications (%): Chronic renal insufficiency/failure Proteinuria Wound hernia Dialysis Other unspecified complication Any late complication*
pM1 RN
pM1 Solitary NSS
pM0 Solitary NSS
404
12
139
30 (7.4) 42 (10.4) 0 (0.0) 7 (1.7) 17 (4.2) 77 (19.1)
3 (25.0) 3 (25.0) 0 (0.0) 2 (16.7) 3 (25.0) 6 (50.0)
26 (18.7) 28 (20.1) 1 (0.7) 13 (9.4) 5 (3.6) 48 (34.5)
* p ⫽ 0.018 for pM1 RN vs pM1 solitary NSS, p ⬍0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.350 for pM1 solitary NSS vs pM0 solitary NSS.
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cell subtype, 11 of the 16 patients in this series were candidates for postoperative immunotherapy after NSS, which would not have been an option if a RN was performed. As other postoperative complications and total hospital stay were not significantly different between the pM1 RN and pM1 NSS groups, time to immunotherapy would not be delayed. Based on the results of this study we believe there is a role for NSS in select patients with pM1 RCC. However, it must be noted that the current study represents a highly select subset of patients. For many patients with imperative indications for NSS, systemic therapy without surgery for the primary tumor may be preferable. The recent Food and Drug Administration approval of sorafenib for the treatment of metastatic RCC has added to the therapeutic options for patients with metastatic RCC. 20 The majority of patients demonstrating stabilization of disease and responses to date have shown apparent central necrosis or liquefaction of tumor. Subsequent recurrences from within these lesions are common. Therefore, the role of surgical resection of persistently visible lesions, including NSS for primary tumors, after systemic therapy with new targeted agents such as sorafenib may prove to be beneficial. Limitations of our analysis include its retrospective design and the limited number of patients and outcome events. However, our experience would suggest that when cytoreductive therapy or renal functional status is important that NSS is safe with low morbidity and should be considered as part of the overall management of pM1 RCC. The NSS approach is particularly ideal when metastasectomy or immunotherapy is subsequently planned. CONCLUSIONS This study demonstrates that NSS can achieve adequate cytoreductive therapy while preserving renal function. Cancer specific survival was not significantly different between the NSS and RN groups, and complete resection of metastases improved cancer specific survival despite the type of resection of the primary tumor. Early and late postoperative complication differences between the pM1 RN and pM1 NSS groups were limited to renal function. Alterations in renal function are not unexpected in patients with imperative indications for NSS, which is illustrated by the lack of difference in postoperative complications between the pM1 NSS and pM0 solitary kidney NSS group. Based on these data we conclude that NSS in patients with imperative indications for NSS with surgically resectable metastatic disease and high preoperative performance status can be performed successfully.
2.
3.
4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Abbreviations and Acronyms NSS pM0 pM1 RCC RN
⫽ ⫽ ⫽ ⫽ ⫽
nephron sparing surgery organ confined disease metastatic disease renal cell carcinoma radical nephrectomy
REFERENCES 1.
Lam, J. S., Shvarts, O. and Pantuck, A. J.: Changing concepts in the surgical management of renal cell carcinoma. Eur Urol, 45: 692, 2004
16.
17.
Pantuck, A. J., Zisman, A. and Belldegrun, A. S.: The changing natural history of renal cell carcinoma. J Urol, 52: 447, 2001 Chow, W. H., Devesa, S. S., Warren, J. L. and Fraumeni, J. F., Jr.: Rising incidence of renal cell cancer in the United States. JAMA, 281: 1628, 1999 Flanigan, R. C.: Debulking nephrectomy in metastatic renal cell cancer. Clin Cancer Res, 10: 6335S, 2004 Fyfe, G., Fisher, R. I., Rosenberg, S. A., Sznol, M., Parkinson, D. R. and Louie, A. C.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received highdose recombinant interleukin-2 therapy. J Clin Oncol, 13: 688, 1995 Lau, W. K., Blute, M. L., Weaver, A. L., Torres, V. E. and Zincke, H.: Matched comparison of radical nephrectomy vs. nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc, 75: 1236, 2000 Lerner, S. E., Hawkins, C. A., Blute, M. L., Grabner, A., Wollan, P. C., Eickhlt, J. T. et al: Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol, 155: 1868, 1996 Patard, J. J., Shvarts, O., Lam, J. S., Pantuck, A. J., Kim, H. L., Ficarra, V. et al: Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. J Urol, 171: 2181, 2004 Fergany, A. F., Hafez, K. S. and Novick, A. C.: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol, 163: 442, 2000 Leibovich, B. C., Blute, M. L., Cheville, J. C., Lohse, C. M., Weaver, A. L. and Zincke, H.: Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol, 171: 1066, 2004 Janzen, N. K., Kim, H. L., Figlin, R. A. and Belldegrun, A. S.: Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am, 30: 843, 2003 Franklin, J. R., Figlin, R., Rauch, J., Gitlitz, B. and Belldegrun, A.: Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol, 14: 230, 1996 Leibovich, B. C., Cheville, J. C., Lohse, C. M., Zincke, H., Frank, I., Kwon, E. D. et al: A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol, 174: 1759, 2005 Flanigan, R. C., Salmon, S. E., Blumenstein, B. A., Bearman, S. I., Roy, V., McGrath, P. C. et al: Nephrectomy followed by interferon-alpha-2b compared with interferon-alpha-2b alone for metastatic renal-cell cancer. N Engl J Med, 345: 1655, 2001 Mickisch, G. H., Garin, A., Van Poppel, H., de Prijck, L., Sylvester, R. and European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group: Radical nephrectomy plus interferon-alpha-based immunotherapy compared with interferon alpha alone in metastatic renal-cell carcinoma: a randomized trial. Lancet, 358: 966, 2001 Flanigan, R. C., Mickisch, G., Sylvester, R., Tangen, C., Van Poppel, H. and Crawford, E. D.: Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol, 171: 1071, 2004 Spencer, W. F., Linehan, W. M., McClellan, M. W., Hass, G. P., Lotze, M. T., Topalian, S. L. et al: Immunotherapy with interleukin-2 and interferon in patients with metastatic renal cell cancer in situ primary cancers: a pilot study. J Urol, 147: 24, 1992
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19. 20.
Robertson, C. N., Linehan, W. M., Pass, H. I., Gomella, L. G., Haas, G. P., Berman, A. et al: Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. J Urol, 144: 614, 1990 Atkins, M. B.: Management of advanced renal cancer. Kidney Int, 67: 2069, 2005 Gollob, J. A.: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer, 4: 167, 2005
EDITORIAL COMMENT The surgical and medical management of renal cell carcinoma has undergone a revolution during the last decade. Refined surgical technique has resulted in nephron sparing surgery in patients with small renal tumors. The survival advantage of debulking radical nephrectomy in patients with metastatic RCC has been validated in 2 prospective, randomized trials in appropriately selected patients (reference 16 in article). More recently systemic therapy targeted at the vascular endothelial growth factor has produced robust clinical effects in metastatic RCC.1,2 With this background Krambeck et al have the stated purpose of investigating the role of NSS in patients with metastatic RCC. This small, single-institution, retrospective, nonrandomized series reports disease specific survival for 16 patients with metastatic RCC who underwent debulking NSS and 404 patients who underwent debulking RN. Of note, 14 of the 16 patients who underwent NSS (87.5%) also underwent complete resection of all metastatic disease. Given that only 22.5% of RN cases that also had complete metastasectomy (p ⬍0.001 compared to the NSS group), comparison of disease specific survival rates is confounded, thus, limiting the usefulness of this series in evaluating the role of NSS in metastatic RCC. Furthermore, other potentially important variables known to affect the disease specific survival of patients with metastatic RCC such as performance status and laboratory variables are not reported for either group or accounted for in a multivariate analysis to determine the impact of type of nephrectomy on outcome. Although generated from a limited number of selected patients, a greater than 50% disease specific survival observed at 5 years in the NSS group does support the benefit of surgical resection of all gross RCC tumors, including the use of NSS to remove the primary tumor. The larger issues in the role of nephrectomy in metastatic RCC are 2-fold. 1) Does the benefit of debulking RN remain in patients who undergo NSS? 2) Does the benefit of debulking nephrectomy remain in patients who receive subsequent vascular endothelial growth factor targeted therapy (in contrast to the postoperative interferon-␣ received in the randomized trials)? The first question is not likely to be applicable to a large number of patients, as most patients with
1995
metastatic RCC present with primary tumors requiring RN. Indeed the present series of only 16 patients was derived from a tertiary care RCC center during many years. In the absence of additional randomized trials to address both these issues (which may be unlikely to occur), an understanding of the mechanism(s) of benefit of debulking RN could provide insight. Unfortunately such mechanisms, including effects on immunological antitumor response (inherent or therapy induced) and angiogenic growth factor production, are not readily apparent. Until the biological effects of primary tumor removal are better understood, it is reasonable to perform debulking NSS in metastatic RCC cases with imperative indications and consider NSS in select elective cases, especially when complete resection of all metastatic disease is possible. Furthermore, given that the response to subsequent immunotherapy was not altered by prior nephrectomy in previous trials, the survival advantage observed must for now be attributed to the surgery itself. Thus, debulking nephrectomy before planned vascular endothelial growth factor targeted (or other) therapy is reasonable in appropriately selected patients. Brian I. Rini Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Center Cleveland, Ohio 1.
2.
Escudier, B., Szczylik, C., Eisen, T., Stadler, W. M., Schwartz, B., Shan, M. et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol, 23: 380s, abstract 4510, 2005 Motzer, R. J., Michaelson, M. D., Redman, B. G., Hudes, G. R., Wilding, G., Figlin, R. A. et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol, 24: 16, 2006
REPLY BY AUTHORS This study is limited by the small number of patients in the pM1 NSS cohort and its retrospective design. With so few deaths observed in the NSS group, a more extensive multivariate analysis that would account for other features such as Eastern Cooperative Oncology Group performance status and preoperative laboratory values is not feasible. Despite these acknowledged shortcomings, this study demonstrates that NSS is feasible without an obvious decrease in cancer specific survival when compared to pM1 cases treated with RN. We agree that until randomized prospective trials become practical we must rely on information obtained from retrospective studies. Accordingly, the results of our study demonstrate that NSS appears to have a role for pM1 RCC with imperative indications.
Purpose: Studies have demonstrated increased time to progression when cytoreductive nephrectomy is performed for metastatic renal cell carcinoma. We evaluated the role of nephron sparing surgery in these patients. Materials and Methods: We selected all patients with pM1 renal cell carcinoma treated with nephron sparing surgery or radical nephrectomy, and all patients with pM0 renal cell carcinoma undergoing nephron sparing surgery for solitary kidney from 1970 to 2002 from the Mayo Clinic Nephrectomy Registry. Results: We identified 16 patients who underwent nephron sparing surgery for pM1 renal cell carcinoma. Solitary kidney was present in 12, 3 had bilateral synchronous disease and 1 had elective nephron sparing surgery. Cancer specific survival rates at 1, 3 and 5 years were 81%, 49% and 49%, respectively. We identified 404 patients who underwent radical nephrectomy for pM1 renal cell carcinoma. Cancer specific survival rates at 1, 3 and 5 years were 51%, 21% and 13%, respectively. The pM1 nephron sparing surgery for solitary kidney cases were more likely to have early (33% vs 10%, p ⫽ 0.009) or late (50% vs 19%, p ⫽ 0.018) complications compared with pM1 radical nephrectomy cases. There were no significant differences in early (p ⫽ 0.475) or late (p ⫽ 0.350) complications between pM1 nephron sparing surgery cases and 139 pM0 nephron sparing surgery cases. Conclusions: Cancer specific survival rates in pM1 nephron sparing surgery cases were comparable to pM1 radical nephrectomy cases. Although there were differences in early and late complications between the pM1 nephron sparing surgery and pM1 radical nephrectomy groups, there were no differences when compared with imperative pM0 nephron sparing surgery cases. This study demonstrates that nephron sparing surgery can achieve adequate cytoreductive therapy while preserving renal function, with postoperative complication rates similar to those of pM0 nephron sparing surgery cases. Key Words: carcinoma, renal cell; neoplasm metastasis
lthough renal cell carcinoma accounts for only 3% of all adult malignancies, it is a highly lethal disease even in the face of aggressive treatment.1 Recent studies indicate an increase in the incidence of RCC of 2.5% per year across all population groups.2,3 While advancements in imaging techniques have improved tumor detection rates, up to a third will present with metastatic (pM1) RCC.2– 4 Currently the only curative treatment for RCC is surgical resection.5 For patients with pM1 disease, surgical resection of the primary and occasionally the metastases has a role in treatment of symptoms and for cytoreduction before immunotherapy. At present, the only accepted indications for NSS are imperative, such as tumor in a functionally or anatomically solitary kidney or bilateral renal masses. Patients with impaired renal function are also considered candidates for NSS. However, during the last decade the role of NSS has
A
Submitted for publication November 1, 2005. Study received Institutional Review Board approval. * Correspondence: Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (telephone: 507-5360044; FAX: 507-284-4987; e-mail: [email protected]). ‡ Requests for reprints: Department of Urology, Mayo Clinic, 200 First Street Southwest, Rochester, Minnesota 55905 (telephone: 507284-2511; FAX: 507-284-4951; e-mail: [email protected]).
0022-5347/06/1765-1990/0 THE JOURNAL OF UROLOGY® Copyright © 2006 by AMERICAN UROLOGICAL ASSOCIATION
expanded to encompass small renal masses in patients with normal contralateral kidneys. Some urologists now believe NSS is the standard of care for renal tumors less than 4 cm regardless of the contralateral kidney status.6 –9 Our institution recently reported no difference in cancer specific and metastases-free survival in patients with 4 to 7 cm RCC tumors treated with open NSS vs RN.10 To our knowledge no investigators have addressed the role of NSS in patients presenting with pM1 RCC. The goal of our study was to identify indications for NSS in patients with pM1 RCC and to determine if cancer specific survival with and without complete metastasectomy is affected by NSS. To assess quality of life, early and late postoperative complications were compared between patients with pM1 disease treated with NSS vs RN. We also compared early and late complications in patients with pM1 disease undergoing NSS to those with organ confined disease (pM0) treated with NSS for a solitary kidney.
MATERIALS AND METHODS Patient Selection Upon approval from the Institutional Review Board, we identified 16 patients who underwent open NSS and 404 patients who underwent open RN with pM1 RCC between
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Vol. 176, 1990-1995, November 2006 Printed in U.S.A. DOI:10.1016/j.juro.2006.07.015
NEPHRON SPARING SURGERY FOR METASTATIC RENAL CELL CARCINOMA 1970 and 2002 using the Mayo Clinic Nephrectomy Registry. Complications in the pM1 NSS group were also compared to 139 patients with pM0 RCC treated with NSS for a solitary kidney during the same time. Overall patients with metastatic RCC who were considered candidates for NSS were those with anatomically or functionally solitary kidneys, chronic renal insufficiency, or bilateral tumors with potentially surgically resectable metastatic disease. Complete resection was defined as no evidence of disease following nephrectomy and metastasectomy. Complications Early surgical complications (within 30 days of surgery) included intraoperative death, perioperative (during hospitalization) death, hemorrhage, deep vein thrombosis, pulmonary embolism, myocardial infarction, wound infection, abscess, urine leak (for NSS cases only), sepsis, need for additional surgery, acute renal failure, dialysis, kidney loss, ileus, pneumothorax, duration of hospitalization, blood loss during surgery (cc), and units of blood transfused during surgery and hospitalization. Late complications (30 days to 1 year following surgery) included chronic renal insufficiency or chronic renal failure (postoperative creatinine greater than 2), proteinuria (protein osmolality ratio greater than 0.12), wound hernia and hemodialysis. Statistical Methods Cancer specific survival was estimated using the KaplanMeier method and compared between groups using the log rank test. Early and late complications were compared using chi-square and Wilcoxon rank sum tests. Statistical analyses were performed using the SAS® software package. All p values were 2-sided and those less than 0.05 were considered statistically significant. RESULTS Table 1 contains a summary of the patient characteristics for the 16 who underwent NSS. Solitary metastases were present in 11 patients, 3 were pulmonary, 3 ipsilateral adrenal gland, 1 bone, 1 brain, 1 nonregional lymph node and 1 thyroid. Five patients had distant metastases to multiple locations, including 1 patient with metastases in 9 sites. Of the 5 patients with multiple metastases 4 had at least 1 occurrence of pulmonary metastases. During followup 12 patients with pM1 NSS died, including 11 who died of RCC at a median of 1.5 years following
TABLE 1. Patient and tumor characteristics for pM1 RCC treated with NSS No. sex (%): Male Female No. indication for NSS (%): Solitary kidney Bilateral disease Elective No. histology (%): Clear cell Ca Papillary Ca No. metastasis (%): Solitary Multiple Mean pt age at NSS (range) Mean cm tumor size (range)
11 5
(68.8) (31.2)
12 3 1
(75.0) (18.8) (6.2)
15 1
(93.8) (6.2)
11 (68.8) 5 (31.2) 59 (46–74) 4.6 (1.0–12.0)
1991
NSS (range 0 to 11). One patient with clear cell RCC had a local recurrence in the same kidney 28 months following NSS. Cancer specific survival rates at 1, 3 and 5 years for the 16 patients with pM1 treated with NSS were 81.3%, 49.2% and 49.2%, respectively. Cancer specific survival rates at 1, 3 and 5 years for the 404 patients treated with RN for pM1 RCC were 50.5%, 21.1% and 12.8%, respectively. Cancer specific survival for the patients with pM1 treated with NSS and RN is shown in figure 1. There was a significant difference in survival between the pM1 NSS cases and the pM1 RN cases (p ⫽ 0.013). Our registry indicated that none of the pM1 NSS cases received adjuvant immunotherapy at our institution. Of the patients with pM1 disease who underwent NSS, complete resection of all metastatic sites was performed in 14 (87.5%) patients compared with 91 (22.6%) of the pM1 RN patients (p ⬍0.001). Of the 2 patients in the pM1 NSS group who did not undergo complete resection, 1 died of RCC 1 month following NSS and the other died of RCC 1.8 years following NSS. The cancer specific survival rates at 1, 3 and 5 years for the pM1 NSS complete resection group were 85.7%, 56.3% and 56.3%, respectively, compared with 64.6%, 29.0% and 20.1%, respectively, for the pM1 RN complete resection group, and 46.0%, 18.4% and 10.5%, respectively, for the pM1 RN incomplete resection group. A comparison of cancer specific survival for pM1 NSS complete resection, pM1 RN complete resection, and pM1 RN incomplete resection patients is illustrated in figure 2. Although the pM1 NSS cases with complete resection appeared to have improved cancer specific survival compared with the pM1 RN cases with complete resection, this difference was not statistically significant (p ⫽ 0.097). For the comparison of early and late complications, only those patients with a solitary kidney in the pM1 NSS group were analyzed (table 2). A significant difference in early postoperative complications was noted between the RN and NSS groups (p ⫽ 0.009), with an overall complication rate in the RN group of 9.9% (40) compared with 33.3% (4) in the NSS group. There were no statistically significant differences between the 2 groups with regards to duration of hospitalization, blood loss, or units of blood transfused during surgery or hospitalization. Early complications in the pM1 NSS group were also compared to the pM0 NSS solitary kidney group. There was no significant difference between the 2 groups (p ⫽ 0.475), with an overall early complication rate in the pM0 NSS of 22.3% (31). There were no statistically significant differences between the pM1 and pM0 NSS groups with regards to duration of hospitalization, blood loss, or units of blood transfused during surgery or hospitalization. A significant difference was noted between the pM1 NSS and pM1 RN groups with regards to late complications (p ⫽ 0.018), with a higher incidence of chronic renal insufficiency, proteinuria, and dialysis in the NSS group (table 3). Dialysis was required in 2 (16.7%) patients in the pM1 NSS group compared with 7 (1.7%) patients in the pM1 RN group. When comparing the pM1 NSS group to the pM0 solitary kidney NSS group, there was no difference in late complications (p ⫽ 0.350). Dialysis was required in 13 (9.4%) patients in the pM0 solitary kidney NSS group. The 3 patients in the pM1 NSS group with bilateral synchronous disease underwent contralateral RN at the time of NSS. These patients were not included in the pM1 NSS group or pM1 RN group when analyzing postoperative
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FIG. 1. Kaplan-Meier curve comparing cancer specific survival for 16 patients with pM1 RCC treated with NSS and 404 patients with pM1 RCC treated with RN. Cancer specific survival rates (standard error, number still at risk) at 1, 3 and 5 years were 81.3% (9.8%, 13), 49.2% (12.7%, 7) and 49.2% (12.7%, 6), respectively, for patients treated with NSS compared with 50.5% (2.5%, 194), 21.1% (2.1%, 73) and 12.8% (1.8%, 40), respectively, for patients treated with RN (p ⫽ 0.013).
complications. Only 1 of these patients had an early complication consisting of a wound infection. The other 2 patients were free of postoperative complications. DISCUSSION Approximately 20% to 30% of patients with RCC present with metastatic disease.4 Overall patients with metastatic RCC have a poor prognosis with a median survival of 6 to 10 months and a 2-year survival of 10% to 20%.11 However, a subset of patients with advanced disease will experience improvements in survival with aggressive therapy.12 Controversy surrounds the role of surgery in the management of pM1 RCC. Previously surgical resection of the primary tumor or metastases was reserved for palliation of symptoms when angioinfarction could not provide adequate symptomatic control. Recently studies demonstrated that complete resection of the primary tumor and all clinically evident metastatic disease improves survival.13 Furthermore, nephrectomy before immunotherapy has been shown to result in a survival benefit in phase III clinical trials.14 –16 The theoretic rationale for surgical resection of the primary tumor includes improved performance status, reduction of tumor burden, prevention of complications during immunotherapy, elimination of paraneoplastic symptoms and eradication of additional metastases source.1,4 Nephrectomy is thought to improve survival in patients receiving immunotherapy by removing the primary tumor as an immunologic sink.17,18 Opponents to cytoreductive surgery question the benefits of surgical intervention in the metastatic setting with concerns over the delay in receiving systemic therapy secondary to surgical mortality, significant morbidity, complications or disease progression. To decrease postoperative morbidity in patients with metastatic RCC who are candidates for surgical intervention, NSS has been instituted in certain circumstances at our institution. This includes those patients with anatomically or functionally solitary kidneys, chronic renal insufficiency, or bilateral tumors who are otherwise good candidates for debulking sur-
gery as defined in the literature.19 This represents a highly select patient population consisting of patients with high preoperative performance status, surgically resectable metastatic disease, and who are potential candidates for postoperative immunotherapy. To our knowledge the outcome of pM1 RCC cases managed with NSS has not been previously evaluated. The 16 patients with pM1 RCC treated with NSS at our institution did not demonstrate inferior cancer specific survival rates compared to those patients with pM1 RCC treated with RN. These patients actually appeared to have improved cancer specific survival compared with the RN group. However, due to the small number of patients in the NSS group, we cannot conclude that NSS improves cancer specific survival compared to RN, but it is reasonable to state that survival is not worsened. The cancer specific survival rate at 1 year in the NSS group was impressive at 81%, however this decreased to 49% by 3 years, which is consistent with the natural history of this disease. Local recurrence was limited to 1 patient in the pM1 NSS group, which occurred more than 2 years after treatment of the primary tumor. This study also confirms an improved cancer specific survival in those patients treated with complete metastasectomy regardless of whether the primary tumor was treated with NSS or RN. When comparing postoperative complications between the pM1 RN and pM1 NSS groups, there was a significant difference when evaluating early events. However, NSS did not significantly increase the duration of hospitalization when compared to the RN group, nor did it affect postoperative blood replacement requirements. Close comparison of the early postoperative complications between the pM1 NSS and pM1 RN groups demonstrated major differences limited only to renal failure and dialysis. One would expect a higher rate of such
FIG. 2. Kaplan-Meier curve comparing cancer specific survival for 14 patients with pM1 RCC treated with NSS and complete resection of metastases, 91 patients with pM1 RCC treated with RN and complete resection of metastases, and 312 patients with pM1 RCC treated with RN and incomplete resection of metastases. Cancer specific survival rates (standard error, number still at risk) at 1, 3 and 5 years were 85.7% (9.4%, 12), 56.3% (13.5%, 7) and 56.3% (13.5%, 6), respectively for pM1 NSS complete resection group; 64.6% (5.0%, 58), 29.0% (4.9%, 23) and 20.1% (4.4%, 15), respectively for pM1 RN complete resection group; and 46.0% (2.9%, 135), 18.4% (2.3%, 50) and 10.5% (1.8%, 25), respectively for pM1RN incomplete resection group. Although patients with pM1 treated with NSS with complete resection appeared to have improved cancer specific survival compared to patients with pM1 treated with RN with complete resection, this difference was not statistically significant (p ⫽ 0.097).
NEPHRON SPARING SURGERY FOR METASTATIC RENAL CELL CARCINOMA
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TABLE 2. Early surgical complications by nephrectomy type for pM1 and pM0 RCC
No. pts No. early complications (%): Intraop death Periop death Hemorrhage Deep vein thrombosis Pulmonary embolism Myocardial infarction Wound infection Abscess Urine leak Sepsis Acute renal failure Dialysis Kidney loss Additional surgery Ileus Pneumothorax Any early complication* Days of hospitalization:† Mean Median (range) Blood loss during surgery:† Mean Median (range) Blood units during surgery:‡ Mean Median (range) Blood units during hospitalization:§ Mean Median (range)
pM1 RN
pM1 Solitary NSS
pM0 Solitary NSS
404
12
139
2 (0.5) 5 (1.2) 6 (1.5) 1 (0.3) 4 (1.0) 1 (0.3) 7 (1.7) 3 (0.7) NA 2 (0.5) 2 (0.5) 1 (0.3) 1 (0.3) 17 (4.2) 5 (1.2) 0 (0.0) 40 (9.9)
0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 3 (25.0) 2 (16.7) 0 (0.0) 1 (8.3) 0 (0.0) 0 (0.0) 4 (33.3)
8.6 7 (1–46)
9.3 9 (4–26)
1,088 633 (3–12,000)
1,184 1,000 (150–3,700)
0 (0.0) 2 (1.4) 2 (1.4) 0 (0.0) 0 (0.0) 2 (1.4) 2 (1.4) 3 (2.2) 6 (4.3) 1 (0.7) 11 (7.9) 3 (2.2) 0 (0.0) 14 (10.1) 5 (3.6) 0 (0.0) 31 (22.3) 9.8 7 (1–60) 996 650 (50–5,400)
2.1 1 (0–21)
1.8 1 (0–9)
1.0 0 (0–8)
3.1 2 (0–26)
2.2 1 (0–9)
1.7 0 (0–10)
* p ⫽ 0.009 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.475 for pM1 solitary NSS vs pM0 solitary NSS. † p Value not significant. ‡ p ⫽ 0.917 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.160 for pM1 solitary NSS vs pM0 solitary NSS. § p ⫽ 0.656 for pM1 RN vs pM1 solitary NSS, p ⬍ 0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.494 for pM1 solitary NSS vs pM0 solitary NSS.
complications in patients with an imperative indication for NSS as in this series. This point is illustrated by the comparison of postoperative complications between the pM1 NSS group and pM0 solitary kidney NSS group, which demonstrated no significant difference in early complications. Differences in late surgical complications between the pM1 NSS and RN groups were also significant, however, the majority of these complications such as chronic renal insufficiency, proteinuria and dialysis are again considered a function of the imperative indication for NSS. Furthermore, comparisons of late complications in the pM1 NSS group and the pM0 solitary kidney NSS group demonstrated no statistically significant differences. The patients with pM1 RCC in our series may have benefited from NSS compared to RN. NSS allowed cytoreduction as well as palliation of symptoms while preserving renal function in the majority of patients. Standard RN in this cohort would have rendered 93.8% of the patients
anephric, thus affecting quality of life and contributing to significant morbidity. Certain studies have suggested that cytoreductive nephrectomy for metastatic RCC before systemic treatment is beneficial.4 However, postoperative morbidity and worsening performance status result in some patients being unable to receive systemic therapy. Thus, appropriate patient selection is mandatory to recognize beneficial results.19 In patients with pM1 with imperative indications for NSS the usefulness of surgery for the primary tumor is unknown. Our data would indicate that in patients where surgical NSS is technically feasible, oncological outcome is not inferior. Furthermore, in the small subset of patients who can be rendered clinically free of disease with NSS and metastasectomy, complete surgical resection may confer a better prognosis.13 Although data on subsequent immunotherapy are not available in this series, the ability to deliver optimal dosing immunotherapy is reduced for patients in renal failure.5 Based on renal function and histological clear
TABLE 3. Late surgical complications by nephrectomy type for pM1 and pM0 RCC
No. pts No. late complications (%): Chronic renal insufficiency/failure Proteinuria Wound hernia Dialysis Other unspecified complication Any late complication*
pM1 RN
pM1 Solitary NSS
pM0 Solitary NSS
404
12
139
30 (7.4) 42 (10.4) 0 (0.0) 7 (1.7) 17 (4.2) 77 (19.1)
3 (25.0) 3 (25.0) 0 (0.0) 2 (16.7) 3 (25.0) 6 (50.0)
26 (18.7) 28 (20.1) 1 (0.7) 13 (9.4) 5 (3.6) 48 (34.5)
* p ⫽ 0.018 for pM1 RN vs pM1 solitary NSS, p ⬍0.001 for pM1 RN vs pM0 solitary NSS, p ⫽ 0.350 for pM1 solitary NSS vs pM0 solitary NSS.
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cell subtype, 11 of the 16 patients in this series were candidates for postoperative immunotherapy after NSS, which would not have been an option if a RN was performed. As other postoperative complications and total hospital stay were not significantly different between the pM1 RN and pM1 NSS groups, time to immunotherapy would not be delayed. Based on the results of this study we believe there is a role for NSS in select patients with pM1 RCC. However, it must be noted that the current study represents a highly select subset of patients. For many patients with imperative indications for NSS, systemic therapy without surgery for the primary tumor may be preferable. The recent Food and Drug Administration approval of sorafenib for the treatment of metastatic RCC has added to the therapeutic options for patients with metastatic RCC. 20 The majority of patients demonstrating stabilization of disease and responses to date have shown apparent central necrosis or liquefaction of tumor. Subsequent recurrences from within these lesions are common. Therefore, the role of surgical resection of persistently visible lesions, including NSS for primary tumors, after systemic therapy with new targeted agents such as sorafenib may prove to be beneficial. Limitations of our analysis include its retrospective design and the limited number of patients and outcome events. However, our experience would suggest that when cytoreductive therapy or renal functional status is important that NSS is safe with low morbidity and should be considered as part of the overall management of pM1 RCC. The NSS approach is particularly ideal when metastasectomy or immunotherapy is subsequently planned. CONCLUSIONS This study demonstrates that NSS can achieve adequate cytoreductive therapy while preserving renal function. Cancer specific survival was not significantly different between the NSS and RN groups, and complete resection of metastases improved cancer specific survival despite the type of resection of the primary tumor. Early and late postoperative complication differences between the pM1 RN and pM1 NSS groups were limited to renal function. Alterations in renal function are not unexpected in patients with imperative indications for NSS, which is illustrated by the lack of difference in postoperative complications between the pM1 NSS and pM0 solitary kidney NSS group. Based on these data we conclude that NSS in patients with imperative indications for NSS with surgically resectable metastatic disease and high preoperative performance status can be performed successfully.
2.
3.
4. 5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Abbreviations and Acronyms NSS pM0 pM1 RCC RN
⫽ ⫽ ⫽ ⫽ ⫽
nephron sparing surgery organ confined disease metastatic disease renal cell carcinoma radical nephrectomy
REFERENCES 1.
Lam, J. S., Shvarts, O. and Pantuck, A. J.: Changing concepts in the surgical management of renal cell carcinoma. Eur Urol, 45: 692, 2004
16.
17.
Pantuck, A. J., Zisman, A. and Belldegrun, A. S.: The changing natural history of renal cell carcinoma. J Urol, 52: 447, 2001 Chow, W. H., Devesa, S. S., Warren, J. L. and Fraumeni, J. F., Jr.: Rising incidence of renal cell cancer in the United States. JAMA, 281: 1628, 1999 Flanigan, R. C.: Debulking nephrectomy in metastatic renal cell cancer. Clin Cancer Res, 10: 6335S, 2004 Fyfe, G., Fisher, R. I., Rosenberg, S. A., Sznol, M., Parkinson, D. R. and Louie, A. C.: Results of treatment of 255 patients with metastatic renal cell carcinoma who received highdose recombinant interleukin-2 therapy. J Clin Oncol, 13: 688, 1995 Lau, W. K., Blute, M. L., Weaver, A. L., Torres, V. E. and Zincke, H.: Matched comparison of radical nephrectomy vs. nephron-sparing surgery in patients with unilateral renal cell carcinoma and a normal contralateral kidney. Mayo Clin Proc, 75: 1236, 2000 Lerner, S. E., Hawkins, C. A., Blute, M. L., Grabner, A., Wollan, P. C., Eickhlt, J. T. et al: Disease outcome in patients with low stage renal cell carcinoma treated with nephron sparing or radical surgery. J Urol, 155: 1868, 1996 Patard, J. J., Shvarts, O., Lam, J. S., Pantuck, A. J., Kim, H. L., Ficarra, V. et al: Safety and efficacy of partial nephrectomy for all T1 tumors based on an international multicenter experience. J Urol, 171: 2181, 2004 Fergany, A. F., Hafez, K. S. and Novick, A. C.: Long-term results of nephron sparing surgery for localized renal cell carcinoma: 10-year follow-up. J Urol, 163: 442, 2000 Leibovich, B. C., Blute, M. L., Cheville, J. C., Lohse, C. M., Weaver, A. L. and Zincke, H.: Nephron sparing surgery for appropriately selected renal cell carcinoma between 4 and 7 cm results in outcome similar to radical nephrectomy. J Urol, 171: 1066, 2004 Janzen, N. K., Kim, H. L., Figlin, R. A. and Belldegrun, A. S.: Surveillance after radical or partial nephrectomy for localized renal cell carcinoma and management of recurrent disease. Urol Clin North Am, 30: 843, 2003 Franklin, J. R., Figlin, R., Rauch, J., Gitlitz, B. and Belldegrun, A.: Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience. Semin Urol Oncol, 14: 230, 1996 Leibovich, B. C., Cheville, J. C., Lohse, C. M., Zincke, H., Frank, I., Kwon, E. D. et al: A scoring algorithm to predict survival for patients with metastatic clear cell renal cell carcinoma: a stratification tool for prospective clinical trials. J Urol, 174: 1759, 2005 Flanigan, R. C., Salmon, S. E., Blumenstein, B. A., Bearman, S. I., Roy, V., McGrath, P. C. et al: Nephrectomy followed by interferon-alpha-2b compared with interferon-alpha-2b alone for metastatic renal-cell cancer. N Engl J Med, 345: 1655, 2001 Mickisch, G. H., Garin, A., Van Poppel, H., de Prijck, L., Sylvester, R. and European Organization for Research and Treatment of Cancer (EORTC) Genitourinary Group: Radical nephrectomy plus interferon-alpha-based immunotherapy compared with interferon alpha alone in metastatic renal-cell carcinoma: a randomized trial. Lancet, 358: 966, 2001 Flanigan, R. C., Mickisch, G., Sylvester, R., Tangen, C., Van Poppel, H. and Crawford, E. D.: Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis. J Urol, 171: 1071, 2004 Spencer, W. F., Linehan, W. M., McClellan, M. W., Hass, G. P., Lotze, M. T., Topalian, S. L. et al: Immunotherapy with interleukin-2 and interferon in patients with metastatic renal cell cancer in situ primary cancers: a pilot study. J Urol, 147: 24, 1992
NEPHRON SPARING SURGERY FOR METASTATIC RENAL CELL CARCINOMA 18.
19. 20.
Robertson, C. N., Linehan, W. M., Pass, H. I., Gomella, L. G., Haas, G. P., Berman, A. et al: Preparative cytoreductive surgery in patients with metastatic renal cell carcinoma treated with adoptive immunotherapy with interleukin-2 or interleukin-2 plus lymphokine activated killer cells. J Urol, 144: 614, 1990 Atkins, M. B.: Management of advanced renal cancer. Kidney Int, 67: 2069, 2005 Gollob, J. A.: Sorafenib: scientific rationales for single-agent and combination therapy in clear-cell renal cell carcinoma. Clin Genitourin Cancer, 4: 167, 2005
EDITORIAL COMMENT The surgical and medical management of renal cell carcinoma has undergone a revolution during the last decade. Refined surgical technique has resulted in nephron sparing surgery in patients with small renal tumors. The survival advantage of debulking radical nephrectomy in patients with metastatic RCC has been validated in 2 prospective, randomized trials in appropriately selected patients (reference 16 in article). More recently systemic therapy targeted at the vascular endothelial growth factor has produced robust clinical effects in metastatic RCC.1,2 With this background Krambeck et al have the stated purpose of investigating the role of NSS in patients with metastatic RCC. This small, single-institution, retrospective, nonrandomized series reports disease specific survival for 16 patients with metastatic RCC who underwent debulking NSS and 404 patients who underwent debulking RN. Of note, 14 of the 16 patients who underwent NSS (87.5%) also underwent complete resection of all metastatic disease. Given that only 22.5% of RN cases that also had complete metastasectomy (p ⬍0.001 compared to the NSS group), comparison of disease specific survival rates is confounded, thus, limiting the usefulness of this series in evaluating the role of NSS in metastatic RCC. Furthermore, other potentially important variables known to affect the disease specific survival of patients with metastatic RCC such as performance status and laboratory variables are not reported for either group or accounted for in a multivariate analysis to determine the impact of type of nephrectomy on outcome. Although generated from a limited number of selected patients, a greater than 50% disease specific survival observed at 5 years in the NSS group does support the benefit of surgical resection of all gross RCC tumors, including the use of NSS to remove the primary tumor. The larger issues in the role of nephrectomy in metastatic RCC are 2-fold. 1) Does the benefit of debulking RN remain in patients who undergo NSS? 2) Does the benefit of debulking nephrectomy remain in patients who receive subsequent vascular endothelial growth factor targeted therapy (in contrast to the postoperative interferon-␣ received in the randomized trials)? The first question is not likely to be applicable to a large number of patients, as most patients with
1995
metastatic RCC present with primary tumors requiring RN. Indeed the present series of only 16 patients was derived from a tertiary care RCC center during many years. In the absence of additional randomized trials to address both these issues (which may be unlikely to occur), an understanding of the mechanism(s) of benefit of debulking RN could provide insight. Unfortunately such mechanisms, including effects on immunological antitumor response (inherent or therapy induced) and angiogenic growth factor production, are not readily apparent. Until the biological effects of primary tumor removal are better understood, it is reasonable to perform debulking NSS in metastatic RCC cases with imperative indications and consider NSS in select elective cases, especially when complete resection of all metastatic disease is possible. Furthermore, given that the response to subsequent immunotherapy was not altered by prior nephrectomy in previous trials, the survival advantage observed must for now be attributed to the surgery itself. Thus, debulking nephrectomy before planned vascular endothelial growth factor targeted (or other) therapy is reasonable in appropriately selected patients. Brian I. Rini Department of Solid Tumor Oncology Cleveland Clinic Taussig Cancer Center Cleveland, Ohio 1.
2.
Escudier, B., Szczylik, C., Eisen, T., Stadler, W. M., Schwartz, B., Shan, M. et al: Randomized phase III trial of the Raf kinase and VEGFR inhibitor sorafenib (BAY 43-9006) in patients with advanced renal cell carcinoma (RCC). Proc Am Soc Clin Oncol, 23: 380s, abstract 4510, 2005 Motzer, R. J., Michaelson, M. D., Redman, B. G., Hudes, G. R., Wilding, G., Figlin, R. A. et al: Activity of SU11248, a multitargeted inhibitor of vascular endothelial growth factor receptor and platelet-derived growth factor receptor, in patients with metastatic renal cell carcinoma. J Clin Oncol, 24: 16, 2006
REPLY BY AUTHORS This study is limited by the small number of patients in the pM1 NSS cohort and its retrospective design. With so few deaths observed in the NSS group, a more extensive multivariate analysis that would account for other features such as Eastern Cooperative Oncology Group performance status and preoperative laboratory values is not feasible. Despite these acknowledged shortcomings, this study demonstrates that NSS is feasible without an obvious decrease in cancer specific survival when compared to pM1 cases treated with RN. We agree that until randomized prospective trials become practical we must rely on information obtained from retrospective studies. Accordingly, the results of our study demonstrate that NSS appears to have a role for pM1 RCC with imperative indications.