CancerGuide: Special Kidney Cancer Section
When I was first diagnosed in 1989, I learned from my doctors that a solitary distant metastasis could be treated with surgery, with occasional long survivals. Review articles I read suggested that few patients have a solitary recurrence, and that surgery is most likely to be beneficial if it's been at least a year or two since nephrectomy. It sounded like surgery benefited only a tiny proportion of patients with metastatic renal cell cancer. I took that to be well settled and didn't look further. But in late 2001, Mike Fisher, a major supporter of CancerGuide and a member of the KIDNEY-ONC e-mail list, alerted me to something I had missed. Over the years, silently, and without fanfare, much encouraging data on the results of surgery has accumulated! My review of the major papers suggests both that the benefit for surgery is on a par with that for the best known immunotherapy, and that far more patients can benefit than is generally realized. Surgery is an important option for a significant number patients with metastatic renal cell cancer!
First, I present my own conclusions and recommendations, based on my review of eight major papers. Following my recommendations, I review my selection of papers and their methodology. Finally, I present summary tables for easy comparison of the papers, followed by the abstract of each of these papers along with my commentary. My analysis has benefited greatly from discussions with Mike Fischer, whose insightful comments have been a major influence.
Conclusions and Recommendations
Because of the retrospective nature of the data it is only possible to hazard a rough guess, but it appears that more patients might benefit than is generally realized. In the papers which included a comprehensive review of all patients treated for metastatic RCC at a given institution (or set of institutions) roughly 10% of patients had a solitary metastasis. In the papers where more than one metastasis was treated, roughly half of the patients had a solitary metastasis. Therefore, 20% is a reasonable first rough estimate. I'm expect additional patients might have been considered to be surgical candidates if their doctors had known of the benefits of surgery, but there's no way to know how many this might be. The effects of modern imaging technology on determining who is really operable could also affect the percentage. Despite these uncertainties, that a significant percentage of metastatic kidney cancer patients can benefit from surgery should prompt more research into this area, especially since the boundaries of what is possible are only beginning to be explored. None of this is directly relevant to any one patient, since you are either operable or not depending on the particular circumstances of your case, but knowing the odds you're operable are better than you might expect should motivate you to look into it.
In addition to considering the factors above separately, you might want to weigh adverse prognostic factors which are not an absolute bar to surgery. If there are several of these, you might decide that surgery isn't as good an option, even if it is a possibility. Surgery, of course, can mean irreversible loss of function, or a hard long recovery. Often neither of these are likely to be true, but certainly these factors should weigh in your decision. Conversely, if surgery would relieve debilitating symptoms or remove a tumor which is immediately life-threatening, these are reasons to go with surgery.
If you're eligible for both surgery and IL-2 based immunotherapy which should you do first? In my opinion surgery first usually makes more sense. The results with both surgery and immunotherapy include a small chance of long term survival, and it's not clear which is better in that respect. It looks to me like if you get a complete resection, surgery is likely to benefit you for at least a few years. If you get a response to immunotherapy, there is also a decent chance of a few years of benefit (and a documented chance of very long term remission). But the chance of getting a complete resection in most cases will exceed the chance of responding to immunotherapy. So I think the overall chance of gaining a real benefit is greater with surgery.
A second reason I think surgery is may be a better first option is that it's better to have two chances at long term survival than just one! If you do immunotherapy first and it doesn't work, as evidenced by growth of your cancer, the tumors might have reached the point of inoperability. But if you do surgery first, and unfortunately don't have a complete resection, then it seems likely you can then try immunotherapy. In the best case, you may have less disease when you try immunotherapy than you had before surgery. I don't have statistics on the percentage of operable patients who become inoperable after failed immunotherapy, or the percentage who are still healthy enough to undergo immunotherapy after a failed attempt at curative surgery, so my judgment that you're more likely to be able to try both if you try surgery first is only an educated guess. Also, as I discussed above, you need to weigh the difficulties of the surgery, as well as any adverse prognostic factors, or immediate palliative benefit.
Because patients with an incomplete resection don't appear to benefit from surgery, it seems logical to make a very careful search for additional metastases before surgery. If any are found that are inoperable, you will be spared unnecessary surgery. If additional operable metastases are found and the total number of metastases is still within reason, surely it's better to get them out now so you have a better chance of getting them all with only one surgery. I think then, that a high quality CT scan of the chest, abdomen, and pelvis, as well as a bone scan are a reasonable starting point. You may also want to investigate adding post surgical adjuvant therapy to reduce the risk of relapse before surgery (see below).
The odds with surgery might be improved beyond the current experience if an effective systemic treatment to reduce the risk of recurrence were given after the surgery. Unfortunately, there is no proven adjuvant therapy for renal cell cancer, but there are more or less promising therapies for this purpose in clinical trials. Some of these trials accept patients with a history of metastatic disease who've been rendered disease free by surgery. If you're going to have surgery, you might want to look into participating in such a trial! Some of these trials are vaccine trials and some vaccine trials require fresh tumor tissue to make the vaccine, so if you are interested in pursuing adjuvant therapy you should investigate it before surgery! Finally, since nothing is proven, I recommend favoring less toxic therapies over more toxic therapies if there is a choice.
In the past few years, innovative techniques for treating individual tumors such as Radiofrequency Ablation, Body Stereotactic Radiosurgery, and others have started to become available. Some of these methods are even outpatient procedures. If you have a reasonable number of metastases but are judged to be inoperable for technical reasons, then it might be reasonable to investigate these techniques. At first glance, the principle that destroying all known metastases can result in long term survival might well hold even if the method of destruction isn't surgery. There is very little long term data so this has to be somewhat speculative. There is certainly a risk that second order interactions, for example adverse effects of radiation on the immune system, could lessen the long term survival. The risk of incomplete destruction of tumor is probably not be as well known, and you lose the close inspection for additional metastasis that normally accompanies surgery, but given the general prognosis of metastatic kidney cancer stretching it a little seems justified. I'd say that especially if the other prognostic factors look good for surgery, it's worth looking into. Just as there are technical considerations which dictate whether surgery is feasible in any given case, each of these techniques has it's own limitations and risks. Just as you may need to consult with a surgeon to determine whether your tumors are technically operable, you may need to consult with experts in the various techniques to determine if they are appropriate in your case.
Review of Major Surgery Papers
The Summary Tables
Resection of Metastatic Renal Cell CarcinomaJ Clin Oncol 1998;16(6):2261-6
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
PURPOSE: Resection of solitary metastases from renal cell carcinoma (RCC) is associated with a 5-year survival rate of 35% to 50%. Selection criteria are not well defined.
PATIENTS AND METHODS: We retrospectively analyzed our experience with 278 patients with recurrent RCC from 1980 to 1993.
RESULTS: One hundred forty-one of 278 patients underwent a curative metastectomy for their first recurrence (44% 5-year overall survival [OS] rate), 70 patients underwent noncurative surgery (14% 5-year OS rate), and 67 patients were treated nonsurgically (11% 5-year OS rate). Favorable features for survival were a disease-free interval (DFI) greater than 12 months versus 12 months or less (55% v 9% 5-year OS rate; P < .0001), solitary versus multiple sites of metastases (54% v 29% 5-year OS rate; P < .001), and age younger than 60 years (49% v 35% 5-year OS rate; P < .05). Among 94 patients with a solitary metastasis, lung (n = 50; 54% 5-year OS rate) was more favorable than brain (n = 11; 18% 5-year OS rate; P < .05). Survival rates after curative resection of second and third metastases were not different compared with initial metastectomy (46% and 44%, respectively, v 43% 5-year OS rates; P = nonsignificant). Favorable predictors of survival by multivariate analysis included a single site of first recurrence, curative resection of first metastasis, a long DFI, a solitary site of first metastasis, and a metachronous presentation with recurrence.
CONCLUSION: Selected patients with recurrent RCC who can undergo a curative resection of their disease have a good opportunity for long-term survival, particularly those with a single site of recurrence and/or a long DFI.
Commentary on Kavolius
This is the latest and greatest major metastectomy paper! It has the most patients by far, and is some of the most recent, and therefore most relevant data. The combination of most patients, most recent means this paper should be weighted heavily. Fortunately, it also has the best results of any! The long term survival curves flatten much like those from IL-2 immunotherapy, but with a lesser initial slope, and a slightly higher 10 year survival, about 20%.
They report encouraging survival, even with multiple operations. Short DFI (Less than 12 months) had an adverse impact on survival, but even so, 33% of patients with DFI less than a year who had a complete resection of metastatic disease survived at least 5 years (Note that the 9% figure in the abstract refers to all patients with short DFI, including those who didn't have a complete resection), and there were a significant number of ten year survivors as well.
In this study, like the others, excepting Jett, complete versus incomplete resection made a definite difference which supports the idea that the treatment had an effect. Interestingly though, there was some level of long term survival in all groups, including those who didn't have a complete resection, but it was much higher when complete resection was achieved (about 20% vs 10% at 10 years). The long term survivors in the non-resection group (and maybe some in the resection group) might represent immunotherapy successes. 1993 is in the early immunotherapy era for metastatic RCC. It does look like patients who underwent a complete resection had significantly better survival than one expects for high dose Interleukin-2 at five years and slightly better at ten years! About a third of patients didn't get a complete resection after their first operation, and of patients who were operated on a second time after an an initial complete resection and relapse, about half didn't get a complete resection. Clearly the high rate of incomplete resection is an area for potential improvement.
Remarkably, of the 141 patients who had a complete resection, 110 or 78% both relapsed and had a second operation. The second time around, a complete resection was achieved in only about half the patients. Given the very high percentage of patients with an initial complete resection who later needed another operation, the willingness to do more than one operation as needed may have been a key factor in the excellent overall results they achieved. I also find it very interesting that such a high percentage of relapsed patients were considered eligible for a second operation in the first place!
Rather than classifying patients as having solitary versus multiple metastases as other papers do, they classify according to whether the patient had solitary of metastasis versus multiple sites of metastasis, where each affected organ counts a separate site (My best guess is that this information is more easily and more reliably obtained from case records than the exact number of tumors resected). This makes the results for this parameter hard to compare to other studies. Because the most common single of metastasis (lung) is also one of the ones with a better prognosis and the next most common sites, such as bone or liver, typically carry a worse prognosis, it may be that multiple sites is was merely a marker for having at least one site that carries a worse prognosis. Nonetheless, multiple sites of disease was an adverse prognostic factor. It is encouraging though that even with multiple sites of involvement, there were about 30% 5 year survivors in patients who had a complete resection.
Patients with brain metastasis didn't do as well as patients with other sites of metastasis in this study, though the five year survival was still about 20%. It's also interesting that they don't report any patients with liver metastasis! This is a common site of metastasis for RCC. I suspect absence of patients with liver metastasis is an indicator of the degree of patient selection since liver tumors are often considered hard to resect, but it may also be that liver metastasis tends to correlate with widespread (and inoperable) disease.
I had trouble determining how many of the patients had metastasis at initial diagnosis. They state in the abstract that this was an adverse prognostic factor, but I can't find any further discussion of it in the paper itself, which actually reads as though such patients were excluded. I don't think this was actually so because there were enough patients who were stage IV at diagnosis in the overall population they considered (many of whom didn't have an operation at all) that it is not mathematically possible that they excluded all patients with synchronous presentation of operable metastasis. In any event, the data as presented, certainly would not lead me to exclude a good result with surgery for synchronous metastasis!
My conclusion: It may actually be that surgery is more effective than the best immunotherapy when all disease can be resected, particularly if DFI is more than a year! It's also clear that there was no significant benefit unless all visible disease is resected.
Metastasectomy in renal cell carcinoma: A multicenter retrospective analysisEur Urol 1999;35(3):197-203
Department of Urology, University Hospital Nijmegen, Rotterdam, The Netherlands.firstname.lastname@example.org
OBJECTIVE: In 60-70% of patients with renal cell carcinoma (RCC), metastases develop in the course of the disease. In the present analysis, the surgical management of metastases is described, and survival data are presented. This retrospective analysis may help in the management of future cases. Due to the retrospective nature of the data, no comparison between surgical and nonsurgical management is possible.
METHODS: Between 1985 and 1995, 152 resections of RCC metastases were performed in 101 patients at four Dutch Hospitals. Thirty-five and 6 patients had metastases resected 2 and 3 times, respectively. In most patients, the primary tumor was resected (n = 95). Resections were performed for metastases at different locations: lung n = 54, bone n = 42, lymph nodes n = 18, cerebrum n = 12 and locations in the spinal canal, thyroid, bowel, and testis. Skin excisions were excluded from the analysis. Solitary metastases were resected in 40 patients.
RESULTS: Median survival after the initial metastasectomy was 28 months. Initial tumor stage, grade, or size were not related to metastasis location or survival. The number of initially resected pulmonary metastases was of no influence on survival, however, multiple consecutive resections were related with longer survival. Patients with solitary metastases (n = 40) did not show longer survival after the first metastasectomy compared to no solitary lesions. Better survival was found for lung metastases compared to other tumor locations (p = 0.0006, log rank test) and for patients that were clinically tumor free after metastasectomy (p = 0.0230, log rank test). Additional immuno- or radiotherapy did not independently influence survival. Time interval between primary tumor resection and metastasectomy correlated positively with survival: a tumor-free interval of more than 2 years between primary tumor and metastasis was accompanied by a longer disease-specific survival after metastasectomy. Eleven patients were free of disease after metastasectomy with a median time of 47 (14-65) months. The median time of hospital admittance for metastasectomy was 9 days (4-64). Lethal complications were found in 2 patients. Long-term (> 5 years) disease-free survival was achieved in 7% of patients whereas 14% of patients were free of disease with a minimal follow-up of 45 months.
CONCLUSIONS: (1) Surgical management of metastases could be performed with short hospital stay, and low complication rates were found. (2) Disease- free survival was found in 14 and 7%, with follow-ups of at least 45 and 60 months, respectively. (3) The longest survival was found after surgery for pulmonary lesions. (4) Resection of solitary metastases did not result in longer survival compared to resection of nonsolitary lesions. (5) An interval shorter than 2 years between primary tumor and metastases was correlated with a shorter disease-specific survival.
Commentary on van der Poel
This is the second largest study, and is the most recent in terms of when the patients were accrued. I'd say the overall results not quite as good as Kavolius, but the general trends were mostly the same, most definitely including the possibility of long term survival.
Patients with a complete resection did better than those with an incomplete resection, though the effect was less dramatic than in some of the other papers. Unlike Kavolius, van der Poel generally did not separate out patients who had a complete resection of metastasis from those who had only a partial resection when they analyzed other prognostic factors. I prefer the way Kavolius analyzed the data, because I expect incomplete resection would have very little to no benefit.
In this study, 40 of the 95 patients (42%) didn't get a complete resection from the initial operation. Of the remaining 55 who did, 35 (64%) had a second operation for relapse. These results are generally similar to Kavolius, and again suggest both that surgical treatment would be improved if it were possible to more accurately predict who is really completely resectable, and that willingness to do multiple operations as needed may be an important factor in the success of surgical treatment.
At any rate, longer DFI before recurrence also mattered in their analysis. In their analysis, they compared patients who relapsed more than two years after nephrectomy to those who relapsed earlier. This two year interval is longer than most of the other papers but the difference in the survival curves was striking at first glance. Still, short DFI didn't actually preclude long term survival, and they think the better survival in patients with longer DFI may have been due to the fact that more of them had lung metastasis rather than bone metastasis. It didn't matter whether there were solitary or multiple metastases, and it also didn't matter overall whether the metastasis was synchronous or developed after nephrectomy. They did multiple resections as needed. While they don't give a statistical analysis of the survival with multiple resections, many of their long term survivors had more than one operation, confirming that multiple operations can be useful. They found lung metastasis to have a better prognosis than metastasis elsewhere. Only one liver metastasis was resected, which, again, is far below the expected number.
This study, like Kavolius extends into the age of immunotherapy which could have affected the results. In fact, they report that overall immunotherapy didn't influence survival but no details are available about what immnotherapies the patients got. It's very interesting that the shape of the survival curve for incomplete resections includes long term survival (at a low rate) like Kavolius. It's possible that a small number of successes with immunotherapy was the cause.
Surgical treatment of metastatic renal cell carcinomaJpn J Clin Oncol 1990;20(3):263-7
Department of Urology, National Cancer Center Hospital, Tokyo
The survivals of 174 patients who underwent nephrectomy for renal cell carcinoma were analyzed to evaluate the influence of the surgical treatment of metastases on their prognosis. For 34 of the 174 patients, surgical resections of the metastases were performed concurrently with nephrectomy. For 38 patients, 44 surgical resections of metastases were performed in the follow-up period after nephrectomy. Apparently curative resections of metastases, at the time of nephrectomy or after nephrectomy, were significantly correlated with good survivals after surgery, irrespective of the number of metastatic foci. Aggressive surgical treatment was beneficial in patients with a longer tumor- free period after nephrectomy or with stable disease for about six months after surgical treatment, although this might simply be a reflection of a longer natural disease course in this specific group of patients.
Commentary on Tobisu
This Japanese study had similar results to most of the other major studies, including a significant number of long term survivors in patients with a complete resection compared to patients with an incomplete resection.
I found this paper's analysis frustratingly abstruse, but basically they divided patients treated surgically for metastatic disease into those who had metastatic disease at the time of diagnosis and those who developed metastasis after nephrectomy. They analyzed the two groups quite differently.
For the 34 patients who had metastatic disease at diagnosis, survival curves are shown out to 20 years! Patients who had an incomplete resection had a survival curve which reached zero at about six years. In contrast, patients who had a complete resection had a curve with a flattening shape and a five year survival of about 40% and a ten year survival of about 18%.
For the 38 patients who developed metastatic disease after nephrectomy, the 27 who had a complete resection had a five year survival of 47% but the survival curve descended more or less linearly and reached the zero at almost seven years. For the 11 patients who had an incomplete resection, the three year survival was zero, so surgery did seem to have an impact (Cautionary Note: These 11 patients are actually a bit of a puzzle. I am pretty sure they indeed had incomplete resection, but the description in the paper is confusing). They also classified patients by DFI, and found that those with very short DFI (less than 6 months) also had a zero percent three year survival. Those who had a longer DFI did much better.
Overall, it is striking that among patients achieving a complete resection, they actually found better very long term survival in those who had metastasis at diagnosis than in those who developed it after nephrectomy. Yet the worst survival was in the six patients who developed metastasis just after diagnosis. I think it's possible that synchronous metastasis is biologically different from very short DFI in some cases and so for the purposes of analysis patients with synchronous metastasis should not be considered to have a zero DFI, but rather grouped in a separate category. Their dismal experience with patients who developed metastasis less than six months after nephrectomy involved too few patients to conclude that surgery is useless in such patients (only six), but it certainly raises a serious question!
Lung metastases of renal cell carcinoma: results of surgical resection.Eur J Cardiothorac Surg 1997;11(1):17-21
Marie Lannelongue Hospital, Le Plessis Robinson, France
OBJECTIVE: The research was designed to evaluate the results of surgical resection of renal lung metastases.
METHODS: Between 1960 and 1994, 50 consecutive patients underwent resection for pulmonary metastases from renal cell carcinoma. Mean age was 59 years (range: 40-78 years). Mean time between nephrectomy and pulmonary resection was 3 years (range: 0-18 years). Nineteen patients had solitary metastase, 13 multiple unilateral, and 18 bilateral. Wedge excision was performed in 28 patients, segmentectomy in 3, lobectomy in 17, sleeve lobectomy in 1, pneumonectomy in 5 and biopsy in 3. Twelve patients had repeat resection for recurrent metastases.
RESULTS: The resection was complete in 45 patients. Three patients also had a complete resection of limited extra-pulmonary disease. There was one postoperative death and 3 complications. Mean follow-up was 42 months without loss of follow-up. The cause of death was always metastatic recurrent disease. Five-year survival in complete resection was 44%. Only one long survivor was observed in the case of incomplete resection in a patient who had a complete response after adjuvant immunotherapy. Five-year survival for the 12 patients with repeat resections was similar to the overall survival rate (42%).
CONCLUSIONS: Resection of renal lung metastases is a safe and effective treatment. No factor influenced the 5-year survival in this series except the complete resection. Extra-pulmonary metastases does not contra- indicate pulmonary resection. In selected patients, repeat resection for recurrent disease is warranted.
Commentary on Fourquier
This study was intended to be restricted to lung metastasis but a very few patients also had metastasis elsewhere. They were willing to treat multiple metastasis even in both lungs. About 2/3 of their patients had more than one tumor. One patient had 17!
They had a high rate of complete resection (90%) but a relatively low rate of re-operation (27% of surgical CR's) even though there was a high rate of relapse. 5 Year survival in surgical CR was good 44%. Ten year survival in surgical CRs was only 4%, but this was due to a sharp drop at the very end of the curve and this may not be reliable.
As with most of the other studies, multiple versus single metastasis didn't make a difference.
They were unusually specific about pre-operative scanning which included a full body and brain CT scan once those technologies became available, and they also thought it was important to do open surgery where the lung could be palpated for nodules not seen on the CT scan. Interestingly, despite the changing technology, the year of resection didn't make a statistical difference in the results. Whether this comparison had reasonable statistical power is unknown.
Pulmonary resection of metastatic renal cell carcinomaChest 1983;84(4):442-5
Mayo Clinic, Rochester, MN
Over a ten-year period, 44 patients with known primary renal cell cancer underwent thoracotomy for pulmonary metastases. The median postthoracotomy survival for all patients was 33 months. The five-year survival was 27 percent. Postthoracotomy survival was significantly better in those patients with a disease free interval of greater than 24 months and patients with metastatic lesions greater than or equal to 3 cm. No difference in survival was detected in patients with one versus more than one lesion or in patients undergoing complete resection versus incomplete resection or biopsy only. Age, sex, grade of tumor, or location of the pulmonary metastasis had no influence on survival.
Commentary on Jett
This paper is limited to lung metastasis, but patients with multiple metastasis were treated.
Alarmingly, they found no survival difference between patients who had successful total resection of all metastases and those who only had partial resection or biopsy. This suggests that the surgery actually didn't affect the natural history of the disease! Fortunately, this conflicts with the other papers, so although I am unable to find any explanation of why this was the case here, the bulk of the evidence supports the idea that those who have a complete resection do much better.
Overall survival was a roughly linear decrease which implies an increasing hazard rate over time. Some of the other papers had survival curves which appeared to become flat or nearly so over time, implying decreasing risk with time though this was not uniformly the case. The 33 months median survival was more than you'd expect for metastatic RCC and generally consistent with the other papers. This might suggest these patients who were considered candidates for resection had less advanced metastatic RCC than average. The five year survival rate is in the range of the other major papers.
They compared patients with a DFI of more than 24 months with those whose DFI was less. It looks to me like patients with metastatic disease at diagnosis were considered to have DFI of zero. I am not able to determine how many patients were in this category. As with the other papers, shorter DFI was better. This has been observed to be true with metastatic RCC in general, so it is not a surprise here, especially if they didn't affect the natural history of the disease. The number of metastases also didn't make a difference.
One puzzling observation was that patients whose largest metastasis was larger than 3cm did markedly better than those with smaller metastases, and in fact represented almost all of the long term survivors. One might expect a larger metastasis to represent a faster growing, more aggressive tumor, with a worse prognosis. Perhaps this indicates instead that patients whose recurrence was not discovered early (thus the large tumor) but was still limited survived longer because it was more likely that the metastasis was truly limited in nature.
One caveat on all of these conclusions is that this paper reports on a total of only 44 patients and random variations could account for some of the observations, including the shape of the survival curve, lack of difference between complete and incomplete resection, and the observation that patients with a larger metastasis did better, which was based on only 11 patients with a > 3cm tumor.
This paper does the best job of any of reporting what testing was done before surgery to determine the extent of their metastasis. Only 1/4 of patients had a lung CT, but patients were treated between 1970 and 1979 before CT scan was routine, and sounds as though in most cases there was not a careful survey for extra-pulmonary disease. It's not possible to compare this to the other papers though since comparable information is absent.
This paper, like O'Dea and Kierney, is from the Mayo Clinic, and the accrual period is a subset of Kierney. They say they evaluated all RCC patients who underwent lung surgery at the Mayo in this period so it appears that some patients in this study might then overlap that of Kierney . I discuss this more in my commentary on Kierney below.
Surgeon's role in the management of solitary renal cell carcinoma metastases occurring subsequent to initial curative nephrectomy: an institutional reviewAnn Surg Oncol 1994;1(4):345-52
Section of Gastroenterologic and General Surgery, Mayo Clinic, Rochester, MN 55905
BACKGROUND: Solitary metastases from a primary renal cell carcinoma (RCC) occur in < 10% of patients with metastatic RCC. To date, the benefit of surgically resecting such apparently solitary lesions has not been well documented.
MATERIALS AND METHODS: Forty-one patients (25 men, 16 women) with metastatic renal cell carcinoma treated by surgical excision of solitary metastases (1970-1990) were retrospectively reviewed. They comprised 9% of patients with metastatic hypernephroma seen during this period. All patients had undergone previous curative nephrectomy with a median disease-free interval of 27 months. Patients with skeletal, spinal cord, and lymph node metastases were excluded.
RESULTS: Metastases were intrathoracic (n = 20), intracranial (n = 7), and intraabdominal or in the extrapleural chest wall soft tissue (n = 10). Three patients had metastases to the thyroid gland and one had a solitary metastasis to an index finger. Median follow-up was 3.2 years. Complete resection was possible in 36 patients (88%) with a single lesion excised in 23 of these 36 patients (64%). There was no operative mortality. Predicted survival from the date of complete resection of metastases was 77%, 59%, and 31% at 1, 3, and 5 years, respectively, with a median survival of 3.4 years. One patient is alive without evidence of recurrent tumor 93 months from the first of 12 complete surgical resections. Varying adjuvant therapy was used in 50% of the patients. An increased histological tumor grade of the metastatic lesion relative to the original RCC was the only significant prognostic indicator identified. Disease- free interval and number of resected lesions were not significantly associated with patient survival.
CONCLUSION: A small fraction of renal cell carcinoma patients are candidates for potentially curative surgical resection of solitary metastatic lesions. Excision of such lesions may contribute to prolonged survival in selected instances.
Commentary on Kierney
This study is limited to patients with an initial solitary metastasis which appeared after nephrectomy. They excluded patients who presented with a solitary lesion at initial diagnosis, as well as those with bone, lymph node, or spinal metastasis (It is not clear to me why!).
The survival curve for patients who had a complete resection has an unusual shape with a period of low risk (plateau) at about a year followed by increasing risk maybe mellowing a bit by the end (5 years). This may simply represent random variation.
11 of the 41 patients had more than one operation, including one patient who was alive and disease free after his twelfth operation in nearly eight years! The number of operations didn't make a significant difference in survival. Unlike most of the other studies, they didn't find Disease Free Interval significant. The fact that they excluded patients who had synchronous metastasis could have had an effect here. The favorable results with synchronous metastasis reported in Tobisu and van der Poel, combined with the dismal results in recurrent disease within six months of nephrectomy reported by Tobisu make it unclear which in direction the effect would be! They had such a high rate of complete resection (88%) that it was impossible to tell whether incomplete resection was an adverse prognostic factor, as was reported elsewhere.
Their surgery patients comprised 9% of their mRCC population which is consistent with the 8.5% from O'Dea, the previous Mayo Clinic Paper.
The authors evaluated the records of all RCC patients treated at the Mayo from 1970-1990, which overlaps the accrual period for Jett, also from the Mayo. 20 of the 41 patients reported here had lung metastasis and thus could have also been reported in Jett (which reports on lung metastasis only). This would be a significant overlap! They do specifically say didn't include any patients who had been reported in O'Dea.
The treatment of renal cell carcinoma with solitary metastasisJ Urol 1978;120(5):540-2
Mayo Clinic, Rochester, MN
Between 1950 and 1970, 44 patients (2.5 per cent) with renal cell carcinoma and a solitary metastatic lesion were treated at our clinic. Generally, treatment was aggressive, involving nephrectomy and excision of the metastatic lesion when possible. Patients presenting with the primary and metastatic lesion at the same time did not do as well as patients who presented with metastasis after nephrectomy. An operation for the metastatic lesion seemed to offer the best results in patients who presented with the solitary metastatic lesion after nephrectomy. The prognosis was uniformly poor in patients presenting with the primary and secondary lesion together, regardless of the mode of therapy. However, an operation seemed to be better marginally and did produce an occasional long-term survival.
Commentary on O'Dea
This is one of the early papers on the subject of surgery for metastatic RCC and it's cited quite frequently in more recent papers. Unlike more recent papers, survival curves are not presented, rather the data is presented in the form of a table describing the treatment and outcome for each patient. Although most of the patients had surgery as the primary treatment some actually got different treatment (Thus accounting for the 28 patients, I cite above compared to the 44 mentioned in the abstract). As with most of the other papers, there were some truly long term survivors, in this case, as long as 17 years!
The authors reviewed the records for all RCC patients who were treated at the Mayo from 1950 to 1970. Thus they are able give the percentage who had a solitary metastasis, which was 2.5%. Their 2.5% figure is quoted in many other papers as if this is the percentage of patients with metastatic RCC who have a solitary metastasis. Not so! It turns out that the denominator used to calculate their 2.5% figure includes those without any evidence of metastasis! (Oddly in their records of 1761 RCC patients treated at the Mayo, only 330 had metastatic disease!) The percentage of patients with metastatic disease who had a solitary metastasis is 44/330 = 13.3%! (Assuming conservatively that all of the solitary metastases that could be surgically treatable were in fact surgically treated, the percentage of patients with metastatic RCC who were surgical candidates as 28/330 = 8.5%). Note that Tolia and Whitmore who reviewed patients with solitary metastasis treated at Sloan Kettering between 1949 and 1969 quote a similar overall incidence of 3.2%, with the incidence among those with metastatic disease 11% which again is similar to O'Dea's results (See "Solitary Metastasis from Renal Cell Carcinoma", Tolia and Whitmore J. Urol. 1975;114:836-8).
The paper claims that those with the metastasis present at the initial diagnosis of RCC did worse compared to those who presented with a solitary metastasis after nephrectomy. Actually this seems to be the main point they're trying to make, but I don't think the paper proves it, because many more of the patients who had metastasis at diagnosis also had an incomplete resection (or even no resection!) so that the issue is confounded. By my count, total resection was attempted in only 6 of the 16 patients with synchronous metastasis, while it was attempted in 22/26 of those with recurrence after nephrectomy.
Strikingly, 14 of the 44 patients in this series had a brain lesion!
Prognostic factors and surgical treatment of osseous metastases secondary to renal cell carcinoma.Cancer 1997;80(6):1103-9
Orthopaedic Service, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.
BACKGROUND: The purpose of this study was to analyze the survival of 38 cases of metastatic renal cell carcinoma with secondary osseous metastases treated at the Orthopaedic Oncology Unit of the Massachusetts General Hospital. The survival was analyzed because it seemed to be considerably longer than any reported previously in the literature.
METHODS: Survival was analyzed with respect to age, gender, site of primary tumor, presence of pathologic fracture, disease free interval, initial presentation with metastasis, solitary versus multiple metastases, and axial versus appendicular metastases.
RESULTS: Survival for the entire group was 90% at 6 months, 84% at 1 year, 55% at 5 years, and 39% at 10 years. Age, gender, and presence of pathologic fracture had no influence on survival. Presentation without metastases, long disease free interval between nephrectomy and first metastases, appendicular skeletal location, and solitary metastases were all correlated with longer survival.
CONCLUSIONS: In the authors' view, patients with the characteristics correlated with longer survival are appropriate candidates for aggressive surgical resection of bone metastasis.
Commentary on Althausen
The data from this paper are very difficult to interpret, and I include it only to illustrate the point that prolonged survival at five and ten years is possible even with metastasis in locations considered to have an unfavorable prognosis such as bone. Indeed the raw survivals are extraordinarily high in this series, and they would probably be even more so if the survivals were calculated on the basis of those patients who underwent surgery with curative intent (the 23-30 I cite).
There are many difficulties in interpreting this paper. First with respect to treatment, at least 11 of their 38 patients were not treated surgically with curative intent - 8 had radiation only and 3 had operations intended to stabilize pathological fractures. The treatment of seven more is totally unspecified! Finally three more were treated surgically with curettage which involves scraping tumor off the bone. Here I'm not sure if the intent of such procedures is curative. Finally, five patients never had a nephrectomy for the primary tumor. The bottom line is I can't determine exactly how many patients were treated surgically with curative intent. There is no record of how many patients had a complete resection. Also there is no record of whether any patients who relapsed had a second operation, and in fact we aren't told how many patients relapsed.
With respect to disease, an unknown number of these patients also had disease elsewhere and what treatment they received for this is not known.
They claim patients with multiple metastases did worse than those with a single metastasis, but they mean multiple metastasis in a much different way than the other papers I've reviewed. They considered patients who relapsed to have had multiple metastasis as well as patients who had multiple metastases initially. I don't think this is a reasonable definition of multiple metastasis and thus I don't accept their conclusion that patients with multiple metastases did worse, or at least their conclusion isn't relevant to whether multiple metastasis as defined in the usual sense is worse than solitary.
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Page Created: April 4, 2002, Last Updated: April 4, 2002