CancerGuide: Special Kidney Cancer Section
Surgery and immunotherapy are the two main treatments for metastatic RCC. For some patients combining these treatments is the key to survival.
It should be no surprise that surgery to remove all residual disease after immunotherapy can be important given the known benefit for surgery alone when all tumor can be removed. When immunotherapy produces only a partial response or a temporary response, the evidence is that surgery has the potential to convert a temporary benefit into a cure. In some cases, patients who were inoperable before immunotherapy become operable after immunotherapy even if they had only a partial or temporary response to the immunotherapy.
Groups like the National Cancer Institute, the UCLA Kidney Cancer Program, and others have at least informally included surgery in their Interleukin-2 immunotherapy programs from the beginning. While a few lucky folks get a permanent complete response from immunotherapy alone, in other cases surgery was needed to obtain long term remission. So as a whole, the long term survival results from IL-2 immunotherapy are really from the combination of IL-2 and surgery. Therefore to obtain the full benefits of Immunotherapy, you must also use surgery when appropriate.
There quite a few different possible immunotherapy-surgery combinations. This list briefly describes the situations I cover in this article along with a link to more detailed information further down in this article for each.
It has long been observed that patients who have a partial response after IL-2 do about as well as patients with a complete response (and that's very well!) if all residual disease can be removed. Because almost all patients with a partial response will relapse within a few years, if you have a partial response and all residual disease can be removed, it's extremely important to do so to try to convert what is very likely to be only a temporary response into a possible cure. Patients with a partial response to Interferon can also do well if all residual cancer can be resected which is particularly important since responses to Interferon tend to of short duration.
For this section I discuss each paper separately in the comments below its reference. That the overall picture supports the idea of resection becomes clear after looking over the published data.
References and Discussion
Phase II trial of interleukin 2, interferon alpha, and 5-fluorouracil in metastatic renal cell cancer: a cytokine working group study.
Clin Cancer Res. 2000 Sep;6(9):3442-50.
Comment: Many papers which aren't specifically about resection after immunotherapy report good results in patients they decided to resect after immunotherapy. In this type of paper, the decision is apparently based on clinical judgment, rather than any formal part of the protocol. Some of the study to study variation in immunotherapy long term results could easily be due to variation in how aggressively surgery was pursued, yet this variable isn't controlled, and often isn't even reported clearly.
This paper is a typical example of good results when surgery is pursued. They treated 50 patients with outpatient IL-2, Interferon and 5-FU. They had 2 complete and 7 partial responses. They resected 8 patients, 3 of the 7 patients who had a partial response, as well as one with a minor response and four with stable disease. Of these 8 with follow-up ranging from 43 to 53 months, 6 were alive and 5 were disease free, which is excellent. Presumably, at least the four patients with stable disease were also resectable before immunotherapy so some of the happy result may have been due to surgery alone.
Interleukin-2, interferon-alpha, 5-fluorouracil, and vinblastine in the treatment of metastatic renal cell carcinoma: a prospective phase II study: the experience of Rambam and Lin Medical Centers 1996-2000.
Cancer. 2002 Oct 15;95(8):1644-9.
Comment: This study added the cytotoxic drug Vinblastine to the Atzpodien outpatient IL-2 protocol (See The Atzpodien Regimen and Beyond for details). Vinblastine was long considered the most active cytotoxic drug against RCC, and there are hints that it may have synergy with Interferon (See my article on interferon for details).
Unlike most, this study made surgical resection of residual disease whenever feasible part of the protocol. This showed in their results. They had 4 complete responses from the drug treatment alone, all of which were durable, but they were able to resect all disease in 7 other patients (5 PR, 2 SD), and 5 of these seven surgical complete responses were durable. All of their long-term survivors were either CRs or surgical CRs, so by including surgery as part of the protocol from the beginning they were able to more than double the number of long-term survivors from 4 to 9. The duration of response for the patients surgically converted to CR was 17, 24, 27+, 32+, 36+, 42+ and 49+ months. For the patients who got a CR from the drug treatment alone, the durations were 26+, 34+, 51+ and 56+ months.
The study is also interesting in that it got a reasonable response rate, 29%, despite the fact that all 62 patients were symptomatic (ECOG status 1) with 17 of them ECOG 2. Although the study allowed ECOG 0 (no significant symptoms) patients, strangely they didn't have any. I have never seen an IL-2 study with no ECOG 0 patients! Most studies require ECOG 0 or 1 and usually there are more ECOG 0 than 1. None of the ECOG 2 patients responded, which suggests that if they'd only allowed ECOG 0 or 1 they'd have had a better response rate. Finally, it's not possible to tell from this whether the Vinblastine made any difference.
Surgical resection following interleukin 2 therapy for metastatic renal cell carcinoma prolongs remission.
Arch Surg. 1992 Nov;127(11):1343-9.
Comment: This paper is the gem of the lot. They analyzed results of surgery for in partial responders from a group of 399 patients who were treated with various forms of high dose IL-2. The results for partial responders who were rendered disease free by surgery couldn't have been better. They did even better than the complete responders (though the difference wasn't statistically significant). In fact, not even one of the partial responders who were rendered surgically disease free relapsed!
Now to some of the details. Out of the 399 patients there were 44 partial responders and 10 of these had surgery after the IL-2. Follow-up was moderate, ranging between 4 and 45 months after surgery (median 21). Although these 10 patients are only 2.5% of the 399 patients treated, these results are still important. If you happen to be one of those 2.5% this information stands to save your life! Moreover, the data analyzed for this study came from 14 different studies at various institutions and as the authors note, there was no uniform policy for surgery and importantly they suspect that more responding patients could have been resected. They also say some of the patients were not operable before immunotherapy which proves that the combination of immunotherapy and surgery is required to save some patients.
While I really doubt that getting a partial response and then being rendered disease free by surgery could actually be better than getting a complete response in the first place, it is pretty clear from this study it at least puts you in the same league as someone who had a complete response to begin with - and that's very good. Be aware that comparing the PR + Surgery patients to the PR without surgery patients, as in the above survival curves is tricky since patients who weren't resected might've had more widespread disease. Still - the eventual relapse of most of the non-resected patients is typical for partial response to IL-2 and the non-relapse of resected patients is decidedly atypical of partial response to IL-2.
Two key differences between this study and some of the others which might account for the superior results here are that these patients had high dose IL-2 and that they reported on patients who had a true partial response rather than patients who merely had stable disease or a minor response. It would have been interesting if they'd reported non-responders who were resected (I suspect there were some) since that could've given us some interesting data on whether immunotherapy and surgery have true synergy beyond immunotherapy rendering some unresectable patients resectable.
Finally, an interesting observation: They also found that a higher than expected proportion of responders were men, something I've not seen mentioned before for high dose IL-2. Another form of immunotherapy called Autolymphocyte Therapy gave men better survival than women, and also men with higher testosterone levels did better than those with lower testosterone (see my article on autolymphocyte therapy).
Efficacy of multimodality therapy in advanced renal cell carcinoma.
Urology. 1998 Jun;51(6):933-7.
Comment: In this study from the Cleveland Clinic, 14 people who'd been treated with various biological therapies had their residual disease surgically removed. 12/14 had IL-2 based treatment, all outpatient. Most of these patients had either stable disease or mixed response (some tumors growing while others shrunk) rather than true response before their surgery. Six of them had been treated with the kidney in place. Responses are rare in the kidney, and for four of these patients the surgery was just to remove the kidney tumor while the other two had both the primary tumor and metastatic tumors removed
Of the 14 patients, 7 were alive with no evidence of disease when the study was reported. Their survival from the time they finished drug therapy to when the study was reported was 4, 8, 25, 45, 52, 60, and 97 months. Three of these seven required additional surgery after relapse to achieve this status (They were the patients alive at 97, 60, and 52 months). Of the remaining seven patients, three were alive with cancer at 80, 57, and 16 months, and four had died. Of these four, three died of kidney cancer at 12, 27, and 45 months, while one died of an unrelated problem at 54 months. While most patients relapsed, the three patients who were again surgically rendered disease free all remained disease free a significant time after the second surgery (74, 54, and 37 months and all still disease free at last follow-up). Even among those who relapsed but couldn't be rendered disease free again, there were some long survivals.
Because 10/14 patients did relapse after their first surgery, you could argue that the results were similar to those with partial response alone. But here 11 of the 14 actually had less than a partial response, such as stable disease, minor response (<50% shrinkage) or mixed response. Given that, in my judgment, surgery did contribute to the long survivals here. The other side of the coin is that all or most of the benefit may have been due to the surgery rather than to the immunotherapy. Many of these patients such as the ones with merely stable disease were presumably operable before the immunotherapy and surgery alone is known to offer a chance of long term survival when all disease can be removed (See our reviews of surgery alone). But even so, if you find yourself in this position, data like this (and the data for surgery alone) make surgery the obvious next step.
Surgery following response to interferon-alpha-based therapy for residual renal cell carcinoma.
J Urol. 1993 Jan;149(1):19-21; discussion 21-2.
Comment: This study from MD Anderson Cancer Center reviewed the results for 17 patients who had surgery following Interferon. Unlike some of the other studies cited here, these were largely true partial responders (16/17 with one minor responder). 3/17 had IL-2 with the Interferon, and 10 had Interferon combined with 5-FU or 5-FU plus another chemo drug called mitomycin. Eight of the patients were treated with the kidney in place and all eight needed surgery to remove the kidney after the immunotherapy. In 5 cases the only remaining disease was the primary tumor (Responses to immunotherapy in primary renal tumors are known to be rare).
Follow-up was 5-29 months and all of the relapses they saw (6) happened during the first year after surgery. 11 patients remained disease free. These are excellent results for Interferon therapy. Although I am not a fan of Interferon, this study underscores that if you do choose Interferon you must be alert to the possibility of surgery - the combination is probably your best hope for long term survival.
Interestingly they gave 13/17 postoperative immunotherapy which consisted of Interferon plus a variety of other things in some patients, including Interleukin-2 (3) and 5-FU (3), as well as other things such as interferon-gamma which are unlikely to add much. Only 1/4 patients who didn't get postoperative therapy remained disease free compared to 10/13 who did get postoperative therapy, but the numbers are far too small to prove much. Especially given that adjuvant Interferon for localized RCC has been shown ineffective in multiple studies, I am skeptical that postoperative Interferon rather than chance really made the difference here.
They say that, based on experience, they evolved towards resecting patients only after they had maintained their response for several months - presumably to avoid useless operations in patients who would have a very brief response followed by widespread progression, but I think their numbers are too small to draw any certain conclusion. Their actual data was that among the six patients who had surgery after less than 4 months of response, 50% relapsed while 27% of the 11 who had been in response for more than four months relapsed after surgery.
It is also interesting that all but two patients had viable tumor in what was resected suggesting that they would have experienced progression without the surgery.
If you have had a response to immunotherapy but then experience renewed tumor growth surgery can be beneficial, and possibly even curative, for some patients. In a study from the National Cancer Institute[Lee 1998] surgery for limited relapse after a response to IL-2 gave relatively good survival, with about a third of patients showing no further relapse after surgery with many years of follow-up. This included a median survival of 84 months and relapse free survival for some patients in excess of five years (the longest nearly ten). The survival curves (see below) show pronounced flattening, which means some are very likely cured by the additional surgery. The authors say that almost all of these patients were inoperable before their IL-2 treatment, and so for these patients, it's quite clear that both immunotherapy and surgery were needed to get an (apparent) cure.
Interestingly, in about a third of the cases they didn't remove tumors which had responded and were still stable. Unfortunately, they don't separate the outcome for these incomplete resections from those who did have complete resection, nor do they say why they didn't do a complete resection. Based on the data for surgery alone, I don't think it makes sense to leave any tumors behind if it's reasonably feasible to remove them. Whether removing only progressing tumors can be of benefit if some stable tumors are left behind is not clear.
Patterns of relapse and response to retreatment in patients with metastatic melanoma or renal cell carcinoma who responded to interleukin-2-based immunotherapy.
Cancer J Sci Am. 1998 Mar-Apr;4(2):86-93.
If surgery is your primary treatment, and all of the metastases were removed, it seems logical to add immunotherapy to try to take care of any tumors too small to be detected. Unfortunately, there is no immunotherapy proven to do this so it's hard to recommend any specific treatment. Clinical trials are a possibility. Further treatment of Stage IV resected to No Evidence of Disease actually falls under adjuvant therapy. See my article on adjuvant therapy for more details.
If you tried surgery as primary treatment but a complete resection was not possible, then certainly you could try drug treatment. If you hadn't previously tried IL-2, it would make sense to try that.
If you had potentially operable disease but tried Interleukin-2 or Interferon based immunotherapy first and it didn't work, then by all means consider surgery if it still looks like all of your metastases can be removed. For two detailed reviews of the literature on the benefits of surgery alone see Surgery for Metastatic Renal Cancer.
In the old days patients who had metastasis at their initial diagnosis often had the kidney removed because it had been observed that sometimes the metastases would shrink if the kidney was removed. But it turns out that this is a rare event and that any shrinkage is usually only temporary. Palliative nephrectomy was sometimes done if the primary tumor was causing serious symptoms, but removing the kidney as a matter of course fell out of favor. Now in the age immunotherapy, there is a controversy over whether to remove the kidney before doing immunotherapy. The pendulum is swinging back to nephrectomy, but now as preparation for immunotherapy, rather than as treatment in itself.
It turns out that figuring out what's best in this area isn't easy. There is less data than you'd like, and it doesn't all agree. In addition, there are a great number of different situations to consider. Because of these factors, I believe deciding whether it's best to have surgery needs to be made in close consultation with expert physicians considering the particular circumstances. My goal here is to give you a good look at the issues so that you can help make an informed decision.
Reasons To Have Nephrectomy
Reasons Not To Have Nephrectomy
Some Specific Situations
Here's some common-sense suggestions for two situations where I think it's possible to offer general advice. There are situations not covered here because they are less clear. In any case, given the complexities, I especially recommend making this decision in close consolations with an expert.
Consider Laparoscopic Nephrectomy
Laparoscopic nephrectomy, an advanced surgical technique, uses special instruments and viewing scopes passed through small incisions to remove the tumor instead of open surgery. The major advantage of laparoscopic nephrectomy is that the recovery time is significantly shorter than for traditional surgery. Given the risks of not getting to immunotherapy due to disease progression during the time it takes to recover, it makes sense to consider laparoscopic surgery instead of traditional surgery if it's possible in your case.
Many patients who have metastasis at initial diagnosis also have large tumors which makes laparoscopic removal difficult, or tumors with complications like spread to the renal vein or inferior vena cava which make it impossible. The best experts in laparoscopic nephrectomy can sometimes remove larger tumors laparoscopically than others, something to consider if you've been told your tumor is too big for laparoscopic surgery.
This approach has already been tried in a small pilot study at the National Cancer Institute [Walther 1999]. They found the fastest time to fitness for high dose IL-2 in patients who had a form of laparoscopic nephrectomy in which the tumor is ground up (Technical term: "morcellation") so that it can be removed from a small "port". Here the median was 37 days compared to 60 for regular surgery, but you should be aware that their results were very limited by a small sample size and historical control rather than randomized design. There may have also been a smaller improvement in time to immunotherapy in patients who had hand assisted nephrectomy where the tumor is removed whole through a small incision, but this is less certain.
The authors seemed concerned that morcellation could carry a small risk of spreading the cancer if any of the morcellated tumor managed to leak out of the laparoscopy bag, but none of their patients had any sign of this. While I would take such a risk very seriously in apparently localized disease, given it is being used here where the cancer has already spread, any small risk should be more than made up for by the quicker recovery time. They removed some rather large tumors laparoscopically, and I had the distinct impression they were pushing the envelope on the size of tumor which can be removed laparoscopically. If you are considering this option and have a larger tumor, I would take special care to find a surgeon with extensive experience in laparoscopic nephrectomy who thinks it's possible.
Information on Nephrectomy and Living With One Kidney
If you are going to have a nephrectomy, spend some time in the Localized Disease Section where you'll find good information on the various kinds of surgery, getting through it, and living with one kidney. Since you have metastatic disease you'll need to adapt some of the information in these articles to account for your situation, but most of it applies.
Expanding the indications for surgery and adjuvant interleukin-2-based immunotherapy in patients with advanced renal cell carcinoma.
Cancer J Sci Am. 2000 Feb;6 Suppl 1:S88-92.
Cytoreductive surgery for stage IV renal cell carcinoma.
J Urol. 1995 Jul;154(1):32-4.
Nephrectomy before interleukin-2 therapy for patients with metastatic renal cell carcinoma.
J Urol. 1997 Nov;158(5):1691-5.
Nephrectomy followed by interferon alfa-2b compared with interferon alfa-2b alone for metastatic renal-cell cancer.
N Engl J Med. 2001 Dec 6;345(23):1655-9.
Cytoreductive surgery in the management of metastatic renal cell carcinoma: the UCLA experience.
Semin Urol Oncol. 1996 Nov;14(4):230-6.
Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.
Lancet. 2001 Sep 22;358(9286):966-70.
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. 1990 Sep;144(3):614-7; discussion 617-8.
Interleukin-2 based immunotherapy for metastatic renal cell carcinoma with the kidney in place.
J Urol. 1999 Jul;162(1):43-5.
Cytoreductive surgery before high dose interleukin-2 based therapy in patients with metastatic renal cell carcinoma.
J Urol. 1997 Nov;158(5):1675-8.
Laparoscopic cytoreductive nephrectomy as preparation for administration of systemic interleukin-2 in the treatment of metastatic renal cell carcinoma: a pilot study.
Urology. 1999 Mar;53(3):496-501.
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: March 8, 2003, Last Updated: February 6, 2004