|
|
|
|
|
|
|
| |||||||||||||||||||||||||
|
| |||||||||||||||||||||||||
|
Metastatic Disease: Surgery and Immunotherapy Combined
|
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.
- Surgery after a partial response to immunotherapy
Most patients who have a partial response, even to IL-2, eventually relapse. Patients who have all detectable disease removed after a partial response seem to do as well as patients who had a complete response to the immunotherapy, which is to say very well! - Surgery for immunotherapy responders who relapse
Patients who've responded to IL-2 and then relapsed with new tumor growth often have only a limited relapse, and there is a real chance of cure if all detectable disease can be removed. - Immunotherapy after surgery
If you had a complete resection of all metastases then you may be eligible for a clinical trial of adjuvant therapy, but there is no standard adjuvant therapy. For more information, see my Adjuvant Therapy article (which is in the localized disease section)
If surgery was unsuccessful and tumor was left behind, you should consider immunotherapy if you haven't already tried it. - Surgery if immunotherapy doesn't work at all
If all of your metastases can be removed, surgery may be your best bet! - Removing the kidney to reduce tumor load (Cytoreductive nephrectomy)
Patients who have metastasis when they're first diagnosed with RCC should consider having the kidney out before immunotherapy, but this is not a simple decision, and careful consideration of your particular situation is essential.
Surgery for Residual Disease After Immunotherapy
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
Dutcher JP, Logan T, Gordon M, Sosman J, Weiss G, Margolin K, Plasse T,
Mier J, Lotze M, Clark J, Atkins M.
Gez E, Rubinov
R, Gaitini D, Meretyk S, Best LA, Native O, Stein A, Erlich N, Beny A, Zidan J,
Haim N, Kuten A. 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.
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!
|
|
Progression Free Survival
Adapted from Kim 1992 Figure 1 |
|
|
Overall Survival
From Kim 1992 Figure 2 |
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).
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
|
|
Progression Free Survival
Measured from completion of biological therapy Kaplan-Meier Plot Created by Steve Dunn from Krishnamurthi 1998 Table 1 |
|
|
Overall Survival
Measured from completion of biological therapy Kaplan-Meier Plot Created by Steve Dunn from Krishnamurthi 1998 Table 1 |
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.
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).
|
|
Progression Free Survival (Measured from the time of surgery)
Adapted from Sella 1993 |
|
|
Overall Survival (Measured from the start of Interferon therapy)
Adapted from Sella 1993 |
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.
Surgery for Relapse after Response to Immunotherapy
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.
|
|
Progression Free Survival After Surgery for Relapse:
The long flat tail strongly suggests surgery cures some patients after relapse.
Adapted from Lee 1998, Figure 3 |
|
|
Overall Survival After Surgery for Relapse
Adapted from Lee 1998, Figure 3 |
References
Immunotherapy After Surgery for Metastatic Disease
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.
Surgery After Failure of Immunotherapy
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.
Cytoreductive Nephrectomy
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
- Nephrectomy Combined With IL-2 May Increase the Response Rate and Long Term Survival
The best evidence for this is a pair of studies from the National Cancer Institute. [Wagner 1999] reported on 51 patients treated with high dose IL-2 with the kidney in place. They recorded a response rate of only 6%. In contrast, [Walther 1997] reported on 195 patients diagnosed with metastatic disease with the kidney in place who had nephrectomy before (mostly) high dose IL-2 and they recorded a response rate of 18% among the patients who made it to immunotherapy after surgery.
The classic objection is that since these comparisons are not from a randomized trial there could easily have been a bias in selecting which patients got nephrectomy first which could account for the difference. - Nephrectomy Combined With Interferon Modestly Increases Median Survival
Two studies of identical design which randomized people to Interferon alone or Nephrectomy and then Interferon showed a modest survival benefit for adding nephrectomy. [Flanigan 2001, Mickisch 2001].
Key Results
- Survival: In Mickisch 2001, adding
nephrectomy gave a fairly large increase in median survival from 7 to 17
months, but in the larger study [Flanigan 2001] adding
nephrectomy increased median survival by only three months, from 8.1 to 11.1
months. The best estimate is somewhere between these extremes, but closer to
the larger, statistically more reliable study.
- Response: The larger study [Flanigan 2001]had a miserable 3-4% response rate in each arm, all of which were partial, while Mickisch 2001 got a much better response rate (15%). The nephrectomy arm did better (19% versus 12%) but this wasn't close to being statistically significant. What was unusual was that there were 5 complete responses in the nephrectomy arm compared to only one in the control arm. Unfortunately, they didn't report the duration of these responses.
Conclusions, Clarifications, and Speculations
- The effect seen here is probably real: Why nephrectomy
improves survival is not known - but often the kidney tumor is the largest
tumor mass in the body.
- Whether the modestly improved survival is worth the trauma of surgery is
very much a personal decision. It takes weeks to a couple of months to be
mostly recovered from a nephrectomy so the gain in high quality time is even
more modest than the overall gain (If laparoscopic
surgery is feasible in your case it may significantly reduce the recovery
time). If you have significant symptoms and they're are mostly caused by the
primary tumor this should weigh in favor of surgery. If you have no symptoms, or
if your symptoms are primarily due to the metastases, this should weigh against.
Combining nephrectomy with other surgery or IL-2 with the goal of long term
survival brings other considerations.
- These studies don't say anything about whether nephrectomy alone
would improve survival or whether it must be combined with interferon to
yield a benefit, since both arms got interferon. It may be that removing the
kidney modestly improves survival regardless of other therapy - we don't know.
- There is no evidence here that adding nephrectomy increases the very
very low cure rate of Interferon alone - the studies weren't designed to
look at long term durable response but there were few if any of those. Other
studies of interferon which include many patients who've had a nephrectomy
don't show any appreciable cure rate. See my article on
Interferon for details.
- These studies don't address whether a similar benefit would be seen adding nephrectomy to IL-2 treatment, but I speculate that it likely would. First, the benefits of nephrectomy might not depend on the immunotherapy at all. Even if they do, IL-2 is a somewhat related therapy which I think is more potent. Second, the evidence that patients who've had their kidney out have a higher response rate to IL-2 suggest IL-2 is more effective when the main tumor mass has been removed.
Survival Curves
Flanigan 2001 Figure 1: Overall Survival 
Mickisch 2001 Figure 3: Overall Survival
Study Group: Nephrectomy + Interferon
Control Group: Interferon Alone
Mickisch 2001 Figure 2: Progression-Free Survival
Study Group: Nephrectomy + Interferon
Control Group: Interferon Alone - Survival: In Mickisch 2001, adding
nephrectomy gave a fairly large increase in median survival from 7 to 17
months, but in the larger study [Flanigan 2001] adding
nephrectomy increased median survival by only three months, from 8.1 to 11.1
months. The best estimate is somewhere between these extremes, but closer to
the larger, statistically more reliable study.
- Nephrectomy Might Make Immunotherapy Possible
If you have been told that you're too ill to tolerate immunotherapy, your doctor should carefully evaluate whether this is due to symptoms caused by the kidney tumor. In some cases people who weren't in shape to take high dose IL-2 due to symptoms from the primary tumor were able to take it after nephrectomy.[Walther 1997]. - Nephrectomy Might Improve Quality of Life
If the kidney tumor is causing serious symptoms such as severe pain, major bleeding, or severe fatigue and weight loss, removing the kidney by itself will help the symptoms although it doesn't cure the disease. Some symptoms are obviously caused by the kidney tumor but others are non-specific. With both the primary tumor and metastases in place you can't automatically tell whether non-specific symptoms like fatigue are due to the kidney tumor rather than the metastases, but if the kidney tumor is large (and large compared to the metastases), it seems likely. In my own case, surgery for a big kidney tumor relieved severe constitutional symptoms even though I had incipient metastasis which was detected only a month after surgery.
Reasons Not To Have Nephrectomy
- Common Sense Reasons
Surgery doesn't make sense if your kidney tumor is inoperable or if you wouldn't be able to take immunotherapy for some reason even if the kidney were removed. If you've been told the surgery is risky, consider that the disease is extremely risky. Taking some extra risk with surgery may be justified. Again close consultation with your doctors is essential.
Nephrectomy other than for just relieving symptoms should be part of an integrated surgery/immunotherapy program so your doctors should have already considered your ability to take immunotherapy after the surgery. - Risk of Not Making it to Immunotherapy
There is a substantial risk that you might not be able to take immunotherapy after surgery. This can happen if the metastases grow during the time it takes to recover from surgery to the point that you are too sick to take immunotherapy. Also patients who have metastasis at diagnosis tend to have large tumors and seem prone to complications after surgery which further delays immunotherapy. There is even a risk of permanent damage from surgery which precludes immunotherapy
The chance of not making it to immunotherapy after nephrectomy has varied tremendously in different studies. On the one end, in the larger Interferon versus Interferon plus nephrectomy randomized trial discussed above,Flanigan 2001, something like 95% of patients randomized to surgery first made it to immunotherapy (the exact percentage depends on how you count). In another study, Fallick 1997, extreme selection of patients for surgery prior to IL-2 resulted in 93% of patients making it to high dose IL-2 after surgery and a superlative 39% response rate, including 18% complete responses and long term survivals. Unfortunately, only 1/3 of patients met their strict inclusion criteria such as no bone or liver metastasis, clear cell sub-type, at least 75% of total tumor bulk in the kidney to be removed, and all criteria for high dose Il-2 met before surgery.
On the other end, Bennett et al [Bennett 1995] had a disastrous experience with cytoreductive nephrectomy. Of 30 patients, only 7 made it to high dose IL-2, although there were 3 responses among those 7. At the National Cancer Institute [Robertson 1990, Walther 1997] only 62% of patients with the kidney in place made it to high dose IL-2 after nephrectomy. Those who made it had a response rate of 18%, which is similar to the response rate for IL-2 in general. - Quality of Life Cost
A nephrectomy is major surgery and takes time to recover from. Complications are always possible and can further delay recovery. Surgery is never risk free. This all has to be weighed against the benefits, particularly if it is being done mainly to relieve symptoms.
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.
- Large Kidney Tumor, Relatively Small Metastases
Nephrectomy makes sense if your tumor burden would be small without the kidney tumor, especially if the kidney tumor is causing symptoms. Presumably if the metastases are relatively small and not immediately life threatening, the risk of not making it to immunotherapy is lower. - Small Kidney Tumor, Relatively Large or Aggressive Metastases
If your kidney tumor is small but you have large metastases or metastases which are threatening to make immunotherapy impossible, or which are known to be growing rapidly, then nephrectomy makes less sense, since the risks of not making it to immunotherapy are higher, while the benefit of removing the small kidney tumor is presumably lower.
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.
References
Flanigan RC, Salmon SE, Blumenstein BA, Bearman SI, Roy V, McGrath PC, Caton JR Jr, Munshi N, Crawford ED.
|
|
|
|
|
|
|
|
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: March 8, 2003, Last Updated: February 6, 2004
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.