CancerGuide: Special Kidney Cancer Section
This article is about an important and promising treatment alternative for metastatic renal cell cancer. In brief:
Note: Unlike an ordinary bone marrow transplant, stem cell transplant does not require the donor to undergo painful procedures to extract bone marrow for the transplant. Stem cell transplants collect special cells from the bloodstream of the donor which are capable of reconstituting all the cells of the immune system in your body.
Background Information: What It is and How It Works
This is a very interesting and promising therapy that has been most extensively researched at the National Cancer Institute by Dr. Richard Childs of the National Heart, Lung, and Blood Institute, National Institutes of Health (and now at other sites as well). It has had some very exciting early results. The idea is to replace your immune system with the immune system from another person, either a matched brother or sister (known as a matched sibling donor) or by a matched unrelated donor (known as a MUD). The hope is that the new, foreign immune system will not attack your normal tissue excessively (because the donor is matched with you for tissue types by testing for your Human Leukocyte Antigens or HLA compatibility) but that it may be able to recognize the tumor as abnormal and destroy it, even though your own immune system does not. There are six HLA Antigens that are commonly tested for; the A, B, C, and DR1 antigens are the most important. Each of the six HLA antigens has a pair of 2 “alleles,” so the ideal match is 12/12 at the high resolution testing level. Testing at the high resolution level is usually only done in the case of MUD’s. For a sibling donor, only low resolution testing is necessary, and only the A, B and DR1 antigens are the most important, so a 6/6 match is ideal for sibling donors.
[The following paragraphs provide deeper understanding but are not vital for RCC transplants. Transplants for some diseases (not RCC) can be either autologous (the transplanted stem cells are taken from the patient himself before the high dose chemotherapy is given) or allogeneic (the transplanted stem cells are taken from another person). RCC transplants are always allogeneic. Most stem cell transplants are done for hematological cancers such as leukemia, not for solid tumors like RCC. Allogeneic transplant is generally used for hematological malignancies when it is believed that the patient's own bone marrow is contaminated by cancer cells, as in certain leukemias.
[In hematological cancers the original idea of the transplant was to allow the use of very high doses of chemotherapy or chemotherapy with radiation to destroy the leukemic cancer cells in the bone marrow. This is called a fully myeloablative conditioning procedure. It is intended to completely destroy the patient’s bone marrow, and the cancer along with it. The leukemic patient’s bone marrow and immune system is then “rescued” by means of the transplanted stem cells. Using high dose chemotherapy to destroy the leukemic cells in the bone marrow was the original principle behind bone marrow transplants for cancer; but over time evidence accumulated that a significant part of the benefit in allogeneic transplantation for leukemias was due to the donor’s new immune system attacking any residual cancer. This is known as Graft Versus Tumor (GVT) effect. In this way, allogeneic stem cell transplant also serves as a form of immunotherapy.]
RCC is resistant to chemotherapy. Therefore, allogeneic stem cell transplant for RCC is strictly a form of immunotherapy. RCC patients do not need to have their bone marrow fully destroyed before the transplant is done, so the transplant is called “nonmyeloablative.” In RCC it turns out that it is possible to replace the patient's immune system with much less drastic conditioning chemotherapy than with myeloablative transplants. With a nonmyeloablative transplant for RCC, relatively modest to moderate doses of chemotherapy are given -- not to attack the cancer, but just to suppress your immune system for a brief period of a week or so, so that it does not attack the donor’s stem cells when they are infused into you. For this period of a week or so, your own white blood cell count is very low; this is known as the “neutropenic period.” During this time you are hospitalized in a very germ-free hospital room with laminar air flow, and other precautions are taken because of the risk of infection. However, beginning at around day 10 to 17 after stem cell infusion into you, the donor’s stem cells “engraft” and you begin to have a white blood cell count that has been made by the donor’s stem cells.
In these non-myeloablative Stem Cell Transplants (SCT’s) for RCC, many of the more drastic side effects of fully myeloablative transplants are much less likely to happen. These include infection, sepsis (serious blood-borne infections), mucositis (painful mouth sores), etc. Although the chemotherapy “conditioning” may be “mini” and the side effects are reduced, you are still getting the full potential benefit of getting a full new immune system from the donor -- an immune system which may be more capable of recognizing your RCC as “foreign” and attacking it than your own immune system has done.
After the initial immunosuppressive “conditioning” chemotherapy, the stem cells are infused painlessly into the patient via a central venous access catheter. Most people think of the infusion as anticlimactic, like just another IV bag of fluids being given, except these cells are pink. Patients are then maintained on immunosuppressive drugs, such as Tacrolimus, low dose methotrexate, or Cyclosporine, in order to prevent the complication of Graft vs. Host Disease (GVHD) (see below). These are the commonly used drugs as of mid-2006; expect new and improved ones to be developed in the future.
Response, when it happens, is associated with withdrawal of immunosuppressive drugs. It normally takes 3-6 months to safely withdraw the immunosuppressive drugs, and so it may take 4-6 months before any graft vs. tumor response is seen. There may well be actual progression of RCC disease before a response is seen. Therefore, most centers have evolved over time into using careful “Patient Selection Criteria” before accepting a patient for transplant. These include patients who do not have advanced widespread bulky disease, patients whose lesions are small and slow growing, and who have good cardiopulmonary and renal functioning. The idea is that to do the patient any good, the patient must be likely to survive the procedure and to survive the 4-6 months of time with no anti-RCC therapy on board, before the time for the graft vs. tumor effect can be expected to manifest. In other words, it should not be done as a “last ditch therapy” in a person with very advanced disease with a life expectancy of less than 6 months, as it has been done often in the past. In those days, SCT’s for RCC were done as “salvage therapy” on poor prognosis patients. When these salvage SCT’s failed, SCT’s for RCC acquired an undeserved negative image by some. Nowadays, with proper “Patient Selection Criteria,” the effectiveness and response rate of SCT’s in the right RCC patient is very attractive; and the procedure is getting much safer as well. Using these newer “Patient Selection Criteria,” experienced transplant centers are achieving 30-40 percent long-term disease control.
Qualifying for the Treatment
Matched Sibling Donors and Matched Unrelated Donors
In order to qualify for some stem cell protocols such as Dr. Childs’ program, you have to have a brother or sister who matches your tissue type. If you don’t have a sibling, you cannot qualify for a matched sibling donor transplant program such as this; your only chance is for a matched unrelated donor (MUD) transplant. If you have one sibling, the chance of a match is only about 25 percent. The more brothers and sisters you have, the greater your chance of having at least one matching sibling. Even if you have six siblings, however, the chance is still not 100 percent. If deemed appropriate for you, Dr. Childs at the NIH will test you and your siblings for HLA compatibility at no charge to you.
If you do have a matched sibling and Dr. Childs feels you are a good candidate, I would strongly suggest that you have the procedure done with him at the NIH in Bethesda, MD. He has done 75 SCT’s for RCC, far more than any other transplanter, and has the highest success rates. Dr. Childs’ preference is that to begin eligibility screening inquiries, you call 1-800-411-1222 or you contact his research nurse, Rose Goodwin, RN, Transplant Coordinator, NIH-NHLBI, 10 Center Dr., Bldg. 10/CRC, Rm. 3-3485, Bethesda, MD 20892-1535, phone: 301-594-8013, fax: 301-480-0195. Her email address is g[email protected].
While you’ll have to stay near the NIH for 100 days post-transplant, all the medical and hospital care in Dr. Childs’ program is free. You are responsible for living expenses in the vicinity of the NIH once you are discharged from the NIH Hospital for the remainder of those first 100 days. Once you are accepted into the protocol, they will even fly one person (usually a relative) out for free if they need to be a caretaker for you.
If you have no sibling Dr. Childs will not test you; you must decide on a transplant center that will consider doing a MUD for you, and have your HLA testing there. What if you have siblings but they are not an HLA match? You can take the results of your HLA testing from Dr. Childs’ lab and ask another center to work you up for a matched unrelated donor (MUD) transplant.
In the past, concern was that there would be higher toxicities and mortality in a MUD transplant. However, recent evidence is that if another additional HLA antigen, DQB1, is matched at the high resolution level in a MUD, the toxicity and mortality from transplant is very similar in degree to a related donor transplant. This means it is important to identify as exact a match as possible in a MUD transplant, but especially at the DQB1 HLA antigen.
If I were looking for a MUD transplant, I would strongly recommend starting with the very experienced solid-tumor transplanter Dr. Naoto Ueno of M.D. Anderson Cancer Center in Houston. He started in 1995 and has done more MUD’s for RCC than anyone. ([email protected] His research nurse’s name is Leah Sanchez; her number is 713-792-7351. Dr. Ueno’s office number is 713-792-8754.) Dr. Ueno also does matched sibling donor transplants as well as MUD’s, but Dr. Childs’ program is free to you regarding medical and hospital costs and Dr. Ueno’s program at MD Anderson is not free of medical and hospital costs.
Dr. Ueno is currently conducting a clinical trial in MUD SCT’s for RCC with the conditioning chemotherapy regimen of fludarabine plus melphalan. The trial is being done not only by him at M.D. Anderson Cancer Center in Houston, but it is a collaborative study also being done at multiple locations around the US. The weblink for the trial is http://clinicaltrials.gov/show/NCT00318110 which lists the locations and Principal Investigator physicians at each location. Fludarabine and melphalan is a somewhat stronger conditioning regimen than Dr. Childs’ regimen of Cytoxan and fludarabine which so far has allowed the achieving of 100 percent donor cells at 30 days after transplantation. This rapid achievement of donor cells in patients may allow the improvement in the efficacy of the transplant, but this is not yet determined.
While you should strongly consider doing the clinical trial for MUD SCT for RCC listed above, you can certainly search for cancer centers which might do a MUD SCT which is not on a research study protocol. The downside of not being in a trial is that your results are “lost” to science, and it will be just that much harder to make conclusions about the safety and efficacy of MUD transplants for RCC.
If you go the “off study” route, it is probably best to select a center where there is an RCC specialist, an experienced transplanting team, and experienced cancer surgeons who all will communicate together as a team on your case. Many of the major transplant centers have web sites with information about transplants. Among the places to consider are the Fred Hutchinson Cancer Center in Seattle (www.seattlecca.org) and the City of Hope in Southern California (www.coh.org/bmt with Dr. Kim Margolin being the RCC specialist there). There is a lot of excellent information on the web site of M.D. Anderson Cancer Center (www.mdanderson.org/departments/bmt). These three cancer centers are among the most experienced transplant centers in the world and have done many MUD transplants over the years for various hematological and other diseases, though as of 2006 not a large number for solid tumors such as RCC.
Some doctors are hopeful that the genetic disparity between MUD’s may actually lead to more GVT (it has in leukemias), but there can also be more GVHD than in sibling donors which will require some additional precautions and possibly treatment.
Risks and Recovery From Treatment
On the whole this therapy is not without risks; and it does have a time requirement of some months to actually get through any complications that come up and get to the point where graft vs. tumor can manifest itself. However, the risks are decreasing substantially over time as doctors learn more about the procedure and how to control the risks. This is similar to how HD IL-2 was riskier in the early days until doctors learned how to manage the side effects. There were several causes of morbidity and mortality from SCT's that have significantly decreased in incidence since various improvements have been made:
Besides the safety advances above, with the evolving patient selection criteria the procedure is likely to have a response rate in the 35 to 50 percent range, similar to what Dr. Childs gets. Currently Dr. Ueno, who is aggressively pursuing the clinical research trial in SCT’s using MUD for RCC (the only such study in the USA as of 2006 under the National Marrow Donor Program /Center for International Bone Marrow Treatment Research protocol, ) needs enough matched unrelated donor patients to get meaningful data on response rate. Thus, it is important that all potential MUD patients participate in this trial, either at MD Anderson or at the other centers which are collaborating and also doing this research protocol. Dr. Ueno is using patient selection criteria similar to Childs’, i.e., patients early in their course without advanced bulky disease, primarily lung lesions, which aren't fast growing, with good organ functioning, and a likely long-enough life span to be able to benefit from the possible graft-vs.-tumor effect several months down the line from the time of the transplant.
If you have made it that far with your transplant, you may have chronic complications such as chronic GHVD (generally annoying but not life-threatening) or infections which reduce your quality of life. Even if the transplant works without such complications, you can expect it to be a while before you have normal energy and sense of wellness. Dr. Childs estimates that about two-thirds of his patients feel pretty well recovered from the transplant (other than chronic GVHD minor complaints such as dry eyes) within about 6 months. Some of the rest have chronic GVHD which resolves in about 75 percent of cases given more time, but doesn't always.
Despite these risks, metastatic RCC is such a serious condition, with such a high risk from the disease itself, that I would still consider this treatment if IL-2 and surgery didn't work for me. To put it bluntly, I’d rather die in an attempt to save my life than to sit around and wait for the inevitable.
Sequence of Treatments and Strategy
Assuming you're interested, a big question is where this risky but promising treatment fits into your overall strategy. Dr. Childs says he advises patients to try IL-2 or interferon first before trying the transplant, and I agree. For practical purposes, you should try it before the transplant because if HD IL-2 works, its effectiveness may last for years and the usual significant side effects are gone very quickly.
However, if HD IL-2 doesn’t work for you, I would immediately investigate SCT for RCC for the following reasons: Even if you are found to be a good candidate for SCT it could take as long as 4-9 months to get it done, because of the difficulties of finding a matched unrelated donor if you don’t have a matched sibling donor, getting insurance approvals and appeals done, etc. This process goes more quickly when you work with an experienced transplant center such as M.D. Anderson, City of Hope, or the Fred Hutchinson Cancer Center. During this 4-9 months of waiting to get everything in place, the transplant team will work with your RCC oncologist; and you can try to maintain your RCC with Nexavar (sorafenib) or Sutent. However, as we all know, eventually patients progress on these; they don’t work forever for most patients. The median time to progression for Nexavar was approximately 6 months in its Phase III trial; for Sutent, 8 months in its 2 Phase II trials. This should be just enough to get you through until the SCT can take place.
As far as other post-transplant treatments, while a few clinical trials might admit you if you have had a transplant, the majority would exclude you because of it. In sum, a transplant is likely to be your last clinical trial treatment, for better or for worse. However, there is nothing to exclude you from taking already FDA approved treatments after your SCT when you have been tapered off the immunosuppressants. Dr. Childs commonly gives people Avastin, Nexavar, and Sutent in the post-transplant setting.
I'd say given the state of treatment today, if IL-2 doesn't work and a complete response via surgery isn't an option, then this treatment is a definite consideration. It is being actively suggested by many well known RCC physicians, such as Dr. Robert Figlin of UCLA and Dr. Fred Appelbaum of the Fred Hutchinson Cancer Center, if HD IL-2 doesn’t work or isn’t tolerable and surgery isn’t an option -- always for patients who meet the aforementioned “patient selection criteria,” of course.
Finding and Selecting a Center
Allogeneic stem cell transplant is used in many other cancers, and many centers are very experienced for many years and know how to do it. Given Dr. Childs’ exciting results, a few other centers other than the NCI are running protocols for kidney cancer. These trials differ in many details. If it were me and I had a matched sibling donor, I would certainly investigate Dr. Childs’ trial if at all possible, since he is definitely getting results and the medical and hospital care in his program is free to you. For another opinion, I would investigate Dr. Ueno’s program at MD Anderson, but it is not free as Dr. Childs’ program is. If Dr. Childs’ matched sibling trial was not an option, I would look for a center which has already done MUD transplants for renal cell cancer, such as Dr. Ueno at MDACC, Dr. Kim Margolin at COH, and the Fred Hutchinson Cancer Center in Seattle.
For contact and other information on Dr. Childs' protocol see its entry in NCI's Clinical Trial DataBase.
The Data and Information Sources
1. Allogenic Hematopoetic Stem Cell Transplantation for Metastatic Renal Cell Carcinoma by Ueno at al,
This highly recommended article includes a summary of all the published case series on SCT’s for RCC to date and includes insightful comments about how it is hard to compare the data because of different techniques and patient selection criteria which were used in each case series.
2. Rapid induction of complete donor chimerism by the use of a reduced-intensity conditioning regimen…in Allogenic stem cell transplantation for metastatic solid tumors, by Ueno et al, in Blood. 2003 Nov 15; 102 (10):3829-36. Epub 2003 Jul 24.
This article is a summary of Dr. Ueno’s experience in stem cell transplants of 8 patients with metastatic breast cancer and 15 with RCC. While 45 percent responded, the article does not say what percent of RCC patients responded and what percent of breast cancer patients responded. 39 percent had grades II to IV GVHD and 43 percent had chronic GVHD. 22 percent died of non-relapse treatment-related complications. Both matched sibling donors and MUD’s were used, but the numbers of each were not specified.
In response to our request, Dr. Ueno did break out his data for the RCC patients that he has transplanted. His team has done 24 RCC patients, all of whom are considered evaluable. Six patients of the 24 had significant response. He had 4 complete responses (16.6 percent CR’s!), 2 partial responses, and 5 minor responses. Dr. Ueno prefers not to include the minor responses, but most RCC patients do value periods of disease stability. Some of his patients are now reaching 4 years after transplant. Dr. Ueno did not specify how many of the 24 patients were sibling donors and how many were matched unrelated donors, nor did he break out the data for rate of GVHD or treatment related mortality by sibling donors or matched unrelated donors, but it’s safe to assume that the vast majority were sibling donors. Still, a response rate of 25 percent in RCC patients refractory to cytokines and another 5 of 24 patients with “minor response” is very encouraging. These results are quite similar to Dr. Childs’ data.
Even more potentially hopeful is that in his first 20 patients, Dr. Ueno was not using the newer, safer “patient selection criteria.” In other words, most of the first 20 patients had borderline renal function and advanced bulky metastatic disease (i.e., poorer prognosis patients he would not transplant now). After these first 20 patients, Dr. Ueno began using the newer patient selection criteria described above in this article, which he feels will substantially improve the efficacy and safety results of SCT’s for RCC. Dr. Ueno cautioned that he has seen sometimes that when patients read research data, that they sometimes get either false hope or false negative impressions. He much prefers to talk about outcome data when he talks to patients “face to face.”
3. The latest update we have on Dr. Childs’ results is as follows. He's done approximately 75 matched sibling donor transplants for RCC patients and has had an overall response rate of about 38 percent. There have been 29 percent partial responses and 9 percent complete responses. This is the best response rate we have ever seen in a reasonable size study for patients who have failed previous immunotherapy! Three-fourths of the complete responses were ongoing. Dr. Childs didn't give exact response durations, but they exceed a few years for some of the early patients. His rate of treatment-related mortality has been 8 percent, about half of which were due to GVHD.
None of his patients with other than clear cell pathology responded; but his numbers of papillary, chromophobe, and collecting duct have been very small, and no generalizations are possible from the small numbers of patients. Dr. Childs has never done a transplant on a patient with hereditary RCC, and he does not know of anyone else who has. However, he says he would do it if the patient was otherwise an appropriate candidate for transplant.
Dr. Childs has had a 60 percent incidence of grade II-IV GVHD over the years but feels his ability to control it is now much improved, using a treatment called daclizumab. He believes his very mild conditioning regimen spares the host antigen presenting cells which stimulate the donor’s immune system into action, causing significant GVHD but also possibly a very potent immune response of Graft vs. Tumor. His rate of chronic GVHD has been approximately 55 percent, but three-fourths of these eventually resolve. As mentioned above he has a new GVHD prevention method which is working much better, and he confirms the information given earlier in this article that the SCT procedure is becoming safer with time, with routine anti-fungal, anti-pneumocystis, anti-viral, and anti-CMV treatments. Dr. Childs is very excited about some of his basic science research he is doing into the underlying mechanisms of response to SCT, such as his work with “natural killer” cells in rat models of RCC.
4. Nonmyeloablative Transplantation: An Allogenic-Based Immunotherapy for RCC, Takahashi Y and Childs R, in Clinical Cancer Research 6353s, Vol 10, 6353s-6359s, Sept. 15, 2004. A detailed article which also gives data on Dr. Childs first 19 patients whom he transplanted for RCC.
5. Prognostic factors for survival in patients with advanced RCC undergoing nonmyeloablative Allogenic Stem Cell Transplantation. Peccatori J et al. Cancer 2005 Oct 11. This article studied 70 patients who had undergone a SCT for RCC and analyzed the results in a multivariate regression model; and found that three factors, performance status, C-reactive protein level, and LDH level, could be used to stratify patients prognostically for consideration of treatment with SCT for their RCC.
Much of the information in this article is based on extensive discussions with Drs. Childs and Ueno in April 2006 who read and approved of the accuracy of the information in this article. I wish to thank them for being so generous with their time and knowledge.
Links to Other Information Sources (Including Information on Finding Trials)
Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.
N Engl J Med. 2000 Sep 14;343(11):750-8.
Comment: Full text of this article is available at nejm.org for free but registration is required.
Nonmyeloablative allogeneic peripheral blood stem-cell transplantation as immunotherapy for malignant diseases.
Cancer J. 2000 May-Jun;6(3):179-87
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: 2002, Last Updated: April 2006, by Dr. Dan, a physician with RCC who has undergone an SCT for RCC. For further information, email webmaster and your inquiry will be answered.