Thalidomide and Thalidomide Combination Therapies For Renal Cell Cancer
Thalidomide is one of the most notorious drugs in medical history. Until recently, Thalidomide was remembered only for its ability to create horrendous birth defects after it was taken by pregnant women as a sedative in the late 1950’s (It was not marketed in the US). The affected children had missing or drastically shortened arms or legs, often reduced to flipper-like appendages. Even today, the phrase “Thalidomide Baby” evokes pure horror. But although Thalidomide can have significant side effects, these devastating effects on fetuses do not pertain to use of the drug in adults (as long as they take great care not to become pregnant!). Much more recently, Thalidomide was found to be a useful treatment for leprosy and is FDA approved for that purpose in the US. But it is actually being used much more in cancer treatment than it is in leprosy, which is a rare disease. Thalidomide is a product of Celgene Corporation.
Researchers discovered that the reason Thalidomide causes birth defects is that it interferes with the growth of blood vessels in fetal limbs. Researchers then reasoned that Thalidomide might also interfere with the growth of blood vessels in tumors. And so now that anti-angiogenic therapies are a hot topic, Thalidomide is being revived, but as a cancer treatment rather than a sedative! Thalidomide also has some effects on the immune system and might synergize with immunotherapy. It has been tested by several groups for metastatic kidney cancer, and more tests are underway.
Thalidomide is given orally (pills) and can be given to patients who are relatively ill, and even if several other treatments have failed. Because Thalidomide is FDA approved, though not specifically for cancer, any doctor can prescribe it for any purpose, and many patients are getting Thalidomide outside of a clinical trial, particularly after better proven treatments fail. Thalidomide is also still being evaluated in clinical trials, alone and in combination with other drugs. If you choose Thalidomide there may be advantages to participating in a trial, including reimbursement for the drug, and of course contributing to knowledge about this drug
Overall Thalidomide by itself is clearly a very weak drug in kidney cancer at best. It has been tried with Interferon and overall the results are that the combination more toxic than either drug alone but not more effective. Thalidomide is still in testing in combination with Interleukin-2 and some early results there have been promising.
Using Thalidomide as a starting point, Celgene has come up with a new experimental drug called Revlimid which is intended to be more effective than Thalidomide, yet with less side effects. Revlimid is in clinical trials for kidney cancer and has already shown promising results in another cancer called multiple myeloma. We don’t yet have any data for kidney cancer. This article doesn’t discuss Revlimid further but it may be an option in clinical trials. If so, it is probably a better option than Thalidomide alone outside of a trial since it’s less toxic and since the benefits of Thalidomide alone are so questionable. Revlimid has also been known as Revimid and CC-5013.
Side Effects of Thalidomide
Thalidomide can have many side effects, but most of them are reversible. Some of the common side effects include sedation (no surprise since the drug used to be prescribed as a sedative) and constipation.
Two potentially serious side effects are Deep Vein Thrombosis (DVT) and peripheral neuropathy,
- DVT: DVT refers to clots in veins, typically in the leg. In the worst case, these clots can break loose and lodge in the lung, causing a pulmonary embolism, which is a potentially life threatening emergency. My impression is that embolism is quite rare as a complication of Thalidomide treatment.
- Peripheral Neuropathy: Peripheral neuropathy refers to damage to certain nerves, and typically is felt as numbness or tingling in the hands and feet. It is a common side-effect of prolonged Thalidomide treatment. Peripheral neuropathy is more than just annoying, it can affect the ability to walk or use one’s hands well. Typically, this side-effect develops over time, starting in the finger tips and toes. It gradually progresses affecting more of the hand or foot as long as you continue to take the drug (sometimes doses are reduced to help with this). After the drug is stopped, usually there is at least a partial recovery. What is not entirely clear to me is the extent to which any peripheral neuropathy goes away after the drug is stopped, but it is clear that there can be long term or permanent nerve damage. Despite these problems, one of the advantages of this drug is that it apparently can be given to people who are not in good enough shape to try rigorous immunotherapy, such as high dose IL-2.
In addition, because Thalidomide causes horrible birth defects, women on Thalidomide must take great caution not to become pregnant, and men on Thalidomide must take equal caution not to start a pregnancy. Celgene has a formal program called S.T.E.P.S to prevent pregnancies while on Thalidomide which all patients must follow.
I don’t think Thalidomide alone is very effective, and it may not be effective at all. Occasional responses and stability can occur in patients for whom immunotherapy such as IL-2 didn’t work, so this can be considered as a second-line therapy if nothing better can be found. I definitely don’t think it’s a reasonable first choice for anyone who can take immunotherapy!
Thalidomide doses have been quite variable in trials ranging from about 100mg per day to 1200mg per day. Interestingly, there is no clear trend to suggest that higher doses are better. Some of the lower dose trials have had some of the best results (Though no trial of Thalidomide alone has had really encouraging results).
Response rates to Thalidomide alone are quite low (in the range of 5% perhaps), and complete responses occur very rarely if ever: Virtually all responses are partial. The most common claimed benefit is stability in about a third of patients, which is occasionally prolonged. In truth, it is difficult to distinguish the stable disease reported here from the natural history of kidney cancer which can include periods of stability, even without any treatment. Results from a randomized study of low dose Interferon alone versus full dose Thalidomide plus low dose Interferon [Gordon 2004]showed no improvement for the combination and no major benefit for either arm. While this isn’t strictly applicable to the question of Thalidomide alone, my judgment is that it is unlikely the low dose Interferon somehow interfered with the Thalidomide in the combination arm, and low dose Interferon is pretty ineffective by itself. Therefore since the combination was not an improvement, it looks to me like Thalidomide alone is probably ineffective.
Eisen T, Boshoff C, Mak I, Sapunar F, Vaughan MM, Pyle L, Johnston SR, Ahern R, Smith IE. Gore ME.
Continuous Low Dose Thalidomide: A Phase II Study in Advanced Melanoma, Renal Cell, Ovarian and Breast Cancer
Br J Cancer 2000 ;Feb; 82(4):812-7[PubMed Abstract (will open in new window)]
Comment: Very interestingly the results of this very low dose study in renal cell cancer look to be as good as the results of the same investigator's high dose study [Stebbing 2001] and maybe better! Could it be that more is not better?
Escudier B, Lassau N, Couanet D, Angevin E, Leborgne S, Garofano A, Mesrati F, Laplanche A.
Phase II Trial of Thalidomide in Renal Cell Carcinoma.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001 20 : Abstract 718 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This high dose study had particularly high rates of deep vein thrombosis and peripheral neuropathy - along with an encouraging number of patients stable at six months and a small number of actual responses. A small puzzle is why more patients continued on therapy after six months then had at least stable disease at that point (18 vs. 11).
Fuelling VD, Sridhar K, Raez LE, Santos E, Silva O.
Response to Low Dose Thalidomide in Renal Cell Carcinoma (RCC) with Lung Metastasis
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001 21 : Abstract 1822 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This single case shows that even very elderly patients with many medical problems may be able to tolerate Thalidomide treatment - note that an intermediate dose of 400mg/day was used.
Li Z, Amato R, Papandreou C, Pagliaro L, Kim J, Millikan R, Loggins-Coffman J, Perez C, Logothetis C, Daliani D.
Phase II Study of Thalidomide for Patients with Metastatic Renal Cell Carcinoma (MRCC) Progressing After Interleukin-2 (IL-2)- Based Therapy (Rx)
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001 20 : Abstract 717 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: These results of this high dose study are consistent with the others, including a low rate of actual response with about 1/3 said to have stable disease.
Comment: This small high dose study had relatively good results - and low toxicity despite the high doses. I understand that the performance status 3 (PS 3) patient was disabled with very extensive disease and was on oxygen when he had his dramatic response.
Comment: The results of this study were similar to those of the British high dose study above in that about a third of patients were stable for at least 6 months though they didn't see any partial responses.
Novik Y, Dutcher JP, Larkin M, Wiernik PH.
Phase II Study of Thalidomide (T) in Advanced Refractory Metastatic Renal Cell Cancer (MRCC): a Single Institution Experience
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001 20 : Abstract 1057 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: Again, stable disease without actual responses. It sounds like the stability only lasted a few months in most cases. It's hard to say if there's any activity at all here.
Comment: This is one of the more encouraging papers with some partial responses and enough follow-up to be able to see that there were a significant number of cases where stable disease lasted longer than 6 months. I still can't entirely exclude the possibility that this was merely a reflection of the variable natural course of metastatic kidney cancer.
Comment: This is just tiny for a randomized study, but it suggests 800mg/day is too much for most patients to tolerate and that nearly everyone can take 200mg/day. But based on the other studies it looks like 400-600mg/day is possible for most patients and 800-1200mg/day for many. Interestingly though, the low dose group actually did better than the high dose group in terms of "responses" by which they mean stable disease (there were no actual responses) - another indication that more is not better? I think though, the study is too small to draw any definite conclusion and that the follow-up is too short and not well enough specified to be able to get a feel for whether stable disease was often prolonged. We can tell that in at least one case the patient was still stable at 48 weeks (6 courses times 8 weeks).
Thalidomide + Interferon
I have found several different reports on trials of Thalidomide plus interferon. A major randomized trial of Low Dose Interferon versus Low Dose Interferon plus Thalidomide [Gordon 2004] showed no benefit for the combination and signs of treatment benefit were minimal in both arms. I see no hint from any of the other studies that this is more effective than either Thalidomide alone, or interferon alone. But it does look like it may be more toxic than Thalidomide alone – one of the trials was closed early due to side effects. I would avoid this combination unless and until there are results that suggest benefit.
Gordon MS, Manola J, Fairclough D, Cella D, Richardson R, Sosman J, Kasimis B, Dutcher JP, Wilding G.
Low dose interferon-a2b (IFN) + thalidomide (T) in patients (pts) with previously untreated renal cell cancer (RCC). Improvement in progression-free survival (PFS) but not quality of life (QoL) or overall survival (OS). A phase III study of the Eastern Cooperative Oncology Group (E2898).
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2004 23 : Abstract 4516 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: The title of this study is misleading. Apparently between the time that the abstract was submitted and the actual meeting the results changed as follow-up times increased. In the final results there is no improvement in PFS in the Thalidomide + Interferon arm. Unsurprisingly, it was still more toxic. To see the final result you will need to look at the slides from the presentation which are on ASCO's website. This randomized study is important.
In brief, the results were terrible. Low dose Interferon alone had about an 8% response rate, while the combination had a 3% response rate and not one complete response. I am sure the difference here in favor of Interferon alone wasn't statistically significant, the message here is that neither treatment worked well. The survival and progression free survival curves were virtually identical. Interestingly, the combination group did have bit higher rate of "stable disease" (31% compared to 19%). This seems consistent with reports of stable disease with thalidomide in other trials, but the fact that there was no discernable difference in the PFS "survival" curves is one indication that reports of short term stable disease without detailed information on the duration can be much ado about nothing.
This study used very low dose Interferon and Thalidomide escalated to patient tolerance, which means high dose. The results either indicate that Thalidomide has no or at best very minimal activity in kidney cancer, or that low dose Interferon actually makes Thalidomide work less well. I know of no specific reason to believe that.
I will add that this randomized trial was for first line treatment of metastatic kidney cancer. When it was open for accrual, I considered it to be a shockingly poor choice for patients since, as far as I know, there was no especially promising clinical data for either low dose Interferon alone or for the combination that would make it plausible that these treatments would be more effective than Interleukin-2 based treatment. The very poor results of this study should serve as a warning that not all clinical trials are good options, and that trials must be chosen with great care.
Nathan PD, Walker D, Bridle H, Ross P, Stevenson A, Lee SM, Eisen TG, Gore ME
A Phase II Study Investigating the Use of Thalidomide in Conjunction with Interferon-a in Patients with Metastatic Renal Cell Carcinoma.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2001 20 : Abstract 1058 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This study closed early because of unexpectedly severe side effects. If the treatment were effective, the benefits could be worth the cost in side effects. Unfortunately, not only was there a distressingly high rate of neurological side effects, but there was no sign this treatment worked.
Comment: This is from the same doctors as the previous reference[Nathan 2001]. I haven't got the paper and I don't have an abstract, but I think the title alone says a lot about what's going on here!
Ridenhour KP, Kubinski D, Stindt D, Hall MC, Patton SE, Torti FM
Phase II Trial of Thalidomide and Interferon-alpha in Advanced Renal Cell Carcinoma
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002 21 : Abstract 2429 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Comment: This study had no partial or complete remissions in 19 evaluable patients, but there were 7 patients with stable disease after 12 weeks of treatment. This is generally similar to results of the studies with Thalidomide alone, some of which had a few partial responses, and others of which had only stable disease. I can see no hint here that adding interferon is making things better.
Thalidomide + Interleukin-2
Two different Phase I studies of this combination were reported at the 2002 ASCO meeting, one of which is extremely promising (though still very preliminary), while the other didn’t have dramatic results. I have more details on this in my Notes on the 2002 ASCO Meeting on the webpage of the KIDNEY-ONC E-Mail List. In short, this is the most promising use of Thalidomide I’ve seen yet, but the results are still preliminary, uncertain, and somewhat conflicting. Time will tell.
Note that these references are both ASCO abstracts. For convenience you may prefer to find them (along with my commentary) in my List of Abstracts From the 2002 ASCO meeting (This is on my KIDNEY-ONC E-Mail List web page and will open in a new window).
Amato RJ, Breheny S, Tracy E.
Phase I/II study of thalidomide + interleukin II (IL-2) for patients with metastatic renal cell carcinoma.
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002 21 : Abstract 759 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Olencki T, Dreicer R, Elson P, Wood L, Bukowski RM.
Phase I trial of thalidomide and interleukin-2 (IL-2) in patients (pts) with metastatic renal cell carcinoma (RCC)
Proc Am Soc Clin Oncol (ASCO Meeting Abstract) 2002 21 : Abstract 2430 [You can find this abstract on the ASCO website (I can’t link directly because ASCO won’t provide a stable URL)]
Thalidomide + Interleukin-2 + GM-CSF
This three drug combination is in phase III testing by Dr. Amato (see references for Thalidomide + IL-2 above). It is an attempt to build on the promising results with Thalidomide and IL-2 so the dose and schedule of these two drugs are kept the same the dose he settled on for the two drug combo. The GM-CSF expected to add little in the way of side effects.
It’s way too early for us to have any real data on this therapy yet. I mention it because we have seen at least one response which can only be called spectacular in a patient on this therapy on the KIDNEY-ONC E-Mail List, and also because we hear it’s going very well in the early patients in general.
This CancerGuide Page By Steve Dunn. © Steve Dunn
Page Created: 2002, Last Updated: September 22, 2004