To many outside of oncology, thalidomide is primarily known for causing severe birth defects in women who received it in the 1960s as a sedative and treatment for morning sickness.  These birth defects, in which babies were born with no arms or legs but with hands and feet directly attached to their trunks, was likely related to the anti-angiogenic (blood vessel blocking) effects of thalidomide.  Over the last several years, however, its anti-angiogenic activity has been employed as an oral treatment for some cancers, and it is an approved treatment for multiple myeloma and has been studied in several other cancer settings, including lung cancer.  Specifically, one of the settings in which thalidomide has been the subject of several studies has been extensive disease small cell lung cancer (ED-SCLC), as small cell is a blood vessel rich tumor that has been suspected to be potentially vulnerable to anti-angiogenic drugs (for instance, I covered some early work with Avastin in SCLC in a prior post).  In addition, thalidomide appears to have immunostimulatory activity in lab-based work, and this may also contribute to potential anticancer activity.

   A friend of mine, Dr. Afshin Dowlati at Case Western Reserve University in Cleveland, recently published on his group’s experience giving thalidomide to patients as a maintenance therapy after initial chemotherapy (abstract here).  They enrolled 30 patients who had received 4-6 cycles of initial chemotherapy, which was not specified, who had achieved either a complete or partial response, or else stable disease.  (In other words, they enrolled patients who did not demonstrate progression on chemo, which we don’t expect to see after first-line treatment of ED-SCLC.)  After 3-6 weeks off of treatment, a total of 30 patients received thalidomide at 200 mg by mouth every evening, with a primary goal of the study to determine the one-year overall survival and overall tolerability of this treatment.  Recall that there is no established benefit for maintenance therapy after initial chemotherapy for ED-SCLC (see my prior post on the topic), but we continue to study it because we know that ED-SCLC is often responsive early and then tends to be much more resistant when it returns.  The idea of postponing that recurrence with a manageable oral therapy is very appealing, but we still haven’t seen a significant survival benefit despite the compelling rationale behind it.  With only 30 patients enrolled, Dr. Dowlati wasn’t going to establish anything definitive, but he did demonstrate that it was a feasible treatment.  Patients stayed on thalidomide for a median of 2.4 months, or 79 days.  The median survival was pretty encouraging at 12.8 months, and the one-year survival was 52%. The leading side effects were peripheral neuropathy (numbness and tingling in the longest nerves of the body, affecting the fingers and toes, primarily) in about 30%, and constipation in 16% of patients, despite a bowel regimen that was started on everyone at the time of starting thalidomide.  The investigators considered the results encouraging enough to warrant further study.

   Pujol and colleagues from France have also recently published their experience (abstract here) of a small randomized trial of chemo with or without thalidomide, this time at 400 mg per day, twice the dose Dowlati and colleagues used.

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They enrolled 119 patients to receive an aggressive 4 drug chemo regimen that not only includes standard cisplatin and etoposide but also additional chemotherapy drugs, cyclophosphamide and epirubicin. F or patients who had a response to the first two cycles of this regimen, they continued for up to four cycles and then added four more cycles of either thalidomide 400 mg per day or a placebo.  A total of 97 patients responded, of whom 92 remained eligible.  There were no differences between the two arms in overall response rates, but overall survival was three months longer in thalidomide recipients, 11.7 vs. 8.7 months (it appears that the aggressive 4-drug PCDE regimen didn’t do any better than you’d expect for a two drug platinum/etoposide combination), although this wasn’t statistically significant with the small numbers involved on the trial.  One year survival was 49% vs. 30%, favoring thalidomide over placebo. 

However, we saw hints of real compliance and tolerability problems with thalidomide, since 32% came off the drug due to toxicity (even after dose reductions on the protocol), and another 20% refused to continue it.  So there are some signals here that while there may be some improvement in survival, it may or may not be feasible.

   These two trials certainly give us reason to be hopeful about thalidomide if people can tolerate it.  But the story doesn’t end here.

   The biggest trial with thalidomide in SCLC was presented at the World Conference on Lung Cancer in Korea, where Dr. Siow-Ming Lee from University College in London presented a phase III randomized trial (abstract here) of chemo with either thalidomide at 100-200 mg daily (escalated as tolerated) or placebo among patients with previously untreated SCLC, either limited or extensive disease.  With 724 patients enrolled from 79 centers in the United Kingdom, evenly split between LD-SCLC and ED-SCLC, this was a far more definitive test of thalidomide than the previously described relatively small trials.  Chemotherapy was carboplatin and etoposide, and radiation to the chest was given to patients with limited disease, as well as prophylactic cranial irradiation given to those with LD-SCLC who had a response to treatment.  Unfortunately, this very large trial experience did not demonstrate any favorable results with thalidomide.  Median as well as one- and two-year survivals were the same between thalidomide and placebo arms and quite average for SCLC overall.  Looking at different patient subgroups, there were no subpopulations in which thalidomide improved survival, and in fact it was worse in patients with marginal performance status or ED-SCLC who received thalidomide.  Moreover, patients on thalidomide were significantly more likely to experience a blood clot, nearly a 70% higher risk (18% vs. 11%).  As in the other trials, patients on thalidomide also experienced neuropathy and constipation.  And just for good measure, in case you were still hopeful about thalidomide in NSCLC, a mere one hour after the Presidential Session, Dr. Lee in a different session presented another 700+ patient randomized trial from the UK (abstract here) of carboplatin/gemcitabine with either thalidomide or placebo in which thalidomide was associated with no benefit and a trend toward worse survival, again with a significantly higher risk of blood clots.

   Although not an uplifting aspect of the Korea meeting, Dr. Lee’s results provided several important conclusions.  First, thalidomide for lung cancer doesn’t look very attractive anymore.  Despite the small trials looking favorable, the two UK trials included about 1500 patients and clearly demonstrated that thalidomide doesn’t help and may very well harm patients with either SCLC or NSCLC.  Second, this provided an example of why the placebo arm isn’t a bad thing, that sometimes our current treatment with a placebo is the group that does better.  Moreover, it highlights that adding new treatments, even when commercially available, to standard therapies can absolutely be harmful.  We also saw this with Iressa in the SWOG 0023 trial for locally advanced NSCLC (post here).  Please also note that this is a case where encouraging small trials didn’t lead to similar results in larger trials more representative of real world experience. And finally, we learned that trials featured in the Presidential Symposium don’t always get the nod because they are positive and will lead to new standards of care.

   Let’s hope the next one shows only breakthroughs.  In the meantime, I’m not recommending thalidomide for my patients with lung cancer.