In 1957, Thalidomide was an over the counter drug used by pregnant women in West Germany, against morning sickness and nausea. Thalidomide, was hailed as a wonder drug that provided a safe, sound sleep. Unfortunately the complete spectrum of Thalidomide’s action were not well understood at that time, and shortly after the drug was brought to the market and sold, between 5000 and 7000 infants were born with malformations. As a result, Thalidomide became a catastrophic drug with tragic side effects. When thalidomide was taken during pregnancy (particularly during a specific window of time in the first trimester), it caused startling birth malformations, and death to babies. Any part of the foetus that was in development at the time of ingestion could be affected. (Ref.). In 1961, Thalidomide was withdrawn from the market (Ref.).
Many years later it was established that this complication was likely secondary to its anti-angiogenic action, inhibiting of blood vessel growth in the development of fetal limb buds (Ref.) Since the process through which new blood vessels are formed is highly relevant to tumor growth and other diseases, the drug has been suggested as a solution for various illnesses dependent on angiogenesis.
Actually, clinical interest in thalidomide resurfaced after Dr Jacob Sheskin first prescribed thalidomide in 1964 as a sedative in a patient with erythema nodosum leprosum (ENL). Sheskin was at the Hadassah University Hospital and Hansen Leper Hospital in Jerusalem. He observed an unexpected and dramatic resolution of the patient’s lepra skin eruption within 48 hours of administration. (Ref.)
Today, Thalidomide is used for a number of conditions including myelodysplastic syndromes (Ref.), erythema nodosum leprosum, multiple myeloma (in combination with dexamethasone), and some other cancers, for some symptoms of HIV/AIDS, Crohn’s disease, sarcoidosis, graft-versus-host disease, rheumatoid arthritis and a number of skin conditions that have not responded to usual treatment. (Ref.)
Therefore, from a killer Thalidomide has become a life saver for many. Although very cheap drug during 50’s, the cost of Thalidomide today goes beyond 1000 euro for a month supply and depending on the dose used may go well beyond that. That is the case in the Western countries. While this price has been artificially increased in the Western countries, the raw material is cheap and fortunately countries such as Mexico have succeeded to keep the price at a relatively low level, so that it can be found about 10x-20x cheaper in some countries. Here is an article on how Canadian patients are buying Thalidomide from Mexico at a price less than a 20th of that charged for the version available in Canada: Ref.
Although Thalidomide, is mainly used as a treatment for multiple myeloma (Ref.), its many anti-cancer mechanism of action discussed in the “Mechanisms” section below makes it relevant to many aggressive cancers that are strongly depended on growing fast new blood vessels such as:
- adrenal cancer:
- renal cell carcinoma
- New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide (Ref.)
- pancreatic cancer
- A case of advanced pancreatic cancer with remarkable response to thalidomide, celecoxib and gemcitabine (Ref.)
- liver cancer
- Thalidomide induces complete remission of advanced hepatocellular carcinoma (Ref.)
- Thalidomide Doubles Disease-Free Liver Cancer Survival Rate (Ref.)
- Phase II Trial of Thalidomide for Treatment of Nonresectable Hepatocellular Carcinoma (Ref.)
- Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up. (Ref.)
- Treatment of Hepatic Epithelioid Hemangioendothelioma: Finding Uses for Thalidomide in a New Era of Medicine (Ref.)
- Complete Response From Thalidomide in Angiosarcoma After Treatment of Breast Cancer (Ref.)
- Response of refractory osteosarcoma to thalidomide and celecoxib (Ref.)
- brain metastases from lung cancer
- A case report of chemotherapy with thalidomide, celecoxib and gemcitabine in the treatment of patients with brain metastases from lung cancer (Ref.)
- prostate cancer (Ref.)
During the recent years, it has been discovered that Thalidomide has multiple anti cancer actions, beyond anti-angiogenesis,
Thalidomide seems to also:
I like a lot Thalidomide but note that not every tumor is equally angiogenic or equally dependent on angiogenesis. The extreme example is renal cancer, which in general presents a strong activation of the VEGF pathway, is highly angiogenic, strongly depends on angiogenesis, and responds well to the VEGF inhibitor bevacizumab and to the VEGF receptor tyrosine kinase inhibitors sorafenib and sunitinib. In contrast to this, some tumors may grow by using preexisting vessels (vascular co-option) or by forming vessels through intussusception (Ref.). Furthermore, tumors can rapidly adapt to inhibition of angiogenesis and develop resistance by switching on different forms of supplies. This is why, some patients may respond well to angio genesis inhibitors at first and latter the tumors may start groing again.
On this line, I think that a treatment strategy that may address multiple mechanisms of survival for cancer cells is the best. For example, we may want too address at the same time
- the blood vessel formation (with angio genesis inhibitors),
- inhibit fibroblasts (with Tranilast) that may help cancer cells with the required supplies,
- inhibit MCT1 transporters through which cancer cells may receive lactic acid from the glycolitic cells (using e.g. Quercetin, and many others discussed in various posts on this website)
- inhibit Glut1 transporters via which cancer cells absorbe glucose (with e.g. Phlorizin)
This is just an idea to tr and maximize the results, but as shown in the Case Reports below, Thalidomide alone can represent a solution to some cancers.
Photo source: Ref.
Case Report in Humans
Dramatic Responses to Therapy in Rare Tumors CASE 2. Response in a Patient With Metastatic Adrenal Cortical Carcinoma With Thalidomide (Ref.)
- The patient developed progressive disease after three cycles of carboplatin and etoposide, and 4 months of mitotane. She was started on thalidomide 100 mg per day, without side effects during the first month. The dose was then increased to 200 mg per day. After 5 months of treatment, she had gained 10 kg, and CT scan showed partial response, which was a marked improvement from the CT scan of 6 months earlier. As of the publication date, she is asymptomatic and continues to take thalidomide 200 mg per day.
Thalidomide therapy for metastatic adrenal carcinoma (Ref.)
- 6 patients: 1) The patient who died of acute liver failure was a known alcohol and recreational drug abuser. 2) & 3) There has been no response in two men. 4) One man had complete resolution of metastatic disease on higher dose of TH+mitotane. 5) & 6) Both women have responded well on thalidomide monotherapy. We conclude that thalidomide therapy is certainly worth further investigation in patients with metastatic adrenocortical carcinoma, especially in combination with mitotane.
Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer (Ref.)
- Eisen et al treated 18 patients with renal cell carcinoma with 100 mg thalidomide daily. Three patients (17%) had a partial response, 3 had a stable disease for 3 months or longer. Two of the responders had failed earlier immunotherapy. These patients had significant palliative benefit within 24 hours of starting thalidomide (reduced insomnia and weight loss) and objective tumour shrinkage started within 2 weeks of starting therapy, which underlines the effect of thalidomide and argues against a spontaneous regression
Low-dose thalidomide in patients with metastatic renal cell carcinoma (Ref.)
- Response rates were available for 75 patients: partial 48 (60%); stable disease 12 (15%); progression 15 (18.8%); while 5 (6.2%) were not evaluated.
Thalidomide for Recurrent Renal-Cell Cancer in a 40-Year-Old Man (Ref.)
- Our overall impression was that the patient should enroll in the thalidomide study. He was informed about the various side effects, the dosing regimen, and the need to practice safe sex. He was initiated on 200 mg of thalidomide per day, to return weekly for a dose escalation of 200 mg/wk. This was achieved in a 6-week period of time, and the patient began to receive 1,200 mg daily. The patient tolerated the increased escalation of thalidomide well. He was taking Senokot-S for constipation and lactulose as needed, and made dietary adjustments that included increased fiber as well as increased fluids. The medication was taken in the evening. Although he maintained his performance status and continued working, the patient did have complaints of some fatigue and sedation. The April 27, 1999, chest CT stated that the right upper lobe mass had slightly increased, and that the liver was unchanged or slightly increased. The patient remained on thalidomide at full dose, and at the June 1999 evaluation began showing improvements in the lung and liver, achieving partial response (defined as greater than 50% reduction in size of metastasis).
New Approaches in the Treatment of Metastatic Melanoma: Thalidomide and Temozolomide (Ref.)
- On initial presentation, the patient was cachectic with a distended abdomen and had a Karnofsky performance status of 40%. She was started on thalidomide at 100 mg/d and dacarbazine on an every-3-week schedule. After 3 months, not only did the ascites completely resolve, but significant shrinkage of metastases in the liver and mesentery was observed, the retroperitoneal adenopathy had completely resolved, and the pelvic adenopathy had markedly improved. The patient elected to discontinue dacarbazine, but remained on thalidomide at a maximum dose of 200 mg/d. After an additional 3 months, resolution of the liver metastases continued and virtually no adenopathy was detected. The patient has now been on single-agent thalidomide at 200 mg/d for over 1 year since stopping dacarbazine and recently has exhibited recurrence only in the leg. These encouraging results prompted us to combine thalidomide with the Dartmouth regimen in two additional patients who had disease progression after treatment with this combination chemotherapy regimen; treatment resulted in stable disease in one patient and a minor response in the other.
Thalidomide in Solid Tumors: The London Experience (Ref.)
- The (renal-cell carcinoma) patient was started on 100 mg of thalidomide at night. At his first assessment at 1 month, he denied feeling any different. However, his wife said that he was, in fact, a changed man. The patient’s appetite had returned, his sweats had stopped, and he was more active. Over the next 4 months of treatment with thalidomide he had a gradual disease response, which resolved to a single residual lung mass in the right lung showing only necrotic tissue on bronchoscopy.It is well recognized that rarely, spontaneous or late responses to immunotherapy may be seen in patients with renal-cell carcinoma. This is unlikely to be the explanation for this man’s response for two reasons: first, the patient had rapidly progressive disease following biochemotherapy, and second, he obtained significant palliative benefit within a short time o starting thalidomide.After 9 months in the study, a SNAP test detected peripheral neuropathy and the thalidomide was stopped, according to the study protocol. The patient did not want to stop treatment then because he was feeling much better and had not noticed the peripheral neuropathy. After 1 month without thalidomide, his SNAP improved and he was restarted at a lower dose (50 mg). He developed peripheral neuropathy again after a month, at which time treatment was stopped. Eleven months later progressive disease was noted in the right lung. Restaging showed no evidence of relapsed disease at other sites and a pneumonectomy was performed. The patient remains well now, 3 years after starting thalidomide.
Thalidomide for the treatment of metastatic hepatic epithelioid hemangioendothelioma: a case report with a long term follow-up. (Ref.)
- Hepatic epithelioid hemangioendothelioma (HEH) is an unusual, low-grade malignant vascular tumor of the liver. Here we describe a case of a 40-year-old woman who presented with abdominal pain in the upper right quadrant and giant hepatomegaly, in which imaging studies and a fine-needle liver biopsy confirmed the presence of a large EHE with an isolated lung metastasis. After balancing all possible therapeutic modalities the patient was treated conservatively with thalidomide (300 mg/day). The drug was well tolerated with minimal toxicity and the patient continues on therapy 109 months after treatment was started with no disease progression. Current therapeutic options for HEH are discussed in light of the clinical case with particular emphasis on anti-angiogenic therapies.
Treatment of Hepatic Epithelioid Hemangioendothelioma: Finding Uses for Thalidomide in a New Era of Medicine (Ref.)
Complete Response From Thalidomide in Angiosarcoma After Treatment of Breast Cancer (Ref.)
- Considering the patient’s advanced age and the questionable efficacy of chemotherapy, she was offered thalidomide. This therapy was started at a dose of 200 mg/day. To our surprise, all the lesions responded dramatically to the treatment and she achieved clinical complete response in 4 weeks (Fig 3B). She developed pruritis and dryness of skin, which are known side effects of thalidomide, and the dose was reduced to 100 mg/day at 8 weeks. Eight weeks after reducing the thalidomide dose to 50 mg, disease recurred in two nodules. The thalidomide dose was increased to 200 mg, which brought about disease stabilization.
Response of refractory osteosarcoma to thalidomide and celecoxib (Ref.)
Thalidomide induces complete remission of advanced hepatocellular carcinoma (Ref.)
- The patient was assessed as inoperable and unsuited for transhepatic arterial chemoembolization or systemic chemotherapy. After discussing the therapeutic alternatives, he decided to receive low-dose thalidomide (100 mg daily) therapy. Fortunately, follow-up liver biochemical tests, serum α-fetoprotein level, and dynamic computed tomography showed complete remission of the HCCs 4.5 months after thalidomide treatment and this was documented for more than 22 months without evidence of tumor recurrence.
A case report of chemotherapy with thalidomide, celecoxib and gemcitabine in the treatment of patients with brain metastases from lung cancer (Ref.)
- Here we report a case of lung cancer patient with brain metastases who had been (previously) treated with chemotherapy and whole-brain radiation therapy (WBRT). He was treated with thalidomide, celceoxib and gemcitabine, after which brain metastases have almost completely disappeared. He tolerated extremely well. This combination may play an important role for patients with NSCLC and brain metastases.
Thalidomide acts via a large set of mechanims that include both immunomodulation and anti-angiogenesis. For example, inhibits the processing of mRNA encoding peptide molecules including
- tumour necrosis factor-alpha (TNF-α) and
- the angiogenic factor vascular endothelial growth factor (VEGF) (Ref.)
- Reduced Sonic hedgehog signaling and the ratio of matrix metalloproteinases to E-cadherin were both reduced (Ref.)
- various interleukins (IL-6, IL-10, and IL-12) production, and NF-κB and COX-2 activity
It modulates the production of IFN-γ and enhances the production of IL-2, IL-4, and IL-5 by immune cells. It also increases lymphocyte count, costimulates T cells, and modulates natural killer cell cytotoxicity (Ref.)
Instead of writing about each mechanism, I share the picture below which is illustrating clearly various anti cancer mechanisms that are related to Thalidomide.
Besides the above mechanisms, I found a new research indicating Thalidomide has MCT1 inhibition properties https://www.sciencedaily.com/releases/2016/06/160617104926.htm More specifically, Thalidomide outcompetes Cereblon for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Cereblon would otherwise activate the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. This research has been recently (July 2016) published in Nature Medicine journal: https://www.ncbi.nlm.nih.gov/pubmed/27294876 To me, this result is great as it shows how relevant is Thalidomide for many agressive cancers not only due to the anti angiogenesis properties but also MCT1 inhibition properties. Note that various pharma companies are currently working on development of anti cancer drugs that would inhibit MCT1. But here we have the drug. We do not need to wait for those developments. Finally, let’s not forget that MCT1 inhibition is a solution for auto immune diseases.
Administration and Dose:
Oral administration. Usually administrated at bedtime due to its sedating actions.
The optimal dosing schedule for thalidomide in cancer therapy has not been well studied. Most studies in myeloma and other cancers have used doses ranging from 200 to 800 mg/d, administered orally as a single dose at bedtime. The usual starting dose in myeloma is 200 mg/d, increased by 200 mg every 2 weeks to a maximum of 800 mg/d. The dose is then adjusted based on toxicity. At present, it is suggested the best dose is the highest dose that the patient can tolerate with a minimum of side effects. For most patients, this translates to a dose of 200 to 400 mg/d. Dose ranges in the presence of hepatic and renal dysfunction have not been established. It is unclear whether there is a dose-response relationship, or whether smaller doses can be equally effective with lesser side effects. Responses in myeloma have been observed even with doses as low as 50 mg/d. However, some patients with myeloma who progress with lower doses of thalidomide (400 mg/d) can respond to dose escalation (600 to 800 mg/d). (Ref.)
Interestingly, after looking from various studies and trials I concluded that low dose thalidomide seems to lead to better results compared to the high dose approach. Latter, I found a similar statement from another cancer warrior (Ref.).
Personally, I would go for 100 to 200mg/day at bedtime. Based on various sources, I think this dose should be in a range where the side effects are minimized while the chance for response may be even better compared to the higher dose.
Administer 100mg/day ASA and/or low-molecular weight heparin (LMWH) during the Thaidomide treatment to reduce Venous and arterial thrombotic risks with thalidomide (Ref.)
IV formulations have been also studied but are not available: https://www.ncbi.nlm.nih.gov/pubmed/10933131
Patients are advised not to get pregnant or father a child while using it, due to Thalidomide’s teratogenic properties.
Most of the patients experienced the known side effects of the sedative, including constipation, weakness, sleepiness and tingling or numbness in their extremities. (Ref.)
Thalidomide is generally well tolerated at doses below 400 mg/d. Most side effects are mild or moderate in severity, and can be controlled by appropriate dose reduction. The most common side effects are sedation, fatigue, constipation, and skin rash. Since severe constipation is a common problem, laxatives are recommended prophylactically. If a skin rash develops, the drug should be discontinued, and restarted at a lower dose after the rash clears. If severe exfoliation, Stevens-Johnson syndrome, or toxic epidermal necrolysis occur, use of the drug should cease, and it should not be used again. Thalidomide is also known to cause peripheral neuropathy, which generally develops following chronic use of the agent over a period of months. However, neuropathy can occur after relatively short-term use as well.
Less common but important side effects include edema, bradycardia, neutropenia, increased liver enzymes, deep-vein thrombosis, menstrual irregularities, impotence, hyper- or hypoglycemia, and hypothyroidism. Of these, the risk of deep-vein thrombosis (and possibly other thrombotic events) needs to be carefully studied, because patients with cancer are already at increased risk for thrombosis (Ref.)
Administer 100mg/day ASA and/or low-molecular weight heparin (LMWH) during the Thaidomide treatment to reduce Venous and arterial thrombotic risks with thalidomide (Ref.)
Selected adverse events occurring in ≥10% of patients as listed in the thalidomide package insert:
|All events||Grade 3–4|
Here are ideas on how each of us may find a/the source of Thalidomide at an accessible price: Ref. I can only say that based on personal experience if we involve enough energy it is possible to get to the source of accessible Thalidomide.
Despite the recent discovery that thalidomide causes limb defects by targeting highly angiogenic, immature blood vessels, several challenges still remain and new ones have arisen. These include understanding the drug’s species specificity, determining molecular target(s) in the endothelial cell, shedding light on the molecular basis of phocomelia and producing a form of the drug that is clinically effective without having side effects. Now that the trigger of thalidomide-induced teratogenesis has been uncovered, a framework is proposed, incorporating and uniting previous models of thalidomide action, explaining how thalidomide causes not just limb defects, but also all the other defects it induces.
‘Accidental’ anti-angiogenic drugs. anti-oncogene directed signal transduction inhibitors and conventional chemotherapeutic agents as examples. http://www.ncbi.nlm.nih.gov/pubmed/10882863
A number of drugs currently being tested in clinical trials as possible angiogenesis inhibitors were not originally developed with the intention of suppressing tumour angiogenesis. Thalidomide and interferon alpha are obvious examples of such drugs. This list of ‘accidental’ angiogenesis inhibitors may include established agents such as conventional cytotoxic chemotherapeutic drugs as well as the new generation of anticancer drugs known as anti-oncoprotein signal transduction inhibitors. With respect to the former, the potential of such drugs to inhibit angiogenesis could be the result of their ability to cause collateral damaging effects on cycling endothelial cells found in newly formed blood vessels, or inhibiting other vital endothelial cell functions necessary for angiogenesis. The antitumour vascular side-effects of chemotherapy may be optimised by administering such drugs continuously on a more frequent (e.g. weekly or even daily) basis at levels well below the maximum tolerated dose (MTD), especially when this is done in combination with newly developed anti-angiogenic drugs such as vascular endothelial cell growth factor (VEGF) receptor blocking antibodies. This strategy may minimise or delay the problems of host toxicity and acquired drug resistance. The possibility of anti-angiogenic effects mediated by signal transduction inhibitors such as ras farnesyltransferase inhibitors (ras FTI’s), or drugs which block receptor tyrosine kinases (e.g. ErbB2/neu) such as Herceptin, may be the consequence of such oncogenes inducing or upregulating various pro-angiogenic molecules such as VEGF (vascular endothelial cell growth factor) in tumour cells. Hence, treatment of tumour cells with such drugs can lead to downregulation of tumour cell-associated VEGF expression and this can contribute to an anti-angiogenic effect of the drug in vivo. In addition, some of these drugs may also affect certain ‘activated’ endothelial cell functions directly so as to block angiogenesis. An awareness of the potential of such conventional or experimental anticancer drugs to affect tumour growth through blockade or suppression of angiogenesis has implications for how anticancer drugs may be used clinically, either alone, or in combination with other drugs to optimally treat cancer.
Thalidomide: from tragedy to promise http://www.smw.ch/docs/pdf200x/2003/05/smw-09947.PDF
Thalidomide is an immunomodulatory and antiangiogenic drug. Although the exact mechanism of action is not fully understood, it has been shown to be active in a variety of diseases. There are multiple trials going on to evaluate the optimal dose of thalidomide and the importance of combining thalidomide with other drugs. This review introduces the properties and putative mechanism of action of thalidomide and summarizes the most important clinical trials with this biological modifier.
The use of thalidomide in the management of bleeding from a gastric cancer http://pmj.sagepub.com/content/23/5/473.abstract
Medical management of severe gastrointestinal bleeding can present a therapeutic challenge. We describe a case of bleeding secondary to gastric cancer that failed to settle, despite treatment with tranexamic acid, etamsylate and sucralfate. Thalidomide was prescribed for its antiangiogenic properties. Bleeding settled within 1 week of starting 300 mg of thalidomide nocte. The effect appeared to be dose dependant, with bleeding recurring only when the dose was reduced to 100 mg of thalidomide nocte.
Treatment of Hepatic Epithelioid Hemangioendothelioma: Finding Uses for Thalidomide in a New Era of Medicine https://www.hindawi.com/journals/crigm/2015/326795/
Hepatic epithelioid hemangioendothelioma (HEH) is extremely rare, occurring in 1 to 2 per 100,000, with chemotherapy options not well defined. Our case involved a 49-year-old female who had hepatic masses and metastasis to the lungs with a liver biopsy revealing HEH. After developing a rash from sorafenib, thalidomide was started with the progression of disease stabilized. Resection is only an option in 10% of the cases; therefore, chemotherapy is the only line of treatment. Newer chemotherapy alternatives are targeting angiogenesis via the vascular endothelial growth factor. Thalidomide was first used as an antiemetic, but, sadly, soon linked to phocomelia birth defects. Given the mechanism of action against angiogenesis, thalidomide has a valid role in vascular tumors. In conclusion, the use of thalidomide as chemotherapy is novel and promising, especially in the setting of a rare vascular liver tumor such as HEH.
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