Thalidomide: From Medical Disaster to Miraculous Cancer Treatment

Background:

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 In 1961, Thalidomide was withdrawn from the market (Ref.).

thalidomideMany 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:
    • Dramatic Responses to Therapy in Rare Tumors CASE 2. Response in a Patient With Metastatic Adrenal Cortical Carcinoma With Thalidomide (Ref.)
    • Thalidomide therapy for metastatic adrenal carcinoma (Ref.)
  • renal cell carcinoma
    • Continuous low dose Thalidomide: a phase II study in advanced melanoma, renal cell, ovarian and breast cancer (Ref.)
    • Low-dose thalidomide in patients with metastatic renal cell carcinoma (Ref.)
    • Thalidomide in Solid Tumors: The London Experience (Ref.)
  • melanoma
    • 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.)
  • angiosarcoma
    • Complete Response From Thalidomide in Angiosarcoma After Treatment of Breast Cancer (Ref.)
  • osteosarcoma
    • 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.)

but also:

  • 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:

  • have anti cachexia properties (Ref.) (Ref.)
  • reduce bone cancer pain (Ref.)
  • stop bleeding (Ref.)

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.

Mechanism:

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.

An external file that holds a picture, illustration, etc. Object name is nihms607407f2.jpg

http://www.ncbi.nlm.nih.gov/pubmed/23931282

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

Pharmacokinetics:

Thalidomide interconverts between the (R)- and (S)-enantiomers in plasma, with protein binding of 55% and 65%, respectively. More than 90% of the absorbed drug is excreted in the urine and faeces within 48 hours. Thalidomide is minimally metabolised by the liver, but is spontaneously hydrolysed into numerous renally excreted products. After a single oral dose of thalidomide 200 mg (as the US-approved capsule formulation) in healthy volunteers, absorption is slow and extensive, resulting in a peak concentration (C(max)) of 1-2 mg/L at 3-4 hours after administration, absorption lag time of 30 minutes, total exposure (AUC( infinity )) of 18 mg. h/L, apparent elimination half-life of 6 hours and apparent systemic clearance of 10 L/h. Thalidomide pharmacokinetics are best described by a one-compartment model with first-order absorption and elimination. Because of the low solubility of the drug in the gastrointestinal tract, thalidomide exhibits absorption rate-limited pharmacokinetics (the ‘flip-flop’ phenomenon), with its elimination rate being faster than its absorption rate. The apparent elimination half-life of 6 hours therefore represents absorption, not elimination. The ‘true’ apparent volume of distribution was estimated to be 16L by use of the faster elimination-rate half-life. Multiple doses of thalidomide 200 mg/day over 21 days cause no change in the pharmacokinetics, with a steady-state C(max) (C(ss)(max)) of 1.2 mg/L. Simulation of 400 and 800 mg/day also shows no accumulation, with C(ss)(max) of 3.5 and 6.0 mg/L, respectively. Multiple-dose studies in cancer patients show pharmacokinetics comparable with those in healthy populations at similar dosages. Thalidomide exhibits a dose-proportional increase in AUC at doses from 50 to 400 mg. Because of the low solubility of thalidomide, C(max) is less than proportional to dose, and t(max) is prolonged with increasing dose. Age, sex and smoking have no effect on the pharmacokinetics of thalidomide, and the effect of food is minimal. Thalidomide does not alter the pharmacokinetics of oral contraceptives, and is also unlikely to interact with warfarin and grapefruit juice. Since thalidomide is mainly hydrolysed and passively excreted, its pharmacokinetics are not expected to change in patients with impaired liver or kidney function. (Ref.)
The mean bioavailability by rectal application compared to oral application is below 40% (Ref.)
.
Side Effects:

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
Constipation 55% 8%
Neuropathy: sensory 54% 4%
Neuropathy: motor 22% 8%
Tremor 26% 1%
Fatigue 79% 17%
Edema 57% 6%
Thrombosis 23% 22%
Rash/desquamation 30% 4%
Leukopenia 35% 7%
Thrombocytopenia 24% 4%

Ref: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573415/table/table1-2040620711413165/

More info: http://chemocare.com/chemotherapy/drug-info/Thalidomide.aspx

Source:

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.

References:

Thalidomide-induced limb defects: Resolving a 50-year-old puzzle

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.

How Thalidomide Went From Medical Disaster to Miraculous Cancer Treatment 

‘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.

Disclaimer:

This site is not designed to and does not provide medical advice, professional diagnosis, opinion, treatment or services to you or to any other individual. Through this site and linkages to other sites, I provide general information for educational purposes only. The information provided in this site, or through linkages to other sites, is not a substitute for medical or professional care, and you should not use the information in place of a visit, call consultation or the advice of your physician or other healthcare provider. I am not liable or responsible for any advice, course of treatment, diagnosis or any other information, services or product you obtain through this site. This is just my own personal opinion regarding what we have learned on this road.

Please read an extended version of the Disclaimer here: http://www.cancertreatmentsresearch.com/?page_id=1794

Related Articles


70 thoughts on “Thalidomide: From Medical Disaster to Miraculous Cancer Treatment

  1. I’m the author of “pancreatic cancer: A case of advanced pancreatic cancer with remarkable response to thalidomide, celecoxib and gemcitabine”
    I think that the secret to make use of thalidomide for cancer treatment effectively is to use it together with celecoxib and valproic acid and begin to take the drugs immediately if cancer is found. In addition low dose of cytotoxic drug should be infused metronomically, e.g. pancreatic cancer gemcitabine, colorectal cancer irinotecan.
    The synthesis of thalidomide and the clinical trial were prohibited in Japan by bureaucratic of Ministry of Health, Labour and Welfare who are idle and inattentive to cancer drugs.

    1. Dear Dr. Masato Hada,

      thank you so much for your comment. I apologize for the delay of my response.
      Fortunately, thalidomide is available and accessible via various routes. For example, 100mg x 50 costs about 100 euro in countries such as Mexico.
      Could you please let me know why you think Valproic acid will work well together with thalidomide, celecoxib and chemo?
      Next to that, what do you think about the effectiveness in other types of cancers, other than pancreatic and colorectal?
      Have you seen response in patients other than the reported case in the above paper?
      Thank you for your contribution!

      Kind regards,
      Daniel

  2.  I classified antineoplastic drugs into three types by the mechanism, and choose one or two drugs from each group.
    1. cytotoxic drugs (irinotecan gemcitabine…)
    2. molecular targeted drugs (thalidomide celecoxib sorafenib …)
    3. epigenetic drugs ( valproic acid…)
    Targeted cancer therapies interfere the growth, progression, and spread of cancer that are controlled by angiogenesis and differ from standard chemotherapy in several ways. The target of epigenetic drugs is histone and DNA(chromatin) through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs), they may act upon most or all tumor types. Targeted therapies and epigenetics are cytostatic. The combination (molecular or epigenetic drugs and cytotoxic drugs) is vital to effective cancer treatment, as is the case of eradication of H.pyrori.

    Reference
    Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors.
    https://www.ncbi.nlm.nih.gov/pubmed/18226465?dopt=Abstract

    1. Dear Dr. Masato Hata,

      Thank you for sharing your view with us. I very much appreciate that. Indeed I also find Valproic Acid as on of the peeks in terms of drugs to be repurposed and intend to write an article on it.

      Can you please let me know what are the doses and treatment strategy you have in mind for the combo you mentioned above? Thanks in advance.

      Kind regards,
      Daniel

    2. Dear Dr Masato Hada,
      We began Gemcitabine(1000 mg) with Avastin 3 weeks ago for ovarian cancer on pertion.But our dr gives2xmonth.2000mg/month.
      Do you think giving by metronomic is more effective?I wonder how you give it to your patients(metronomic).
      And he add oxaliplatin which makes neuropathy.I think you dont give any of platin compounds.
      Can we compare avastin with thalidomide?Avastin made a very bad side effect on stomach.So he reduced avastin to 1xmonth.
      What do you think about adding celecoxip and valporic acid near to oxaliplatin+avastin?
      Thank you.
      Kind Regards
      Ergin

  3. To Mr Daniel
    Synergistic effects can be obtained by using drugs with different mechanism.
    I begin the treatment with thalidomide200mg, celecixib400mg, valproic acid600mg/day for the first week to make the patient’s condition (good appetite, sleep well and no pain) stable, trying to attain the blood findings more than normal, especially albumin4.2g, hemoglobin12g, white blood cell 3000. Then begins and select low dose cytotoxic drug according to the cancer.

    I hope you understand my poor English, because we Japanese do not write in English at all in daily life.

    1. Dear Dr. Masato Hada,

      Thank you for your response. It is very clear and helpfull indeed.
      Have you also considered/used lower dose Thalidomide, e.g. 50 to 100mg? According to several publications/observations (some of those cited in the post above) lower dose thalidomide may be more effective than higher doses.

      Kind regards,
      Daniel

  4. Dear Mr Daniel,
     I think dose determination of thalidomide is difficult because of the combination with other targeted or epigenetic drug. I have treated more than 600 patients with thalidomide (100-200mg/day), celecoxib and low dose cytotoxic drug with good efficacy.
    You should pay more attention towards dangerous side effect ,not to the doses.
    The dangerous side effect is caused by the combination of concomitant drugs and patient pathological conditions. It is difficult to explain briefly now.
                     
                     Masato Hada from Japan

    1. Dear Dr. Masato Hada,

      Thank you. I think I understand what you mean by the danger related to the combination of the side effects and patient condition. One example is exactly what I was speaking earlier today with a friend, i.e. Thalidomide should not be used in patients that just had surgery, due to its anti angiogenesis action. Or it should not be used in those susceptible to thrombosis unless they are using blood thinners in parallel, and so on …

      Whenever you feel there is additional information that may help others please continue adding comments here. Also, if you like to let us know the clinic in Japan where you combine the above treatments, please share the web address with us here. Thank you.

      Kind regards,
      Daniel

      1. To Mr Daniel
        One of the side effects usually known is thromboembolism whe used to Europian patients. But Asian people are relatively tolerant.
        The patients, most carefully treated with thalidomide, celecoxib and cytotoxic drug, are those who have external drainage due to obstructive jaundice. Granuloma, preventing leakage of bile, between liver and peritoneum is necrotized by the three drugs. Severe bile panperitonitis is the cause of death. Setting internal drainage is essential.

        HadaClinic
        Inquiry Form (English)
        http://www.123contactform.com/form-2347368/Enquiry-Form

        Inquiry Form(Japanese) http://form1.fc2.com/form/?id=742fcc9a23d88201

        Masato Hada ReseachGate
        https://www.researchgate.net/profile/Masato_Hada

        Homepge
        http://hadaclinic.com/
        Masato Hada

  5. Dear Mr ergin
    I usually treat the ovarian cancer patient with thalidomide 200mg/day, celecoxib 400mg/day and gemcitabine1000mg/every 10days. If the regimen could not lower Ca-125, I add valproic acid 600mg/day or solafenib 200mg-400mg. I’ve never used platins, because they are not effective for severe side effects.
    I hope you think of the mechanism of Avastin. Avastin could not get into the cancer cells, so it does not work directly on the reduction of VEGF. Thalidomide and celecoxib work directly and synergistic with less side effects than Avastin.
    Hada Clinic
    Masato Hada from Japan

    1. Hi Ergin,

      I totally agree with your remark. Great explanation.

      Just a kind reminder from my side: if you want dr. Masato to receive an e-mail notification with your reply, you need to add your comment as a “Reply” to his comment and not as a “New Comment”. I apologize for insisting with this reminder.

      Kind regards,
      Daniel

  6. Hi Daniel,
    I always reply after your reminder,but now may be forget it now.
    I understand the importance of reply when i saw my messages unlogically everywhere after some one replies:)

  7. Hello everybody,

    Does anybody know a reliable and not very expensive source of thalidomide? I am willing to travel to Mexico if I know where exactly I can buy a quality drug.

    Thank you.

    Tanya

  8. HI Tanya,

    I think every pharmacy in Mexico should have it. You could ask dr. Alberto (from the Citric Acid discussion) maybe he knows as he is from Mexico.

    Later (my evening) I will send you anyway the contact details from the company where I ordered.As it is a factory it is reliable, and I remember the price was about 100 euro from one box of 50x100mg capsules. I will send the details on private so that we protect a little the source, just in case. Also, you need a prescription or any other document indicating that Thalidomide will help you.

    If I forget to send the details please send me an e-mail as a reminder.

    Kind regards,
    Daniel

    1. Hi Daniel,
      Could you please send me the adress where we can buy thalidomide if you still have the adress..
      Because i couldnt find it on internet,sigma is very very expensive.
      Kind Regards
      Ergin

      1. Hi Ergin,

        The address is in your e-mail box.
        I do not write the address in public as I have seen that in Canada it became public and it was not allowed anymore for the Canadians to order from them, as the prices were too low.

        Kind regards,
        Daniel

    1. Thanks a lot! I will check it in the evening when I am back home, but it looks very helpful.
      I also like this statement of yours: “Many cancer information is flooded on TV, newspaper, and the Internet. I set up this corner from a mindset that I want you to be aware of tens of thousands of patients with cancer of the late stage pushing back from the depths of despair and pushing for the disastrous circumstances. Cancer treatment can not be solved by idealism. There is no compromise in natural science. It is important to analyze and deal with reality with calm eye.”
      Translated by Google.

    2. Dear Masato Hada,
      I am searching for Lenalidomide,and i wonder,if you have experience about it?
      It says derivative of thalidomide and used for multiplemyeloma in my country.
      Can we compare Thalidomide and Lenalidomide?
      After a small search of your protocol,i am lost,especially in valporic acid.
      Avastin works on inhibition of αvβ3 integrin.(we can easily reach that target by depletting T4 hormone).
      And it says inhibition of αvβ3 integrin is good but not enough for ovarian cancer.
      So we have to inhibit more integrins.I wonder how thalidomide works,which integrins?.Is it still not known from lab results?
      Or working independently?
      Very honestly i am afraiding to use thalidomide because of its name.But when i see they are using Lenalidomide here with lots of patients, i am a little bit relaxed.
      Interestingly i am confused because of VEGF.My mothers gene sequencing results show no VEGF mutation.
      Does it mean that inhibitor doesnt work on her?On mouse models VEGF drugs doesnt work on periton.
      Do you have experience about peritoneal ca with thalidomide?
      I am sorry about too long message and questions,but as you see noone is interested in thalidomide,because they are afraiding to use,and not easy to buy.I believe it and want to begin in next days with your valuable experiences.THANK YOU.
      Kind Regards
      Ergin

      1. To erigin,
        I have never treated patients with lenalidomide.
        We have to confirm the targets of the drugs before beginning the treatment.
        The stream of targets:
        Receptors⇒signal transductions⇒transcriptional factors⇒DNA ⇒ RNA ⇒ribozome⇒functional proteins.

        Avastin works only on the receptor VEGFR2 after that nobody knows how it works. Its efficacy is very low. Thalidomide is thought to work between DNA ⇒ RNA. The efficacy is excellent and less side effects than Avastin (I’ve never used Avastin becase of weak action).
        The combination of thalidomide and celecoxib can control ascites and pleural effusion completely.
        I hope you do not afraid of using thalidomide to help the patients.

        Kind Regards
        Masato Hada from Japan

        1. Dear Masato Hada,
          One more time thank you very much for giving your time to us.
          At last we had find a time with our dr and talked about thalidomide.He is amased when read how many patients you have treated.
          In the last course of chemo,there was a very big reaction occured with my mother.Plaxitaxel!!!
          So we switched to your protocol.I have a question,you have a great experience on this protocol.
          Did you see any reaction with your protocol?Because my mother begin to give reactions to most of the treatments like IV vitC.
          Kind Regards
          Ergin

  9. To Mr Daniel
    I changed my website in Japanese into the English version (rogueorgan.com).
    I’m not good at writing in English.
    When you find wrong English sentences, please e-mail me the right English.
    Masato Hada from Japan

    1. Dear Dr Hada,
      Everything is clear in your website and helpfull.
      Only i dont understand is valporic acid.In which way it is working?
      And if Gemzar doesnt work on ovarian cancer,what would you suggest to your patients?
      Kind Regards
      Ergin

    2. Hi Dr. Hada,

      I’m wondering if you have any experience with high grade neuroendocrine tumours (eg. Small cell carcinoma; large cell neuroendocrine carcinoma; of any organ of origin), and if so, how did you proceed with treating them?

      1. To Mr Meech
        I have treated neuroendocrine tumors with thalidomide, celecoxib and low dose cytotoxic drugs with good efficacy. In neuroendocrine tumors, I think we should not take the cancer type into account so much.

            1. Dr Hada

              we appreciate your explanation and rationale, its great to see an Oncologist here and to me your strategy looks very clever. i have a few questions;

              – I saw your 3 basic tiers (molecular, cytotocix, epigenetive drugs), do you suggest anything else to your patients? supplements etc?
              – In general, what is the approach of japanese doctors, are they open to alternative options during or after chemo? I have read somewehere that they tend to recommend Chlorella ? is it true?

              thank you again,
              W

              1. The fundamental thought concerning chemotherapy is how to carry out the safe chemotherapy with less side effects.
                1.improve anemia with erythropoietin (Epogen)
                2. improve low white blood cell with G-CSF (Gran or G lasta)
                3. keep blood albumin concentration(over 4.2g/100cc) with 25%albumin50cc

                I think it is better to select the drugs that are approved by USA-FDA, even though for cancer or not for cancer. I usually recommend healthy and nutritious food not supplements, to enjoy life.

                Masato Hada
                http://www.rogueorgan.com

  10. To Mr Erigin,
    As to valproic acid, please refer to valproic acid on my homepage, and then access the reference “Valproic acid as epigenetic cancer drug: preclinical, clinical and transcriptional effects on solid tumors.” The mechanism of valproic acid action is “Differently from other agents targeting a single gene product, epigenetic drugs have chromatin as their target through inhibition of histone deacetylases (HDACs) and DNA methyltransferases (DNMTs) therefore, yet unspecific, they may act upon most or all tumor types, as deregulation of the methylation and deacetylation machinery are a common hallmark of neoplasia.”.

    Ovarian cancer:
    Selecton of cytotoxic drug except gemcitabine, adding thalidomide, celecoxib and solafenib. Please refer to “What are anticancer drugs? “on my rougeorgan.com

    1. Thank you very much DR HADA.
      We are very lucky that you are here.
      I was very interested on HDAC inhibitors but didnt know that valproic acid is a good inhibitor with non-toxic dosages.
      It is also synergetic with cispilatin on ovarian cancer as i read.
      Kind Regards
      Ergin

      1. Ergin, Daniel and All,

        I am still trying to get Thalidome, without success. I contacted a mexican pharmany Daniel recommended but they did not provide any feedback.

        Can anybody recommend any supplier ?

        thanks
        W

                1. Hey Emad

                  thanks for spotting that. Good point. Probably one of the reasons why it has anti cancer affect. Will not use in parallel to 3-bp.

                  The thing is that customs is holding my 3-bp since ages ago, they are investigating as it looked suspicious to them. I am afraid it will be sh*t by the time it arrives.

                  Or maybe they just put me in jail 🙂

                  Re the price: it is indeed very competitive so i am just doing some doublechecks…1 USD per day is great. Even Mebendazole costs more.

          1. Dear Dr. Hada,

            is there any mention in the Japanese web sphere of 3-BP? I am always interested in the available access of 3-BP in different regions of the world. What might be the Japanese regulatory stance concerning the treatment of terminally ill cancer with non-approved medications such as 3-BP (In the US, Right to Try laws have been passed into law).

            Thank you for your very helpful comments on this site.

            1. Hi J,

              I always think about how nice it would be to connect somehow the alternative (or not YET mainstream)oncologic knowledge of the Western (repurposed drugs, egcg, melatonin, curcumin, dca, 3-bp, hyperthermia, etc..)and that of China. Japan too of course but i have the gut feeling that Japan is more connected… Maybe there are projects like this…. But i am not aware…. I have read several medical reports about patients going through spontaneous remissions who used a list of several chinese herbs… but the doctors (usually western ones) did not think that the 2 (remission and herbs) were related or that anybody would be interested in a scientifically meaningful study…

          1. Hello Alternmed.
            Are you getting any Talidimida pills available?
            Maybe you can tell me and where did she order?
            I must urgently start treating my wife and I do not know where to buy as soon as possible.
            Thank You
            Sive

  11. I received, thanks a lot. Now the wife finishes the third series of 3bp / salinomycin, next week she goes into a three-week break. I would like to start Thalidomide therapy immediately. Wondering, could you tell us if you started treatment with Thalidomide, and if so, are there any results?

    1. Hi sive

      no we didnt as i don t like the side effects of thalidomide so we used other medics/supplements instead
      how is she after 3bp and sal?

      where did you do the 3bp/sal

      if you can provide as much information as you can
      thanks

  12. After 2 series of 5 days (3bp / sali/ 3bp/ sali / 3 BP) I can not say that I see something transformed for the better. After finishing the third series, we’ll go back to the markers and tell you how the situation is. To do, we do a private clinic, but responsibility is ours. There were 2 people who finished the 3 series, but I can not tell you the results because they did not make the markers at the end of the cycle.

    1. Hi Sive

      I’m doing almost the same protocol for my mother at home , I’m using Salinomycin monosudiom salt version , are you using the same one or you are using the expensive base version ?

      also please share any results you have with this protocol , thank you so much

  13. Hi Emad ,
    I think it’s the basic version, because it took quite a long time to come. There was a lot of talk I needed to know. I do not know exactly the supplier. As for the results, I do not know what to say. The first person who completed the 3-week cycle had higher markers than initially, but he had an infection in the implantable camera, possibly higher. My wife had before she started abdominal pain when she moved over 50 feet or stood for several minutes. Now after two weeks of treatment, the pains are almost permanent, and it can hardly stand for a few minutes. Markers do next week and I can tell you what and how. In the next 3 weeks, I’m tempted to start Thalidomide treatment, I really do not know what else to do.

    1. If you can tell me if you tried Thalidomide and what results, for colon cancer surgery, but now multiple metastases. I saw that Dr. Hada had good results with exposed therapy. Has anyone else followed here?

    2. sorry to hear about the challenges you have

      is this treatment are done in a hospital or clinic ? could you share the place of this clinic ? and how much it cost for this 3 weeks treatment ?

      to note : I think there are some people who have higher markers after doing Sali , as it may increase due to tumor lysis , I’m not sure but in anyway I hope it will help

      also for thalidomide its also a very good thing to consider , but using it with 3-BP may inhibit the 3-BP effect , so I think you will not use them both

      I don’t want to talk about what to do more but just hope things will be fine , then later we may know what to do in time

      1. Yes Emad. Very good point. Sal produces necrosis when effective and can be experienced as a temporarily jump in markers and LDH. It may take about a week until the markers and LDH willl drop below the initial level – based on my personal experience – may not always apply.

    3. you may want to make sure if the pain is because of cancer or because of treatment

      some people may have increased pain in tumor side when using treatments like Sali

      hope your wife get better soon, always wish the best for you

    1. Hi there,
      I took it for appr 10 days. One pill per day. I stopped as i am marker negative (i was before too). By now i am unsure if i have active cancer, i might have a rare syndrom instead. (Cfs/me).
      I believe in thalidomide and it worked temporarily for people with my cancer according to studies so i tried.
      I noticed side effects early. Strong sleepiness after one hour. Bloody stool. Eye twitching. Fatigue the next day until noon. Nothing very brutal though. Hope it helps.

  14. Hi , English for me goes through google translator, so I apologize for misunderstandings in previous posts. The treatment is done in a special room for treatment, to a friend, the one who got 3 BP and salinomycin. The treatment is obtained for his mother and some prayers and because the quantity he had bought, he could have done my treatment and my wife. So it is similar to what Emad does at home. May I tell you that your wife has bigger pains than 3bp, but it’s easier to handle than salinomycin in which we had to stop the infusion for about an hour to get back. The tension increases from 10 as normal to 16, somewhere when half the dose is exceeded. We are trying to increase the infusion time from 2 hours to 3.5 hours, but the same happens with the increase in blood pressure. One over the other today ended the first 3-week cycle. Let’s go for a week and we’re going to make tumor markers. The treatment was largely done in the afternoon after the friend came from work. We have failed to observe the indication that it should be done in the morning, but the wife ate at least or not at all until after the treatment. Likewise, it did not take supplements before treatment except curcumin. How many days after 3bp / salinomycin can be started with Thalidomide, I was thinking about 3/4 days?

Leave a Reply