Thyroid Hormone T4 (Thyroxine) Suppression

Property	Information
Drug Name	Thyroid Hormone T4 (Thyroxine) Suppression
FDA Approval	No (Used off-label for cancer treatment; specific regimen for cancer not FDA-approved)
Used for	Investigational use in cancer treatment, particularly in glioblastoma, based on observations of improved outcomes with hypothyroid status
Clinical Trial Phase	Early clinical trials and case studies, including a phase 2 clinical trial in Israel (NCT02654041)
Clinical Trial Explanation	Not specified
Common Side Effects	Carefully monitored to avoid clinical symptoms of hypothyroidism; includes potential for fatigue if not properly managed
OS without	Not specified
OS with	In early studies, hypothyroid patients showed median survival of 10.1 months compared to 3.1 months in non-hypothyroid patients. Remarkable long-term survivors in informal cohort studies with advanced cancer, including glioblastoma patients surviving 36 and 48 months.Property "Has OS with" (as page type) with input value "In early studies, hypothyroid patients showed median survival of 10.1 months compared to 3.1 months in non-hypothyroid patients. Remarkable long-term survivors in informal cohort studies with advanced cancer, including glioblastoma patients surviving 36 and 48 months." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.
PFS without	Not specified
PFS with	Not specifically documented; focus on overall survival improvements
Usefulness Rating	3
Usefulness Explanation	Not specified
Toxicity Level	2
Toxicity Explanation	The toxicity level of Thyroid Hormone T4 Suppression Therapy is rated as a 2, which indicates a low level of toxicity. This is because the therapy is designed to suppress the hormone levels in the body and replace them with a synthetic version to help fight cancer cells. The side effects, such as fatigue, are typically manageable, especially when the treatment is carefully monitored. Nonetheless, this therapy is not without potential side effects and it is applied off-label, hence it's necessary to discuss with your healthcare provider.

Notes: Thyroid Hormone T4 Suppression Therapy involves inducing chemical hypothyroidism via propylthiouracil or suppressing T4 levels with methimazole and supplementing with synthetic T3 (Cytomel) to mitigate cancer-promoting effects of thyroid hormones while avoiding hypothyroidism symptoms. Discovery of thyroid hormone receptors on cancer cells provides a mechanism for their potential cancer-promoting effects. Early studies and case reports suggest potential benefits in cancer treatment, especially glioblastoma, with notable long-term survival in some patients. Further research, including ongoing clinical trials, is needed to validate these findings and optimize treatment protocols.

Links: NCT02654041

From Ben Williams Book: Based on observations of the relationship between hypothyroid status (depressed thyroid function) and improved outcomes in cancer patients dating at least back to 1988, Aleck Hercbergs and colleagues at the Cleveland Clinic conducted a clinical trial, published in 2003, in which 22 high grade glioma patients were treated with propylthiouracil to induce chemical hypothyroidism, and high dose tamoxifen (349). 15 of the patients had the diagnosis of glioblastoma and the remainder were grade 3 gliomas. Half of the patients (11 of 22) attained hypothyroid status, although no clinical symptoms of hypothyroidism were observed. A survival analysis determined that median survival in the 11 hypothyroid patients was 10.1 months, while median survival in the non-hypothyroid group was only 3.1months. After adjusting for the younger age of the hypothyroid patients, survival was still longer in the hypothyroid group, with borderline statistical significance (p=0.08).

Later, in 2005, the discovery of cell surface receptors for thyroid hormones on avB3 (alphaVbeta3) integrins, provided a mechanism for their cancer-promoting effects (350). This particular integrin tends to be overexpressed on cancer cells, and stimulation of this integrin by thyroid hormones leads to increased angiogenesis, tumor cell proliferation, and resistance to apoptosis (351).

Following publication of the 2003 trial, many cancer physicians and cancer patients reached out to Hercbergs, resulting in a cohort of 23 advanced cancer patients treated informally with thyroid suppression therapy in addition to standard treatments (351). Patients who were taking synthetic T4 for pre-existing hypothyroidism were abruptly switched to synthetic T3 (Cytomel) and in three of these patients there was a rapid and durable tumor remission observed in conjuction with standard treatments. In the remaining patients, methimazole was used to depress T4 levels to below the reference range, and patients again received synthetic T3 hormone (Cytomel). The rationale for this 31

is that even though T3 is the active form of thyroid hormone, the affinity for T4 at the thyroid hormone receptor on the integrin is greater than for T3, and T4 is a stronger inducer of cancer cell proliferation. The suppression of T4 and supplementation with T3 (Cytomel) is therefore thought to reduce the major cancer-promoting effect of thyroid hormones while avoiding the clinical symptoms of hypothyroidism, such as fatigue.

Four patients with glioblastoma were included in this study, including a 67 year old male with a KPS of 70 and a partial resection who survived 36 months (3 years), and a 64 year old male with a KPS of 60 who had undergone a biopsy only and lived for 48 months (4 years). Both of these patients had an expected survival of 10 months. A third female glioblastoma patient, aged 68, had a low KPS of 40 and survived for 8 months.

Several patients were excluded from the study who had either failed to achieve free T4 depletion, or who voluntary discontinued treatment (perhaps due to a perception of lack of benefit or an actual lack of benefit). Therefore the 100% response rate observed in this study is perhaps an exaggeration, although the long survival of two out of four advanced GBM patients certainly suggests an effect of the treatment, as standard treatments alone rarely lead to such positive outcomes. Additionally, Hercbergs et al. published a case report of a 64 year old patient with optic pathway glioma, progressive after standard treatments, who responded to T4 depletion with propylthiouracil followed by carboplatin chemotherapy with a remission period of 2.5 years and overall survival of 4.5 years (352).

A phase 2 clinical trial testing T4 suppression with methimazole and Cytomel (synthetic T3) in addition to standard treatment for newly diagnosed glioblastoma has started recruiting in Tel-Aviv, Israel early in 2016 (NCT02654041).Property "Has original text" (as page type) with input value "Based on observations of the relationship between hypothyroid status (depressed thyroid</br>function) and improved outcomes in cancer patients dating at least back to 1988, Aleck</br>Hercbergs and colleagues at the Cleveland Clinic conducted a clinical trial, published in</br>2003, in which 22 high grade glioma patients were treated with propylthiouracil to induce</br>chemical hypothyroidism, and high dose tamoxifen (349). 15 of the patients had the</br>diagnosis of glioblastoma and the remainder were grade 3 gliomas. Half of the patients</br>(11 of 22) attained hypothyroid status, although no clinical symptoms of hypothyroidism</br>were observed. A survival analysis determined that median survival in the 11 hypothyroid</br>patients was 10.1 months, while median survival in the non-hypothyroid group was only</br>3.1months. After adjusting for the younger age of the hypothyroid patients, survival was</br>still longer in the hypothyroid group, with borderline statistical significance (p=0.08).</br></br>Later, in 2005, the discovery of cell surface receptors for thyroid hormones on avB3</br>(alphaVbeta3) integrins, provided a mechanism for their cancer-promoting effects (350).</br>This particular integrin tends to be overexpressed on cancer cells, and stimulation of this</br>integrin by thyroid hormones leads to increased angiogenesis, tumor cell proliferation,</br>and resistance to apoptosis (351).</br></br>Following publication of the 2003 trial, many cancer physicians and cancer patients</br>reached out to Hercbergs, resulting in a cohort of 23 advanced cancer patients treated</br>informally with thyroid suppression therapy in addition to standard treatments (351).</br>Patients who were taking synthetic T4 for pre-existing hypothyroidism were abruptly</br>switched to synthetic T3 (Cytomel) and in three of these patients there was a rapid and</br>durable tumor remission observed in conjuction with standard treatments. In the</br>remaining patients, methimazole was used to depress T4 levels to below the reference</br>range, and patients again received synthetic T3 hormone (Cytomel). The rationale for this</br>31</br></br>is that even though T3 is the active form of thyroid hormone, the affinity for T4 at the</br>thyroid hormone receptor on the integrin is greater than for T3, and T4 is a stronger</br>inducer of cancer cell proliferation. The suppression of T4 and supplementation with T3</br>(Cytomel) is therefore thought to reduce the major cancer-promoting effect of thyroid</br>hormones while avoiding the clinical symptoms of hypothyroidism, such as fatigue.</br></br>Four patients with glioblastoma were included in this study, including a 67 year old male</br>with a KPS of 70 and a partial resection who survived 36 months (3 years), and a 64 year</br>old male with a KPS of 60 who had undergone a biopsy only and lived for 48 months (4</br>years). Both of these patients had an expected survival of 10 months. A third female</br>glioblastoma patient, aged 68, had a low KPS of 40 and survived for 8 months.</br></br>Several patients were excluded from the study who had either failed to achieve free T4</br>depletion, or who voluntary discontinued treatment (perhaps due to a perception of lack</br>of benefit or an actual lack of benefit). Therefore the 100% response rate observed in this</br>study is perhaps an exaggeration, although the long survival of two out of four advanced</br>GBM patients certainly suggests an effect of the treatment, as standard treatments alone</br>rarely lead to such positive outcomes. Additionally, Hercbergs et al. published a case</br>report of a 64 year old patient with optic pathway glioma, progressive after standard</br>treatments, who responded to T4 depletion with propylthiouracil followed by carboplatin</br>chemotherapy with a remission period of 2.5 years and overall survival of 4.5 years (352).</br></br>A phase 2 clinical trial testing T4 suppression with methimazole and Cytomel (synthetic</br>T3) in addition to standard treatment for newly diagnosed glioblastoma has started</br>recruiting in Tel-Aviv, Israel early in 2016 (NCT02654041)." contains invalid characters or is incomplete and therefore can cause unexpected results during a query or annotation process.

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