MEBENDAZOLE/ FENBENDAZOLE

Mebendazole is an established anti-parasitic drug and in the same family as fenbendazole. The latter has similar activity, and is used in animals, but lacks safety guidelines for use in humans. Based on laboratory evidence and some older case studies, some of which are highly publicized, a few clinical trial has been completed with no impacts reported. To the contrary, these few studies typically confirm no impacts, or even increased progression rates.

A 2021 phase IIa trial in digestive system cancers, mainly advanced stage colorectal, but also liver, pancreas and esophageal patients were included. All patients were withdrawn due to accelerated disease progression The average time to progression on mebendazole was reduced over 60% compared to chemotherapy alone. And concerningly 4 of 8 that could be assessed fully showed signs of so called hyperprogression, unnatrually fast disease spread occurred during to the treatment with mebendazole. The same team had earlier reported successful treatment with mebendazole in colorectal cancer for a single case study similar to one from 2011. This shows the weakness of individual cases, which almost always have included approved cancer therapy, even immunotherapy such as pembrolizumab (keytruda) where there are often long term responders to be found in the data.

Trials are continuing in glioblastoma (brain cancer) there is a pilot study that was underpowered to show risk reductions in patients with mebendazole but the tendencies were positive enough to continue this to phase 2. This is the most promising indication of a targeted use, and 2 of the twenty or so patients in the trial got sustained benefit. A second recent trial showed no benefits, essentially hitting a risk reduction rate that met the criteria for failure. Any use of these drugs, as always, must come from your oncologists recommendation.

With fenbendazole, clinical evidence is limited to a few case studies on patients self medicating “fenben”. There are reports in kidney and bladder cancers of sustained remission (Highlight 4). But the effects on an individual or two clearly have not scaled into broader patient groups, and randomly assuming that “fenben” reduces risks for progression is alarmingly simplistic in light of the evidence with its close cousin mebendazole.

The concept of using multiple re-purposed drugs for so called metabolic cancer therapy has included mebendazole with metformin, dipyridamole and doxycycline. This has been withdrawn from its phase 3 trials, due to a lack of benefit and high burden from side effects in patients; https://clinicaltrials.gov/study/NCT02201381

All patients showed rapid disease progression and 4 of the 8 patients with CT-evaluations even fulfilled criteria suggested for hyperprogressive disease. At this stage the relationship between exposure to Mbz and tumour growth stimulation resulting in HP [hyperprogression] is inconclusive. Mbz has not been shown to stimulate tumour cell growth in any experimental tumour model. In this study, all patients were in progress when they were enrolled and most had poor prognostic features, e.g. disease resistant to several lines of chemotherapy, rapidly...

Preclinical studies suggest that the antiparasitic drug, mebendazole, has anticancer activity in several cancer types, including glioblastoma and other brain cancers. Here, we establish safety and dosing of high-dose mebendazole in combination with temozolomide during a 6-year observation period. The lack of toxicity and encouraging (but not statistically significant) survival supports further evaluation in a phase 2 study….While this preliminary study had too few patients to demonstrate efficacy, we conclude that mebendazole has sufficient...

A 48-year-old man with adrenocortical carcinoma had disease progression with systemic therapies including mitotane, 5-fluorouracil, streptozotocin, bevacizumab, and external beam radiation therapy. Treatment with all chemotherapeutic drugs was ceased, and he was prescribed mebendazole, 100 mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving mebendazole as a sole treatment for 19 months, his disease remained stable. He did not experience any clinically significant adverse effects,...

Herein we describe the cases of three patients with various genitourinary malignancies who demonstrated complete response after receiving FBZ [fenbendazole] therapy as a single or supplementary chemotherapeutic agent. In two patient scenarios, they had experienced progression of metastatic disease despite multiple lines of therapy prior to initiation of FBZ. No side effects from FBZ were reported. FBZ appears to be a potentially safe and effective antineoplastic agent that can be repurposed for human use in treating genitourinary malignancies

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URL	Rating	Highlight	Highlight 2
https://academic.oup.com/noa/article/3/1/vdaa154/5979487	3.5	In this safety trial, as with others, survival determinations are preliminary owing to the small study size, heterogenous population (eg, inclusion of both WHO grade III and IV tumors) and sample bias. While a 21-month median survival and 4-year survival of 25% may sound promising, it may be difficult to reproduce this in a larger trial that focuses only on grade IV glioblastomas. However, this study and animal studies16 support that mebendazole given at these doses does not interfere the standard of care temozolomide, is safe in combination and may enhance survival.	Because mebendazole appears to have low toxicity when used in combination with temozolomide, it opens the possibility for further testing in combination with of the standard of care including radiation and perhaps eventually with promising experimental therapies. The combination of mebendazole plus other therapies for intracranial malignancies may increase efficacy, while not substantially increasing therapy induced toxicity. While this preliminary study had too few patients to demonstrate efficacy, we conclude that mebendazole has sufficient safety, plasma levels, and lack of toxicity to proceed to randomized phase II trials.
https://www.tandfonline.com/doi/full/10.3109/0284186X.2013.844359	3	We conclude that mebendazole is seemingly a promising ‘new’ drug for treatment of advanced colorectal cancer. A number of pharmacodynamic, clinical trial, drug formulation and dosing issues need to be addressed before mebendazole might become an established drug in this indication. However, the case, together with its preclinical background, illustrates the potential of drug repositioning to improve the development of new and better cancer therapy	The patient experienced no adverse effects from the treatment and at CT evaluation May 2013 there was near complete remission of the metastases in the lungs and lymph nodes and a good partial remission in the liver (Figure 1). At this stage, the liver enzymes AST and ALT were found elevated up to five and seven times above upper limit of normal and mebendazole was temporarily stopped and then reintroduced at half dose. Liver enzymes slowly decreased and the patient still reported no adverse effects from mebendazole.
https://www.endocrinepractice.org/article/S1530-891X(20)40443-4/abstract	3	Mebendazole may achieve long-term disease control of metastatic adrenocortical carcinoma. It is well tolerated and the associated adverse effects are minor...	A 48-year-old man with adrenocortical carcinoma ...Treatment with all chemotherapeutic drugs was ceased, and he was prescribed mebendazole, 100 mg twice daily, as a single agent. His metastases initially regressed and subsequently remained stable. While receiving mebendazole as a sole treatment for 19 months, his disease remained stable
https://www.medicinacomplementar.com.br/biblioteca/pdfs/Cancer/ca_Fenbendazol_como_anticencer.pdf	3	There remains limited data with few published studies on the anti-oncogenic properties of FBZ. Other benzimidazoles have been studied to a larger extent, and the knowledge can be drawn upon to help guide future FBZ studies and to gauge the efficacy of this drug class whether as a solitary agent or in combination therapy. Given the potential benefits of FBZ with what seems to be a limited toxicity profile, further research is warranted to evaluate the clinical settings in which this medication may be beneficial and repurposed for patients with progressive genitourinary malignancy and possibly in other malignant settings as well.	In summary, we have three patients with different primary genitourinary tumors who demonstrated complete response after receiving FBZ therapy. This raises the question of how effective FBZ can be as an anti-oncogenic agent and merits further investigation. To our knowledge, there has not been a similar case series reported. FBZ belongs to a class of microtubule-destabilizing agents known collectively as the benzimidazoles. The ability to disrupt microtubule polymerization to induce mitotic arrest and promote apoptosis is a feature shared with the vinca alkaloids. Proposed mechanisms for FBZ’s anti-tumor properties include inhibition of proteasomal activity, p53 activation, cytotoxicity via tubulin disruption, and downregulation of glycolytic enzymes crucial for cancer cell surviva
https://www.nature.com/articles/s41598-021-88433-y	N/A	Speculatively, it might be that Mbz should be combined with a cytotoxic drug that stops tumour growth while an immune effect from Mbz allows time to act22. Thus, pending further analyses and investigations and despite the very promising prior preclinical and pilot clinical observations pointing to Mbz being highly prioritized for repositioning as a cancer drug21, given these results Mbz cannot be recommended for use in cancer outside of carefully designed clinical trials with close tumour growth surveillance to allow for early stop of treatment.	The problem to reach a high and stable drug exposure reasonably contributed considerably to the poor outcome in the present trial and overall, we conclude that Mbz is a promising pharmacophore but not the drug to bring forward in ongoing or future repositioning efforts. We rather suggest development of Mbz prodrugs with improved PK properties resulting in higher and less variable Mbz exposure. We have pilot in vivo data in mice indicating that such prodrugs are feasible to synthesize and development along this line has also been described recently
https://ascopubs.org/doi/10.1200/JCO.2022.40.16_suppl.2029	N/A	t 17.4 months, 68 events for OS analysis had occurred. The 9-month overall survival was 36.6% (95%CI 22.3-51) and 45% (95%CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively. ECOG PS was the only independent prognostic factor impacting OS (HR-0.47)	The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients with poor PS of 2-3. In patients with ECOG PS 0-1, CCNU-MBZ had a 9 month OS of 57.9% and needs to be evaluated further.

MEBENDAZOLE/ FENBENDAZOLE

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