Field
This application relates to ameliorating radiotherapy- and chemotherapy-induced cognitive and emotional impairment and to treating cancer with cannabinoids.
Background Information
Chemotherapy-associated cognitive or emotional impairment, commonly known as chemo brain and chemo fog (chemo brain/fog) has become a scientifically recognized and established consequence of chemotherapy, particularly during treatment of head, neck, and breast cancer. For example, patients undergoing treatment for glioblastoma often demonstrate symptoms of chemo brain/fog following radiotherapy and chemotherapy.
This cognitive or emotional impairment can negatively affect memory, tasking, and decision making capabilities. Chemo brain/fog may be transient or long term, often impairing a patient's quality of life for years or decades after treatment is completed.
The development of chemo brain/fog is influenced by the intensity and severity of the chemotherapy treatment, the specific chemotherapy agent, concurrent radiation treatment, and the tumor type and site. Chemotherapy agents including taxanes, platinum compounds, vinca alkaloids, thalidomide, bortezomib, corticosteroids, and bevacizumab have all been implicated as causative agents of chemo brain/fog.
There is evidence that visuospatial working memory, defined as the ability to retain and manipulate information during brief tasks, is impaired in chemo brain/fog. It has been postulated that in chemotherapy-associated cognitive impairment, activation of the dorsolateral prefrontal cortex is impaired. The dorsolateral prefrontal cortex controls the intraparietal sulcus located within the posterior parietal cortex, which is the main storage site of visuospatial working memory. See Raffa, J. Clin. Pharm. Ther. 2013, 38:265-268. Although the mechanisms responsible for chemo brain/fog are not known, it is thought that excessive release of pro-inflammatory cytokines, especially TNF-α, induced by the chemotherapy agents plays an important role in neural impairment.
Cognitive behavioral therapy has been shown to be somewhat effective for treating chemo brain/fog. To date, no drugs have been approved for treating this condition.
As mentioned above, chemo brain/fog is more prevalent when treating specific types of tumors. For example, patients undergoing treatment for glioblastoma often demonstrate symptoms of chemo brain/fog following radiotherapy and chemotherapy. Long term follow-up of these patients with respect to chemo brain/fog is not possible, as more than 80% of glioblastoma patients die within two years of diagnosis.
Typically, glioblastoma is treated by surgical excision of the greatest amount of tumor possible, followed by focal radiotherapy and adjuvant chemotherapy. Complete removal of the tumor is often not possible due to the tumor's infiltrating nature.
Although a number of chemotherapy agents have been used for treatment of glioblastoma, none have been able to reverse tumor size or volume, or increase survival rate significantly. Chemotherapeutic agents with approved indications for glioblastoma include temozolomide, bevacizumab, lomustine, and carmustine, to be given either orally or as injections. Other chemotherapy agents that have been used for treating glioblastoma without specific regulatory approval include topotecan, irinotecan, procarbazine, vincristine, and carboplatin. None of these agents actually decrease the size of tumors, but may temporarily halt progression. Notably, glioblastoma is highly aggressive, with a high rate of recurrence after treatment is completed.
Cannabinoids have long been administered orally for ameliorating nausea resulting from chemotherapy. Numerous in vitro studies have shown that cannabinoids can have an antiproliferative effect on glioma cells. Cannabinoids have also been shown to prevent the expansion of tumors in vivo animal tumor models. Yet, none of the animal studies showed the reversal or reduction in size of a tumor as a result of cannabinoid treatment. See a review by Rocha et al., J. Neurooncol. 2014, 116:11-24. One human study in which tetrahydrocannabinol (THC), i.e., a cannabinoid, was instilled into a glioblastoma tumor failed to demonstrate a clear-cut benefit from the THC. See Guzman et al., British J. of Cancer 2006, 95:197-203.
A single study combining cannabinoids and temozolomide showed growth suppression of two different glioma tumor xenografts in nude mice as compared to temozolomide or cannabinoids alone. See Torres et al., Mol. Cancer Ther. 2011, 10:90-103. Notably, the cannabinoids in this study were directly injected into the tumors.
The need exists to develop effective therapies for intractable cancers such as glioblastoma and for ameliorating the side-effects of radiotherapy and chemotherapy with respect to brain function.