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Running Head: Phytocannabinoid Therapy in Metastatic Breast Cancer
Author(s) and Affiliations:
AN EFFECTIVE ANTIPROLIF...
Breast Cancer and Cannabinoid Therapy Case Report 2 
present in the plants of genus ​Cannabis Sativa​and ​Cannabis Indica....
Breast Cancer and Cannabinoid Therapy Case Report 3 
The patient had a radiolabeled PET image interpreted in November reve...
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  1. 1.     Running Head: Phytocannabinoid Therapy in Metastatic Breast Cancer Author(s) and Affiliations: AN EFFECTIVE ANTIPROLIFERATIVE AND ANTITUMOR THERAPY FOR RECURRENT METASTATIC BREAST CANCER: DAILY HIGH DOSE CANNABINOID ADMINISTRATION UTILIZING A STANDARDIZED CANNABIS DERIVED DRUG SUBSTANCE IN LIPID-BASED SUSPENSION __________________________________________________________________________________________________________________________________________________________________ _   A CASE REPORT Introduction: Invasion and metastasis of aggressive breast cancer cells is the final and fatal step during cancer progres- sion, and is the least understood genetically. We experienced a delay in disease progression in a patient with a history of aggressive metastatic breast cancer administered high daily doses Δ-9-tetrahydrocannabinol and cannabidiol as standardized lipid-based suspension, a treatment which was initiated upon confirmation of their third recurrence of neoplastic malignancy by radiolabeled PET imaging. During the period between PET scans, the patient did not undergo any targeted treatment and was instead maintained on high daily doses of Δ-9-tetrahydrocannabinol and cannabidiol as a standardized lipid-based suspension of cannabis derived drug extract. General Considerations and Rationale: Cannabinoids and the endocannabinoid system has been implicated both ​in vivo​and ​in vitro​in the numerous pathways mediating the effects of pharmacotherapy in the reduction of breast cancer cell proliferation, invasion, and metastasis (Cafarel et. al 2010, Braun & Harbeck, 2001, Mo et. al 2004). The exogenous administration of cannabinoids has demonstrated significant promise in the symptomatic treatment of breast cancer via their well documented analgesic, antiemetic and anxiolytic effects. Novel research has shown that ​in vivo​this is coupled with antiproliferative (McAllister et. al, 2007) and antitumor (Ligresti et. al 2006) effects. Research proposes that that the phytocannabinoid Cannabidiol (“CBD”) “represents the first nontoxic exogenous agent that can significantly decrease Id-1 expression in metastatic breast cancer cells leading to the down-regulation of tumor aggressiveness” (McAllister et. al, 2007). ​In vivo, ​in both the orthotopic and i.v. models of breast cancer, CBD was also highly effective at targeting metastatic foci ≥2 mm, leading researchers to hypothesize that CBD could be effective at inhibiting the growth of secondary tumors even after their initial establishment in lung tissue In contrast to the moderate doses of CBD needed to inhibit metastatic progression, higher doses of CBD have been required to inhibit tumor growth after subcutaneous injection into the flank of athymic mice (Massi et al., 2004; Torres et al., 2011). Another phytocannabinoid, THC functions completely independently of CBD by acting with a primary mechanism for antitumor activity of autophagy pathway upregulation caused by its binding affinity as an agonist of both the CB1 and CB2 receptors. Via direct activation of the endocannabinoid receptors CB1 and CB2, the phytocannabinoid delta-9-tetrahydrocannabinol (THC) has been demonstrated to inhibit the progression of multiple aggressive cancer by inhibiting tumor growth through resultant autophagy and apoptosis (Velasco et al., 2012). Whole-plant cannabis extracts contain at least ten cannabinoid compounds, all of which are bioactive. Although the two most well-researched cannabinoids are CBD and THC, the effects of other compounds present in the raw plant and BDS-derived medicaments exhibit synergy first proposed as the “entourage effect” (McPartland & Russo, 2001) of the various isoprenoids, sesquiterpenoids and phytocannabinoids  
  2. 2. Breast Cancer and Cannabinoid Therapy Case Report 2  present in the plants of genus ​Cannabis Sativa​and ​Cannabis Indica.​This has been enforced by attempts to recreate the anecdotal evidence of cannabis’ success with novel synthetic compounds targeting the same mechanism. ​In vivo, ​the resorcinol derivative and novel cannabinoid analogue O-1663 produced regression of established metastatic foci proposed as the “result of efficiently targeting cannabinoid antitumor pathways that have been associated with the activity of both CBD and THC”; researchers noted “the combined administration of CBD and THC produced a similar magnitude of anti-metastatic activity when compared to O-1663 alone” and, additionally, that “O-1663, however, is significantly less potent than THC at targeting CB1 receptors and demonstrated limited activity in ​in vivo​assays”. While novel synthetic cannabinoid analogues have either not been tested in humans or have been shown to have low therapeutic indexes, increased incidences of adverse drug reactions and intolerable side effect profiles while failing to mimic the outcomes achieved using BDS derived medicaments (i.e. JWH-018), Cannabis has demonstrated to be a safe and effective means of treatment with a gestalt therapeutic potential - that is to say the results produced by the sum are greater than any individual compound or combination thereof. There is currently a general lack of faith in the medical community to the value of whole plant cannabis in the treatment of malignancies beyond its well-established use and efficacy for the symptomatic relief of hyperemesis and anorexia during chemotherapy. It is the intention of this report to encourage interest in controlled large scale research regarding the promise of phytocannabinoids, combinations thereof and the apparently synergistic compounds found in the plant ​Cannabis Sativa​in oncological pharmacotherapy. Presented is an objectively valid and empirical report of a patient’s progress, as evidenced by radioimaging and clinical assessments, while under the care of an oncologist and pharmacist providing a treatment plan and dosing regimen. The medicaments utilized were pharmaceutically prepared botanical drug substance (BDS) containing a specified ratio of cannabinoids and cannabinoid concentration [a botanical drug extract (BDE) in lipid suspension; prepared as homogenized raw plant material obtained from one specific and consistent chemovar of ​Cannabis Sativa ​subjected to supercritical carbon dioxide extraction and filtration of plant material and waxy ballast, heated into a lipid based suspension and packaged into individual oral syringes for dosing accuracy] confirmed by independent laboratory GC/MS analysis. We encourage the reader’s consideration of these controls as justification for the differentiation and increased validity of this report. Case Presentation (this is from memory and I need more information to complete) A 49 year old female presented to Compassionate Care Center, a medicinal cannabis dispensary, during September of 2014 on the reccomendation and certification of her oncologist. Her chief complaint was neuropathic pain status post a chemotherapeutic regimen paclitaxel/trastuzumab. She also complained of anxiety and insomnia and was seeking relief by adding cannabis as a medication. During intake she denied allergies to any medication, and was currently being maintained on gabapentin 2400mg PO qD, alprazolam 0.5mg PO b.i.d. Her past medical history was significant for aggressive breast cancer with metastases of uncertain nature. She was initially diagnosed with an HER2-positive carcinoma of the left breast in 2010, which spread to the right breast. Her operative history showed a two invasive surgical attempts at completely removing this malignant neoplasm. She had underwent four courses of chemotherapy (herceptin/taxol) and radiation. Her operative history shows that she had underwent a lumpectomy followed by a bilateral mastectomy.       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 2 of 8  
  3. 3. Breast Cancer and Cannabinoid Therapy Case Report 3  The patient had a radiolabeled PET image interpreted in November revealing two small nodules on the right upper lobe of the lung or potentially the intercostal lymph nodes as well as a slightly larger swelling of the right cervical lymph node, confirmed by biopsy to be a regional recurrence. The lung nodules were initially of uncertain nature but have been revealed as a distant recurrance of malignancy and measured to 3cm and 2cm adenocarcinomas of the right upper lobe of the lung. When her outine PET imaging/biopsy confirmed a recurrence, her treatment plan was modified from focus on symptomatic relief to maximize the purported antitumor and antiproliferative effects of cannabis, more specifically of CBD and THC, respectively. She was titrated to a high dose of THC at a 1:1 ratio due to the numerous uncertainties in her case and the recent research revealing CBD did not inhibit the antitumor effect of THC as it does the psychoactive effect. The treating oncologist did not believe that it was worth it to undergo another round of chemotherapy/radiation/surgery. The patient’s most recent PET interpretation has shown the adenocarcinomas have grown, although slightly and certainly significantly less than what would be expected in a similar case not receiving chemotherapy/radiation, and the nodule of the right cervical lymph node is no longer present on imaging. With this in mind, the oncologist has recommended the patient to continue with cannabinoid treatment to attempt to avoid chemotherapy, radiation or surgery as long as possible. There are key changes needed to be made to her treatment plan, which would currently bring her past her monthly limit. This case report has been amended for presentation to the Connecticut Department of Consumer Protection Medical Advisory Board. Clinical Findings: Timeline. September 2010: Diagnosis of HER2+ Breast Cancer. Patient to undergo first round of chemotherapy, radiation and bilateral mastectomy. September 2014: Intake Assessment completed at Compassionate Care Center of Connecticut. Longest consecutive period of remission in the past four years has been three months total. October 2014: Patient complaints of neuropathic pain due to previous taxane treatment seem to subside with cannabinoid treatment. Treatment high in THC, in the form of vaporized raw material is used to focus on analgesia, anxiolysis and antiproliferation. November 2014: PET Imaging:​No Metastic Activity. Two (2) neoplasms of uncertain behavior, 1cm and 2cm in size, noted in the upper right lobe of the lung. CBD Incorporated into Treatment Plan at a ratio of 1:1 CBD:THC with intent of delaying metastases and preventing proliferation of existing neoplasms. December 2014: ROA Issues of Vaporization make Precise Dose recording difficult January 2015: Edibles Released, treatment plan setup as it currently stands. February 2015: Treatment plan continued, Patient response to CBD as an antagonist to the psychoactive effects of THC subjectively confirmed. March 2015: PET Imaging: ​No metastases, marking the 13th month of clinical remission, the longest in the patient’s history. In the opinion of the treating oncologist, cannabinoid treatment has “delayed the progression of the cancer” and the findings regarding proliferation are significantly less than what would be typical of the patient’s case receiving no chemotherapy or radiation. The lack of further metastatic       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 3 of 8  
  4. 4. Breast Cancer and Cannabinoid Therapy Case Report 4  activity is also an outcome reasonable attributed to the patient’s treatment with cannabinoids, considering the numerous metastases since her initial diagnosis. April 2015: Patient is tolerating treatment plan well and has no complaints. May 2015:​PET Imaging: ​Metastatic Activity to the Liver confirmed. Patient to begin 12 week chemotherapeutic regimen of Kadcyla (ado-trastuzumab emtansine). Paitent reports complaints of nausea and headache in between doses at intervals of 5 hours. [Report Amended to be made Public]. Diagnostic Focus and Assessment. The diagnostic focus of this case was primarily to rule out the proliferation of existing malignancies and to monitor and assess for any previously unnoticed neoplastic activity. Assessment performed using radiolabeled PET imaging on regular intervals to monitor disease activity and to assess the response to therapy. It has been established between patient and physician that the risk to the patient resulting from a lack of this knowledge presents as much greater than the risk from exposure to test radiation, the PET scans were not performed specifically to assess the success of cannabinoid therapy but were coincidental. Therapeutic Focus and Assessment: The therapeutic focus of this case was, initially, to ensure the patient was comfortable and able to cope with both the physical and psychological consequences of her past medical history. When she was diagnosed with having a recurrance of neoplastic activity, the focus became treating her as aggressively as possible. There were initial limitations to treatment based on available medicaments. Attempts to ensure 1:1 THC:CBD ratio was affected by product availability and daily dosage was affected by prohibitive costs of necessary dosing, which was covered by Compassionate Care Center’s Need Program. The first product she was maintained on after her diagnosis of recurrance was Theraplant 14023x, which was a BDE containing roughly 43% CBD and 48% THC. She was considered cannabinoid naive at the time in relation to the necessary dosages required to prevent metastatic growth, and was given a titration schedule to allow her to medicate utilizing vaporization of roughly one quarter gram concentrate per day. Through careful observation it has been established that the patient was a stronger responder to the oral route in terms of side effects and could withstand higher doses without unwanted psychoactivity when administered THC. It is possible the first pass metabolism of THC into 11-OH-THC played a role in this. Her treatment plan was switched to Curaleaf T20 Coconut Oil (switched to Connecticut Pharmaceutical Solutions Concentrated Oil to minimize confounding variables presented by amount of lipid based solvent for BDS) with decarboxylated Fioraleve A kief. During the ramp up period, a dose twice that of her normal morning dose was taken. When she came into the dispensary, it was evident that the psychoactivity of the THC had caused a state of intoxication. She was provided with a vapor cartridge containing only CBD to assess whether the ability of CBD, as an inverse agonist of the CB2 receptor, would reduce the psychoactive and intoxicating effect of the high dose THC. Her subjective       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 4 of 8  
  5. 5. Breast Cancer and Cannabinoid Therapy Case Report 5  report indicated that the result was almost immediately sobering. This was made note of, in case her PET scan were to show no metastases but proliferation of existing neoplasms, so our treatment would include an equal increase in CBD dosage to offset the necessary increase in THC dosage and grant the patient the highest potential quality of life while still treating her cancer. With careful consideration, the patient has been maintained on a dosage of 3.0mg/kg/day of CBD and 3.0mg/kg/day of THC PO, spread out qid, until the receipt of her most recent radioimaging report referenced above. Patient complains of nausea and vomiting, headaches and tiredness in between dosages and is considering ceasing treatment due to the perception that this is a “withdrawal”. The possibility of a withdrawal syndrome from cannabis displaying these symptoms is unlikely, rather it is likely that the attenuation of chemotherapeutic side effects achieved while under the effect of the cannabinoids wears off every 5 hours and becomes once again noticeable. It is considered and the patient has been advised to consider a more regular dosing interval to assess if keeping symptoms at bay by maintaining consistent plasma levels is possible. Justifications in Proceeding: In a study conducted by Organix, Inc., a contract research and synthetic laboratory who received an SBIR grant to design compounds to inhibit breast cancer by supressing ld-1 expression, awarded by the National Cancer Institute, it was found that in eight mice with animal models of aggressive breast cancer, those receiving five times the amount of cannabidiol than the lower dose group had double the amount of survivors without metastases. There were no incidences of a complete lack of metastases in the control group. They go on to quote “the ability of CBD to inhibit primary tumor growth at the doses evaluated is limited” (Murase et. al 2011). The differences in the potency of CBD for targeting processes involved in cancer cell growth and survival versus invasion and metastasis may explain why the cannabinoid is less efficient at inhibiting primary tumor growth. For example, CBD has been shown to be at least four times more potent at inhibiting cancer cell invasion in comparison to proliferation/viability , while THC has been shown to activate autophagy pathways via mixed CB1/CB2 agonism - the binding affinity and intrinsic activity elicited by THC’s binding is subject to positve allosteric modulation by coadministration of CBD, although selective agonists of the CB2 receptor have not been demonstrated to activate the same pathways (Massi et al., 2004; McAllister et al., 2007; McAllister et al., 2011; Vaccani et al., 2005). The patient’s overall therapeutic assessment reveals current doses are well-tolerated and successful in preventing metastases, but not succeeding absolutely in preventing the proliferation of her lung carcinoma. All those involved in the treatment of the patient have agreed that, based on her previous clinical response and the currently available ​in vivo ​research, it will best practice to provide her with a precipitous increase in daily THC dosage with a mimic of increase in CBD to combat the increased psychoactive effect during the titration period as well as continue the presumed inhibition of genetically modulated metastases of the primary tumor. Follow-up and Outcomes: The patient will continue to be seen by the dispensary at least once per week, physician and dispensary relations will be continued and maintained on a regular basis as is the case currently. A case discussion with professionals within cannabinoid research and/or expertise in the cannabis oncological treatment       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 5 of 8  
  6. 6. Breast Cancer and Cannabinoid Therapy Case Report 6  is encouraged, given the lack of current available research and comprehensive analytical results of products available. Discussion. Discussion Pending.  Informed Consent. The authors ensure that informed consent regarding the sharing of her current case has been obtained from the patient both verbally and in writing. The Patient has provided informed consent to have her case report shared with anyone by the authors.       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 6 of 8  
  7. 7. Breast Cancer and Cannabinoid Therapy Case Report 7  Citations and References Caffarel, MM, Andradas, C, Mira, E, Perez-Gomez, E, Cerutti, C, Moreno-Bueno, G, et al (2010) Cannabinoids reduce ErbB2-driven breast cancer progression through Akt inhibition. Mol Cancer. 9: 196. Carracedo, A, Gironella, M, Lorente, M, Garcia, S, Guzman, M, Velasco, G, et al (2006a)Cannabinoids induce apoptosis of pancreatic tumor cells via endoplasmic reticulum stress-related genes. Cancer Res 66(13): 6748-6755. Carracedo, A, Lorente, M, Egia, A, Blazquez, C, Garcia, S, Giroux, V, et al (2006b) The stress regulated protein p8 mediates cannabinoid-induced apoptosis of tumor cells.Cancer Cell 9(4): 301-312. Ligresti, A, Moriello, AS, Starowicz, K, Matias, I, Pisanti, S, De Petrocellis, L, et al (2006) Antitumor activity of plant cannabinoids with emphasis on the effect of cannabidiol on human breast carcinoma. J Pharmacol Exp Ther 318(3): 1375-1387. Marcu, JP, Christian, RT, Lau, D, Zielinski, AJ, Horowitz, MP, Lee, J, et al (2010) Cannabidiol enhances the inhibitory effects of delta9-tetrahydrocannabinol on human glioblas- toma cell proliferation and survival. Mol Cancer Ther 9(1): 180-189. Massi, P, Vaccani, A, Bianchessi, S, Costa, B, Macchi, P, Parolaro, D (2006) The nonpsychoactive cannabidiol triggers caspase activation and oxidative stress in human glioma cells. Cell Mol Life Sci 63(17): 2057-2066. Massi, P, Vaccani, A, Ceruti, S, Colombo, A, Abbracchio, MP, Parolaro, D (2004) Antitumor effects of cannabidiol, a nonpsychoactive cannabinoid, on human glioma cell lines. Ponz-Sarvise, M, Nguewa, PA, Pajares, MJ, Agorreta, J, Lozano, MD, Redrado, M, et al (2011) Inhibitor of differentiation-1 as a novel prognostic factor in NSCLC patients with adenocarcinoma histology and its potential contribution to therapy resistance. Clin Cancer Res 17(12): 4155-4166. Ramer, R, Bublitz, K, Freimuth, N, Merkord, J, Rohde, H, Haustein, M, et al (2011) Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1. FASEB J. Salazar, M, Carracedo, A, Salanueva, IJ, Hernandez-Tiedra, S, Lorente, M, Egia, A, et al (2009) Cannabinoid action in-duces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 119(5): 1359-1372. Showalter, VM, Compton, DR, Martin, BR, Abood, ME (1996) Evaluation of binding in a transfected cell line expressing a peripheral cannabinoid receptor (CB2): Identification of cannabinoid receptor subtype selective ligands. The Journal of Pharmacology and Experimental Therapeutics 278: 989-999. Shrivastava, A, Kuzontkoski, PM, Groopman, JE, Prasad, A (2011) Cannabidiol induces programmed cell death in breast cancer cells by coordi- nating the cross-talk between apoptosis and autophagy.       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 7 of 8  
  8. 8. Breast Cancer and Cannabinoid Therapy Case Report 8  J Pharmacol Exp Ther 308(3): 838-845. McAllister, SD, Murase, R, Christian, RT, Lau, D, Zielinski, AJ, Allison, J, et al (2011) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129(1): 37-47. McAllister, SD, Christian, RT, Horowitz, MP, Garcia, A, Desprez, PY (2007) Cannabidiol as a novel inhibitor of Id-1 gene expression in aggressive breast cancer cells. Mol McAllister, SD, Murase, R, Christian, RT, Lau, D, Zielinski, AJ, Allison, J, et al (2011) Pathways mediating the effects of cannabidiol on the reduction of breast cancer cell proliferation, invasion, and metastasis. Breast Cancer Res Treat 129(1): 37-47. Salazar, M, Carracedo, A, Salanueva, IJ, Hernandez-Tiedra, S, Lorente, M, Egia, A, et al (2009) Cannabinoid action induces autophagy-mediated cell death through stimulation of ER stress in human glioma cells. J Clin Invest. 119(5): 1359-1372. Mol Cancer Ther 10(7): 1161-1172. Swarbrick, A, Roy, E, Allen, T, Bishop, JM (2008) Id1 cooperates with oncogenic Ras to induce metastatic mammary carcinoma by subversion of the cellular senescence response. Proc Natl Acad Sci U S A 105(14): 5402-5407. Vaccani, A, Massi, P, Colombo, A, Rubino, T, Parolaro, D (2005) Cannabidiol inhibits human glioma cell migration through a cannabinoid receptor-independent mechanism. Br J Pharmacol 144(8): 1032-1036. Velasco, G, Sanchez, C, Guzman, M (2012) Towards the use of cannabinoids as antitumour agents. Nat Rev Cancer. Wiley, JL, Beletskaya, ID, Ng, EW, Dai, Z, Crocker, PJ, Mahadevan, A, et al (2002) Resorcinol derivatives: a novel template for the development of cannabinoid CB(1)/CB(2) and CB(2)- selective agonists. J Pharmacol Exp Ther 301(2): 679-689.       __________________________________________________________________________________________________________________________________________________________________    4 Garella Road • Bethel, CT 06801 • USA • Telephone: 203.909.6869 • E-mail: ​projects@ccc-ct.com​• Web: www.ccc-ct.com • Protected Health Information has been Redacted • File Code: DBRD-CCC0412 • Last Updated: 04/12/2015 ∙​Page 8 of 8  

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