Fade Mahmoud

Established and potential therapeutic applications of cannabinoids in oncology

Abstract. Cannabis occurs naturally in the dried flowering or fruiting tops of the Cannabis sativa plant. Cannabis is most often consumed by smoking marihuana. Cannabinoids are the active compounds extracted from cannabis. Recently, there has been renewed interest in cannabinoids for medicinal purposes. The two proven indications for the use of the synthetic cannabinoid (dronabinol) are chemotherapy-induced nausea and vomiting and AIDS-related anorexia. Other possible effects that may prove beneficial in the oncology population include analgesia, antitumor effect, mood elevation, muscle relaxation, and relief of insomnia. Two types of cannabinoid receptors, CB1 and CB2, have been detected. CB1 receptors are expressed mainly in the central and peripheral nervous system. CB2 receptors are found in certain nonneuronal tissues, particularly in the immune cells. Recent discovery of both the cannabinoid receptors and endocannabinoids has opened a new era in research on the pharmaceutical applications of cannabinoids. The use of cannabinoids should be continued in the areas indicated, and further studies are needed to evaluate other potential uses in clinical oncology.

Assessment of nutritional status and prognosis in advanced cancer: interleukin-6, C-reactive protein, and the prognostic and inflammatory nutritional index.

Abstract. The Prognostic Inflammatory Nutritional Index (PINI) is a simple scoring system that has been used to evaluate nutritional status and prognosis in critically ill patients. The PINI has never been evaluated in advanced cancer. Fifty consecutive patients with advanced cancer, weight loss, and anorexia were studied. C-reactive protein (CRP), albumin, pre-albumin, interleukin-6 (IL-6), and alpha 1-acid glycoprotein (AAG) were evaluated. The individual values for AAG, CRP, and IL-6 were markedly elevated. In contrast to albumin and prealbumin, CRP levels were very high. The PINI was significantly elevated, and higher than reported in critically ill intensive care patients. Elevated IL-6 levels correlated with high PINI and CRP values. CRP, IL-6, and PINI should be considered in future research on nutritional status and prediction of prognosis in advanced cancer.

Assessment of nutritional status and fluid deficits in advanced cancer.

Malnutrition and cachexia are frequent manifestations of cancer and are major contributors to morbidity and mortality. The assessment of nutrition status in cancer patients can be easily accomplished. The first step is to record a complete medical history and to perform a thorough clinical examination to uncover signs of nutritional deficiency. Simple and inexpensive tests are available to assess the body composition, such as: anthropometric measurements, skinfold thickness, arm muscle circumference and area, and weight and body mass index (BMI). Biochemical measurements are also available, such as serum albumin, transferring, and prealbumin. Fluid deficit is divided into two categories based on pathophysiology (dehydration and volume depletion) and to three subtypes based on plasma sodium concentration (hyponatremic, hypernatremic, and isotonic). Dehydration (total water deficit, especially intracellular) is always hypernatremic, while volume depletion (intravascular water and sodium deficit) is either hyponatremic, hypernatremic, or isotonic. There are no clear clinical differences among the various categories, but a delay of capillary refill, tachycardia, and orthostatic hypotension is more common with volume depletion. Careful clinical assessment and laboratory tests, especially serum sodium, are the keystones for diagnosis and effective management. Bioelectrical impedance (BEI) is an easy way to assess both nutrition status and fluid deficits in advanced cancer and should be used more often than it currently is. This article reviews the subjective and objective methods of assessing fluid deficit and nutrition in advanced cancer.

Respiratory function during parenteral opioid titration for cancer pain

Background: Respiratory depression is the most feared opioid-related side-effect yet research on the topic is sparse. We evaluated changes in respiratory parameters during parenteral opioid titration for cancer pain to determine if opioid titration was associated with evidence of hypoventilation. The primary outcome measure was to measure changes in end-tidal CO2 (ET-CO2) during opioid titration to pain control. Methods: Subjects with severe cancer pain admitted for parenteral opioid titration for poorly controlled pain were eligible. Those who were oxygen dependent were excluded. ET-CO2, O2 saturation, respiratory rate (RR), and vital signs were monitored daily until pain control was achieved. Results: 30 patients completed the study of which 29 are reported. The mean ET-CO2 at initial evaluation was 33.39 ∓ 5.0 and 34.79 ∓ 5.7 mmHg at pain control (P =0.14, 95% CI -0.5 to 3.3). None had an ET-CO2 ≥50 mmHg. All maintained O2 saturation ≥92%. RR dropped transiently below 10/minute in two subjects. Conclusions: Parenteral opioid titration for relief of cancer pain was not associated with respiratory depression as demonstrated by significant changes in ET-CO2 or oxygen saturation in non-oxygen dependent cancer patients.

A Phase II Dose Titration Study of Thalidomide for Cancer-Associated Anorexia

CONTEXT Sixty-five percent of people with advanced cancer suffers from loss of appetite. Several inflammatory cytokines appear to cause appetite loss in animal models. Thalidomide is an immunomodulatory drug that has been associated with improved appetite in those with HIV infections and cancer. OBJECTIVES We completed a two-stage Phase II dose titration study of thalidomide, the primary purpose of which was to assess appetite response to thalidomide in cancer-associated anorexia. METHODS Individuals older than 18 years of age with active cancer, loss of appetite by numerical rating scale (NRS), life expectancy of at least four weeks, and Eastern Cooperative Oncology Group performance status of 0-3 were entered into the study. Pretreatment screening included medical history, neurologic examination, and symptoms by NRS and categorical scale (CAT). Patients received 50mg of thalidomide by mouth at bedtime for two weeks. Individuals who did not respond were dose escalated to 100mg at night for two weeks. Assessment of appetite, early satiety, fatigue, insomnia, night sweats, pain, and quality of life (QOL) occurred at two-week intervals. Toxicity also was assessed. The primary outcome was appetite response defined as a two-point reduction in the NRS or a one-point improvement in the CAT. RESULTS Thirty-five patients entered the study; 33 completed 14 days of therapy and were analyzed for efficacy and toxicity. Sixty-four percent who completed at least two weeks of thalidomide had improved appetite. The CAT scores for appetite, insomnia, and QOL improved significantly. The 95% confidence intervals did not overlap. Five participants dropped out because of toxicity: two before two weeks and three later. CONCLUSION Thalidomide reduced multiple symptoms commonly associated with cancer-related anorexia and improved QOL. Our findings confirmed and validated a previously published single-arm trial. A recent randomized trial demonstrated greater benefits when thalidomide is used combined with other agents to treat cancer-associated anorexia and cachexia. Thalidomide helped cancer-associated anorexia in most patients. It also improved insomnia and QOL in advanced cancer.

METHYLPHENIDATE SIDE EFFECTS IN ADVANCED CANCER: A RETROSPECTIVE ANALYSIS

Introduction: Methylphenidate (MP) is often recommended for symptom control in advanced cancer. Little is known about its side effects in frail adults. Objectives: To evaluate MP-associated symptoms or side effects (S/E). Methods: Data was collected from 2 published prospective cohort series and a phase 2 study of MP for symptom control in advanced cancer. All 3 reports had identical dosing schedules and symptom assessments. Initial MP doses were 10 mg/d (5 mg at 8 AM and at 12 noon) titrated up to a maximum of 30 mg/d. Depression, fatigue, and symptoms identified as possible MP S/E were evaluated for presence (prevalence) and for severity (using categorical scales) before MP (day 0) and on days 3, 5, and 7 thereafter. The categorical scale used was none, mild, moderate, and severe. Results: 62 patients were enrolled. Fifty completed 7 days of MP with a median age of 69 (range 30-90) years. Thirty-five received MP 10 mg/day. Most (96%) had improvement in depression and/or fatigue. Among the 62 patients, new symptom prevalence throughout the study was agitation (16%), insomnia (16%), dry mouth (15%), nausea (10%), tremors (6%), anorexia (5%), headache (3%), palpitations (2%), and vomiting (2%). Patients could have more than 1 symptom simultaneously. Seven (11%) withdrew due to MP S/E. Some symptoms present before MP showed significant improvement during MP therapy. Conclusions: (1) Treatment with MP (10-20 mg/d) in advanced cancer is well tolerated. (2) S/E symptoms with MP appeared to improve spontaneously despite continued MP therapy. (3) Depression and fatigue improved at doses lower than those recommended in other clinical conditions. (4) MP improved depression and fatigue, and some secondary symptoms associated with them. Methylphenidate (MP) appears safe when used in the treatment of depression and fatigue in advanced cancer.

A Pilot Study of Taste Changes Among Hospice Inpatients With Advanced Cancer

Identification of taste abnormalities can help understand difficulties in nutrition. We evaluated 15 hospice inpatients with advanced cancer for subjective taste changes. The majority had both subjective and objective taste changes. Most thought all food was tasteless followed by loss of sweet sensation and meat aversion. About half of the participants exhibited anorexia and weight loss with decreased energy intake. Both detection and recognition thresholds for these basic tastes were abnormal for the majority of participants. Reduced sensitivity for sweet and salt taste and altered perception for sour predominated in formal taste testing.

The intravenous to oral relative milligram potency ratio of morphine during chronic dosing in cancer pain

Morphine (M) is the opioid analgesic of choice for severe cancer pain. The IV to PO M equipotent switch ratio (CR) is controversial. We designed this prospective observational cohort to confirm the efficacy and safety of M IV to PO CR of 1:3. Consecutive cancer patients admitted to an inpatient palliative medicine unit were screened for inclusion. Pain was managed by palliative medicine specialists. They were blinded to the patient data collected, and the calculated CR. The switch was considered successful if the following criteria were met: (1) Pain adequately controlled: pain rated as none or mild (2) Number of RD less than 4 (for non incident pain) per 24 hours (3) No limiting side effects. We used Day 3 ATC M dose for CR calculations. The major outcome measures were the IV : PO CR ratio, morphine doses (mg/day), pain severity, number of PRN doses, and day 1 and day 3side effects. Descriptive statistics were used to report mean, median, standard deviation and range of different variables. Two hundred and fifty six consecutive admissions were screened, and 106 were eligible for the study. Sixty two underwent a successful M route switch and were included in this analysis. A ratio of 1:3 was safely implemented over a wide M dose range. About 80% were successfully switched with a calculated CR of 1:3. 20% required an oral M dose adjustment after route switch either to better pain control or reduce side effects with a resultant higher (e.g. 1:4) or lower (e.g. 1:2) calculated potency ratios respectively. A potency ratio of 1:3 was safe as evaluated by common M side-effects, the dose also easy to calculate. The 1: 3 M IV to PO relative milligram potency ratio appears correct and practical for most patients over a wide M dose range.