Alfredo Navigante

Effect of topical morphine for mucositis‐associated pain following concomitant chemoradiotherapy for head and neck carcinoma

Oral mucositis is the dose‐limiting toxicity for patients receiving concurrent chemoradiotherapy regimens for tumors of the head and neck area. Currently, the management of established mucositis includes the use of topical anesthetics and systemic analgesics. Based on the clinical evidence of pain alleviation by topical morphine in patients with some inflammatory and painful conditions, a clinical study was undertaken to determine this effect on mucositis‐associated pain.

Effects of Eicosapentaenoic and Docosahexaenoic n-3 Fatty Acids From Fish Oil and Preferential Cox-2 Inhibition on Systemic Syndromes in Patients With Advanced Lung Cancer

Abstract Under the common denomination of Systemic Immune-Metabolic Syndrome (SIMS), we grouped many symptoms that share a similar pathophysiologic background. SIMS is the result of the dysfunctional interaction of tumor cells, stroma cells, and the immune system, leading to the release of cytokines and other systemic mediators such as eicosanoids. SIMS includes systemic syndromes such as paraneoplastic hemopathies, hypercalcemia, coagulopathies, fatigue, weakness, cachexia, chronic nausea, anorexia, and early satiety among others. Eicosapentaenoic and docosahexaenoic n-3 fatty acids from fish oil can help in the management of persistent chronic inflammatory states, but treatments compliance is generally poor. Preferentially, Cox-2 inhibition can create a favorable pattern of cytokines by decreasing the production of certain eicosanoids, although their role in SIMS is unknown. The aim of this study was to test the hypothesis that by modulating systemic inflammation through an eicosanoid-targeted approach, some of the symptoms of the SIMS could be controlled. We exclusively evaluated 12 patients for compliance. Patients were assigned 1 of the 4 treatment groups (15-, 12-, 9-, or 6-g dose, fractionated every 8 h). For patients assigned to 15 and 12 doses, the overall compliance was very poor and unsatisfactory for patients receiving the 9-g dose. The maximum tolerable dose was calculated to be around 2 capsules tid (6 g of fish oil per day). A second cohort of 22 patients with advanced lung cancer and SIMS were randomly assigned to receive either fish oil, 2 g tid, plus placebo capsules bid (n = 12) or fish oil, 2 g tid, plus celecoxib 200 mg bid (n = 10). All patients in both groups received oral food supplementation. After 6 wk of treatment, patients receiving fish oil + placebo or fish oil + celecoxib showed significantly more appetite, less fatigue, and lower C-reactive protein (C-RP) values than their respective baselines values (P < 0.02 for all the comparisons). Additionally, patients in the fish oil + celecoxib group also improved their body weight and muscle strength compared to baseline values (P < 0.02 for all the comparisons). Comparing both groups, patients receiving fish oil + celecoxib showed significantly lower C-RP levels (P = 0.005, t-test), higher muscle strength (P = 0.002, t-test) and body weight (P = 0.05, t-test) than patients receiving fish oil + placebo. The addition of celecoxib improved the control of the acute phase protein response, total body weight, and muscle strength. Additionally, the consistent nutritional support used in our patients could have helped to maximize the pharmacological effects of fish oil and/or celecoxib. This study shows that by modulating the eicosanoid metabolism using a combination of n-3 fatty acids and cyclooxygenase-2 inhibitor, some of the signs and symptoms associated with a SIMS could be ameliorated.

Potential utility of the peripheral analgesic properties of morphine in stomatitis-related pain: a pilot study.

To determine the potential clinical utility of peripheral opioid action using a clinical model of cancer treatment‐induced inflammation and pain that allowed for topical application of morphine in the damaged tissue (oral mucosa). This pilot study followed a two blocks design. Ten patients with painful oral mucositis were enrolled in the first block (dose–response relationship finding) and randomized in two groups to receive oral rinses with 15 ml of either 1‰ or 2‰ morphine solution. Twenty‐two patients were enrolled into the second block (efficacy and safety determination). Additionally, serum concentrations of morphine were measured in five representative patients. In the first block (n=10) a dose–response relationship for topical morphine was found. Rinses with 2‰‐morphine solution showed better pain relief (median 80%, range 70–80%) than those with 1‰ (median 60%, range 55–70%; P=0.0238). Therefore, subsequent patients enrolled for the second block (n=22) received oral rinses with 2‰‐morphine solution. In these patients the time to good (≥50%) or to complete (100%) pain relief was 28 (±12) min after the first mouthwash, and the duration of relief was on average 216 (±25) min. Twenty patients (90%) received the successive mouthwashes every 3 h and 10% of them every 2 h. The duration of severe pain at the moment of swallowing was 5.17 (±1.47) days. Only six patients needed supplementary analgesia, and the time elapsed before the first supplemental analgesic was 1.18 (±0.8) days. The duration of severe functional impairment was 1.52 (±1.31) days, thus allowing us to feed the patient by mouth with liquid‐food supplementation. During our experiment no systemically active detectable concentrations of morphine were found (GC–MS analysis). The most important side effect attributable to morphine mouthwashes was burning/itching sensation (very mild to mild intensity). Patients with painful chemoradiotherapy‐induced stomatitis could be alleviated using topical morphine mouthwashes.

Morphine Versus Midazolam as Upfront Therapy to Control Dyspnea Perception in Cancer Patients While Its Underlying Cause Is Sought or Treated

CONTEXT Cancer patients with dyspnea may be able to have the symptom pharmacologically controlled while its underlying cause is sought or treated. OBJECTIVES This study was done to determine whether symptom control can be achieved while the cause is evaluated or treated and whether morphine or midazolam would be more suitable in this setting. METHODS Sixty-three ambulatory patients with advanced cancer and dyspnea were clinically characterized and then randomized to receive either oral morphine or oral midazolam. A fast in-clinic drug titration scheme was implemented followed by an ambulatory five-day period in which the patients received the effective dose that relieved their dyspnea. During this period, the patients were followed daily while the underlying causes of dyspnea were sought out or treated. RESULTS Thirty-one patients with dyspnea entered the morphine arm and 32 patients entered the midazolam one. During the initial in-clinic phase, dyspnea was alleviated by at least 50% in all patients, whether they received morphine or midazolam. During the ambulatory phase, midazolam was superior to morphine in controlling baseline and breakthrough dyspnea. Both treatments were well tolerated, with mild somnolence being the most common adverse event. Neither morphine nor midazolam affected the outcome and/or implementation of additional diagnostic and/or therapeutic interventions. CONCLUSION Our results suggest that cancer-related dyspnea in ambulatory patients can be pharmacologically treated while its most probable specific cause is sought and/or while an etiology-oriented intervention is implemented. In this setting, midazolam appeared to be a better option than morphine for the immediate and long-term relief of the symptom.

Cardiovascular autonomic function in anthracycline-treated breast cancer patients.

SummaryPreclinical studies suggest that in addition to the well-known direct damage to the myocardium, anthracycline antineoplastic drugs exert toxic effects on the cardiovascular autonomic system as well. To investigate whether this phenomenon occurs in the clinic, we carried out noninvasive, widely used tests of cardiovascular autonomic physiology in 55 women with stage II or III breast cancer. In all, 31 were being treated with anthracycline-containing chemotherapy regimens, and 24 who were receiving CMF (cyclophosphamide, Methotrexate, and fluorouracil) served as controls. Of 279 tests conducted in anthracycline (A)-treated patients, 123 were abnormal, vs 54 of 216 tests carried out in 24 controls (44% vs 25%;P <0.005). Abnormal variations in heart rate on standing and in diastolic blood pressure during handgrip was found in 25 (81%) and 17 patients receiving A, vs 9 (37%;P <0.005) and 5 (21%;P <0.0001), respectively, in controls. The incidence of abnormal tests was significantly higher in A-treated patients >60 years of age (41%) vs 67%;P <0.05). Radionuclide ventriculography was carried out in 19 patients who showed abnormal tests of cardiovascular autonomic function after ⩾ 6 courses of a-containing chemotherapy; only 1 of them had abnormal cardiac contractility (global hypokinesia), suggesting that abnormal tests of cardiovascular autonomic function may occur in the absence of a detectable deterioration in left ventricular ejection fraction. A large number of factors may alter cardiovascular autonomic function in cancer patients, including age, radiation therapy to the chest, and multidrug treatment. Even after correcting for the most obvious of these, chemotherapy with anthracyclines is associated with a significantly higher percentage of abnormal tests for cardiovascular autonomic function. Although indirect and semi-quantitative, our results are compatible with the idea of A-induced cardiac autonomic dysfunction.

Inhibition of Tumor Progression and Paraneoplastic Syndrome Development in a Murine Lung Adenocarcinoma by Medroxyprogesterone Acetate and Indomethacin

Mice bearing LP07 lung adenocarcinoma present some characteristics similar to those shown in patients with several malignant diseases. LP07 tumor bearers develop paraneoplastic syndromes such as cachexia, leukocytosis, and hypercalcemia, partly due to a systemic inflammatory response. We analyzed some of the mechanisms involved in the effectiveness of the association of the appetite-stimulant medroxiprogesterone acetate (MPA) and the nonselective cyclooxigenase (COX) inhibitor indomethacin (INDO) in LP07 tumor bearing mice. INDO and INDO plus MPA treatments significantly inhibited tumor growth, which was not inhibited by MPA. The number of lung metastatic nodules was decreased with all treatments, being most effective INDO alone and INDO plus MPA. A significant decrease of plasmatic levels of the matrix metalloproteinases MMP-9 and MMP-2 correlated with these results. Paraneoplastic syndromes, leukocytosis, and cachexia were abolished by all treatments. We determined effects of the treatments on circulating cytokines shown to regulate cachexia and inflammation. Both treatments alone, and INDO plus MPA, reduced circulating IL-6 throughout tumor evolution. A pronounced increase in serum IL-1β levels was detected in untreated tumor bearers. These levels decreased and were closer to normal serum values when LP07 mice were treated with INDO plus MPA. The combination of a nonsteroidal antiinflammatory drug as INDO and MPA showed to be effective in inhibiting tumor and metastatic growth and diminishing paraneoplastic symptoms and SIR. A variety of specific molecules are implicated as playing a role in cancer-induced cachexia and hematological alterations.

CONVENTIONAL CHEST RADIOGRAPHY IN THE INITIAL ASSESSMENT OF ADULT CANCER PATIENTS WITH FEVER AND NEUTROPENIA

Infection continues to be a leading cause of morbidity and mortality in patients with neoplastic disorders who are treated with myelosuppressive chemotherapy.1 In a granulocytopenic patient, fever may be the first and only sign of infection.2 Other clinical signs and symptoms that often indicate an infectious process may be blunted or missing in the presence of neutropenia. Thus, treating all febrile neutropenic patients with broad-spectrum antibiotics has become the standard of care. Initial evaluation of such patients usually includes a complete history, physical examination, blood culture, urinalysis, urine culture, and chest radiography.3 Some investigators advocate routine chest radiography to detect signs and symptoms of pneumonia that may be absent in the neutropenic host despite the presence of a consolidate pneumonic process.2 Others report that the yield of abnormal findings on a diagnostic chest radiograph in febrile neutropenic children is low in the absence of clinical signs of pneumonia.4-6

Relationship between skeletal muscle function, body composition, and weight loss in patients with advanced pancreatic and gastrointestinal cancers

BackgroundMuscle function and its correlation with body composition and weight loss have not been studied deeply in pancreas and gastrointestinal cancers. This research aims to determine the skeletal muscle function and its relationship with body compartments, significant weight loss, and performance status (ECOG) 0-2 in a population with advanced digestive cancers.MethodsA cross-sectional study was designed to determine the relationship between muscular function, weight loss, and body composition. Patients with advanced digestive adenocarcinomas were evaluated. Muscle strength was examined by hand grip technique and body composition by bioimpedance analysis. Values of hemoglobin and albumin were measured in plasma.ResultsA sample of 81 patients was included. They had adenocarcinoma of stomach (n = 9), pancreas (n = 28), or colorectum (n = 44). With regard to skeletal muscle function, sub-maximal strength increased when percentage of weight loss decreased (p = 0.002) or when any of the following variables increased: skeletal muscle (p < 0.001), waist-hip ratio (p < 0.001), body surface area (p < 0.001), and body mass index (p = 0.001). According to multivariate analysis of these variables, only percentage of weight loss and skeletal muscle remained statistically significant. Endurance had no correlation with any of the variables. Higher weight loss was found in tumors of the upper tract (stomach and pancreas) in comparison with those of the lower tract (colorectal) (p = 0.005).ConclusionsIn advanced digestive cancer, sub-maximal strength correlated inversely with weight loss and directly with skeletal muscle such as in lung and head and neck cancers. On the other hand, endurance had no correlation with any of the variables considered.

Treatment (T) of T2 N0-1 larynx cancer (LC) with hyperfractionated radiotherapy (HRT) and cetuximab (C): Final report.

5570 Background: Local control rate for T2 LC with HRT alone at our Institution is about 61% and 75-80% with salvage surgery (S) The addition of C to HRT significantly enhanced the local control and survival rates compared to HRT alone with similar toxicity for locally advanced head and neck cancer. C was added to HRT for the treatment of T2N0-1 LC with the primary objective of enhancing local control rate and the secondary objective of extending the time free of laryngectomy (TFL) for T2 LC. METHODS Twenty patients (pts) (19M /1F) with T2 LC were enrolled: 10% had N1, 65% glottic and 35% supraglottic; median age: 65 years. T: HRT was delivered to a total dose of 76.8 Gy in 6.5 weeks. C was delivered at 400 mg/m2 one week before HRT and then 7 weekly doses of 250 mg/m2. Pretreatment evaluation consisted of CT scan and fiberlaryngoscopy (FLC). Toxicity assessment was done weekly. After T pts were evaluated monthly during the first year and then every three months with FLC. All pts signed an informed consent and the trial was approved by the institutional review board and the countrys medical authorities. RESULTS Compliance: 18/20 pts completed HRT (90%). Median HRT dose: 76.65 Gy. Median HRT duration: 7 weeks. 17/20 pts (85%) received 8 doses of C. Median T duration was 8 weeks. RESPONSE 16/20 pts (80%) achieved a complete response (CR), 3 pts (15%) had persistent disease and all had S and 1 pt had a sudden death not related to T and was not evaluable for response. Five pts with CR recurred at a median time of 10 months (m) (range 6.5-12.3) and had S. At present, with a median follow up of 35 m (r 6.7 - 42.8 m+), 16 pts are alive and disease free (80%) and 10 preserve their larynx (62.5%). Median TFL was 35 m (r 6.7-42.8 m+). Toxicity G3/4 (pts): stomatitis (6); acneiform rash (4); radiation dermatitis (5); dysphagia, diarrhea, vomiting, fatigue, skin infection and pneumonia: (1 each). Six pts were admitted to the hospital due to toxicity. Four pts died: 1 had a sudden death not related to C and 3 due to progressive disease. CONCLUSIONS 1) 85% of the pts received T according to protocol. 2) Local control, disease free survival and TFL rates were higher than the historical ones at our institution, 3) Larynx preservation rate was similar.