WO2009071405A1 - Acétate de mégestrol pour réduire la mortalité et/ou améliorer la qualité de vie chez les patients atteints d'un cancer - Google Patents

Acétate de mégestrol pour réduire la mortalité et/ou améliorer la qualité de vie chez les patients atteints d'un cancer Download PDF

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Publication number
WO2009071405A1
WO2009071405A1 PCT/EP2008/064886 EP2008064886W WO2009071405A1 WO 2009071405 A1 WO2009071405 A1 WO 2009071405A1 EP 2008064886 W EP2008064886 W EP 2008064886W WO 2009071405 A1 WO2009071405 A1 WO 2009071405A1
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Prior art keywords
megestrol acetate
acceptable salt
pharmaceutically acceptable
megace
prevention
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PCT/EP2008/064886
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English (en)
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Stefan Anker
Jochen Springer
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Charité - Universitätsmedizin Berlin
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Publication of WO2009071405A1 publication Critical patent/WO2009071405A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/06—Anabolic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • Megestrol acetate for reducing the mortality and/or improving quality of life in cancer patients
  • the present invention relates to the treatment of patients suffering from cachexia as a comorbidity of cancer using megestrol acetate (MA), in particular using megestrol acetate oral suspension (MegaceTM), more precisely using the advanced nanoparticulate formulation of megestrol acetate oral suspension having improved solubility and bioavailability (MegaceTM ES).
  • MA megestrol acetate
  • MegaceTM megestrol acetate oral suspension
  • the present invention further relates to the prevention and reduction of cardiovascular problems in cancer patients.
  • Cachexia is a very common co-morbidity in cancer patients which drastically reduces quality of life and survival. In an estimated 22% of cancer patients the exact cause of death is cachexia.
  • Megestrol acetate is a synthetically produced derivative of the naturally occurring steroid hormone progesterone.
  • Megestrol acetate is a white, crystalline substance having the chemical name 17- ⁇ -acetoxy ⁇ 6-methylpregna-4,6-diene-3,20-dione (C 24 H 32 O 4 ) and a molecular weight of 384.5.
  • Megestrol acetate has the following formula:
  • Megestrol acetate is primarily excreted via the kidneys; however, the mechanisms that affect bio-availability are not completely elucidated.
  • Megestrol acetate is the main agent of the pharmaceutical product Megace® from Bristol-Myers Squibb Company which either has the formulation as an orally active solution or as a tablet (see also EP 0 338 404).
  • megestrol acetate is used as an appetite stimulant that acts by a still unknown mechanism. Initially, megestrol acetate was used for the inhibition of malignant post-menopausal hormone dependent rumours of the breast [Gregory EJ, Cohen SC.
  • megestrol acetate has been used for several years successfully in patients having mammary carcinoma or other malignant tumours.
  • US 6,268,356 describes an oral pharmaceutical composition in the form of a stable flocculated suspension in water comprising: megestrol acetate; at least one compound selected from the group consisting of polyethylene glycol, propylene glycol, glycerol, and sorbitol; and a surfactant, wherein polysorbate and polyethylene glycol are not simultaneously present.
  • Novel MegaceTM essentially is the same medication as the commonly used megestrol acetate, but having a micro-crystalline structure which significantly improves resorption. Both oral suspensions contain the same active agent; however, MegaceTM ES has a different formulation whereby resorption is significantly improved.
  • Par Pharmaceutical, Inc. manufactures this advanced formulation, as disclosed in the PCT application WO 03/086354 Al. The improvement is caused by a nanoparticulate composition comprising megestrol acetate and preferably at least one surface stabilizer associated with the surface of the drug.
  • nanoparticulate megestrol particles have an effective average particle size of less than about 2000 nm.
  • This advanced formulation in a preferred embodiment thereof, utilises NanoCrystalTM Dispersion technology to improve the bioavailablity of the drug as compared to alternative, non-particulate formulations of the product as disclosed in WO 04/050059.
  • the product is disclosed as a low viscosity liquid dosage form comprising particles of an active agent, a surface stabilizer, and a pharmaceutically acceptable excipient, carrier, or a combination thereof, wherein the active agent particles have an effective average particle size of less than about 2 microns and the dosage form has a viscosity of less than about 2000 mPa.s at a shear rate of 0.1 (1/s).
  • NanoCrystalTM Dispersion is a trademark of Elan Corporation, pic, Dublin, Ireland. Megace is a registered trademark of Bristol-Myers Squibb Company licensed to Par Pharmaceutical, Inc.
  • MegaceTM ES With MegaceTM ES, this reduction in bioavailability is minimized in the fasted state, resulting in improved bioavailability in patients who have not eaten. MegaceTM ES 625 mg/5 ml and megestrol acetate oral suspension 800 mg/20 ml are bioequivalent in a fed state.
  • the reference Drugs R D. 2007;S (6);403-6 also describes megestrol acetate MegaceTM ES 625mg/5ml) oral suspension for the treatment of anorexia, cachexia or an unexplained, significant weight loss in patients with AIDS.
  • megestrol acetate MegaceTM ES 625mg/5ml oral suspension for the treatment of anorexia, cachexia or an unexplained, significant weight loss in patients with AIDS.
  • a more rapid onset of action, more convenient dosing and a lower dosing regimen compared with the original marketed formulation of megestrol acetate oral suspension is described.
  • Patients are administered a teaspoon (5ml) of the new NCD formulation once daily, compared with a daily 20ml dosage cup of the original formulation.
  • the megestrol acetate NCD formulation represents a line-extension of Par's megestrol acetate oral suspension (40mg/ml or 800mg/20ml), which has been marketed for anorexia, cachexia or an unexplained, significant weight loss in patients with AIDS since July 2001.
  • US 7,101,576 to Elan Pharma International describes MegaceTM ES 625 mg/5ml oral suspension.
  • the patent includes claims relating to the advanced formulation of megestrol acetate, specifically, to the reduction of the food effect seen with previous formulations of megestrol acetate.
  • Subject of the present invention is megestrol acetate or a pharmaceutically acceptable salt thereof for reducing the mortality and/or for improving of quality in life in cancer patients. Most importantly megestrol acetate or a pharmaceutically acceptable salt thereof is administered to a patient in need thereof for reducing the mortality in cancer patients. Thus, megestrol acetate or a pharmaceutically acceptable salt thereof improves survival.
  • megestrol acetate or a pharmaceutically acceptable salt is administered for prevention and/or reduction of cardiovascular problems in cancer patients.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is administered for prevention and/or reduction of cardiovascular problems caused by chemotherapy or caused by the tumour itself.
  • megestrol acetate or a pharmaceutically acceptable salt thereof is used for prevention and/or reduction of cardiovascular problems in cancer patients before the patient exhibits symptoms of cardiovascular disease. These symptoms are shortness of breath, fatigue, weakness (independent of loss of appetite, independent of presence of weight loss).
  • a cardiac effect may be as follows: prevention of weakening of cardiac function, particularly prevention of ventricular dilatation or prevention of reduction in left ventricular ejection fraction - and reversal of cardiac dysfunction if necessary
  • megestrol acetate is used in micro-crystalline structure (MegaceTMES). This means that the patients group is preferentially not selected from patients exhibiting chronic heart insufficiency, hypertension or other illness.
  • the preferred use of Megestrol acetate or a pharmaceutically acceptable salt thereof is protection of the heart and prevention of cardiovascular disease.
  • megestrol acetate or a pharmaceutically acceptable salt thereof is used for the prevention of cardiovascular problems in cancer patients.
  • megestrol acetate in its micro-crystalline structure is preferred. Every chemotherapy regime used today is cardiotoxic to various degrees and caries the risk of acute and/or chronic cardiovascular problems that can eventually lead to the development of cardiomyopathy. Shortness of breath, a hallmark symptom of chronic heart failure, is also a very common phenomenon in cancer.
  • megestrol acetate, preferred MegaceTMES The preventive therapy with megestrol acetate, preferred MegaceTMES, during chemotherapy will reduce acute cardiovascular problems due to cardiotoxicity of the chemotherapy, reduce the onset of shortness of breath and chronic cardiac remodeling and cardiomyopathy. Overall, megestrol acetate, preferred MegaceTMES, improves heart function in cancer patients and subsequently reduces the mortality. Experimental data are shown in Example 1.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof for the prevention and reduction of tumour-cachexia associated mortality.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is preferentially used for the prevention and reduction of tumour-cachexia associated mortality in cancer patients before the patient exhibits signs of cachexia.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is administered at a BMI > 22 kg/m , preferentially > 24 kg/m 2 and before the BMI reaches a BMI ⁇ 18.5 kg/m 2 .
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is administered before a significant weight loss has occurred.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is used in a cancer which is selected from cancers of the liver, pancreas, colon, prostate, lung, kidney, brain, thyroid, blood, bone, skin, pancreas, ovaries, breast, uterus, testicles, eyes, gall bladder, oesophagus, skin, and stomach.
  • Megace® useable according to the present invention can be provided in any number of forms suitable for administration. Suitable pharmaceutically acceptable forms comprise salts or pre or pro-forms of Megace® .
  • rnegestrol acetate in its micro-crystalline structure is preferred (MegaceTMES).
  • Examples of pharmaceutically acceptable salts comprise without limitation non toxic inorganic or organic salts such as acetate derived from acetic acid, aconitate derived from aconitic acid, ascorbate derived from ascorbic acid, benzoate derived from benzoic acid, cinnamate derived from cinnamic acid, citrate derived from citric acid, embonate derived from embonic acid, enantate derived from heptanoic acid, formiate derived from formic acid, fumarate derived from fumaric acid, glutamate derived from glutamic acid, glycolate derived from glycolic acid, chloride derived from hydrochloric acid, bromide derived from hydrobromic acid, lactate derived from lactic acid, maleate derived from maleic acid, malonate derived from malonic acid, mandelate derived from mandelic acid, methanesulfonate derived from methanesulfonic acid, naphtaIine-2 -sulfon
  • Megace® or a pharmaceutically acceptable salt thereof can be bound to microcarriers or nanoparticles in parenterals like, for example, to finely dispersed particles based on poly(meth)acrylates, polylactates, polyglycolates, polyamino acids or polyether urethanes.
  • Parenteral formulations can also be modified as depot preparations, e.g. based on the "multiple unit principle", if Megace® or a pharmaceutically acceptable salt thereof is introduced in finely dispersed, dispersed and suspended form, respectively, or as a suspension of crystals in the medicament or based on the "single unit principle” if Megace® or a pharmaceutically acceptable salt thereof is enclosed in a formulation, e.g.
  • implants or depot medicaments in single unit and multiple unit formulations often consist out of so called biodegradable polymers like e.g. polyesters of lactic and glycolic acid, polyether urethanes, polyamino acids, poly(meth)acrylates or polysaccharides.
  • Adjuvants and carriers added during the production of the medicaments usable according to the present invention formulated as parenterals are preferably aqua sterilisata (sterilised water), pH value influencing substances like, e.g. organic or inorganic acids or bases as well as salts thereof, buffering substances for adjusting pH values, substances for isotonisation like e.g. sodium chloride, sodium hydrogen carbonate, glucose and fructose, tensides and surfactants, respectively, and emulsif ⁇ ers like, e.g. partial esters of fatty acids of polyoxyethylene sorbitans (for example, Tween ® ) or, e.g.
  • aqua sterilisata sterilised water
  • pH value influencing substances like, e.g. organic or inorganic acids or bases as well as salts thereof
  • buffering substances for adjusting pH values e.g. sodium chloride, sodium hydrogen carbonate, glucose and fructose, tensides and surfactants, respectively
  • fatty acid esters of p ⁇ lyoxyethylenes for example, Cremophor ®
  • fatty oils like, e.g. peanut oil, soybean oil or castor oil
  • synthetic esters of fatty acids like, e.g. ethyl oleate, isopropyl myristate and neutral oil (for example, Miglyol ® ) as well as polymeric adjuvants like, e.g. gelatine, dextran, polyvinylpyrrolidone, additives which increase the solubility of organic solvents like, e.g. propylene glycol, etlianol, N,N-dimethylacetamide, propylene glycol or complex forming substances like, e.g.
  • organic solvents e.g. propylene glycol, etlianol, N,N-dimethylacetamide, propylene glycol or complex forming substances like, e.g.
  • citrate and urea preservatives like, e.g. benzoic acid hydroxypropyl ester and methyl ester, benzyl alcohol, antioxidants like e.g. sodium sulfite and stabilisers like e.g. EDTA.
  • preservatives like, e.g. benzoic acid hydroxypropyl ester and methyl ester, benzyl alcohol, antioxidants like e.g. sodium sulfite and stabilisers like e.g. EDTA.
  • Megace® is not included in a liquid drug formulation in its basic form it can be employed within the parenterals in the form of its acid addition salt solvates.
  • a further important systemic application formulation is peroral administration in the form of tablets, hard or soft gelatine capsules, coated tablets, powders, pellets, microcapsules, compressed oblongs, granulates, cachets, lozenges, chewing gum or sachets.
  • These solid perorally administered formulations can also be formulated as retard and depot systems, respectively.
  • Comprised therein are medicaments with a content of one or more micronised active agents, diffusion and erosion forms based on matrix, e.g. by using fats, waxy or polymeric substances or so called reservoir systems.
  • the medicament is formulated to release Megace® over a prolonged period of time retarding agents and agents for the controlled release, respectively, can be added like film or matrix forming substances, for example, ethylcellulose, hydroxypropyl methyl cellulose, poly(meth)acrylate derivatives, (e.g. Eurdragit ® ), hydroxypropyl-methylcellulose phtlialate both in organic solutions and in the form of aqueous dispersions.
  • bioadhesive preparations should also be mentioned wherein an extended dwelling time in the body is caused by the intimate contact with the mucous membranes of the body.
  • An example of a bioadhesive polymer is, e.g. the group of Carbomere ® .
  • the medicament formulation can be coated, for example, with mixtures of films, substances, compounds or compositions soluble in gastric juice and resistant to gastric juice, respectively.
  • the same purpose of affecting the release in different sections of the gastro-intestinal tract can also be reached with appropriately produced coated tablets with a core, wherein the coating releases the active ingredient in gastric juice rapidly and the core releases the active ingredient in the environment of the small intestine.
  • the aim of a controlled release in different sections of the gastro-intestinal tract can also be achieved by multiple coated tablets.
  • Mixtures of pellets with differentially releasable active agent can be filled into, for example, hard gelatine capsules.
  • a further adjuvant employed in the production of compressed formulations like e.g. tablets, hard and soft gelatine capsules as well as coated tablets and granules are, for example, counter glue agents, lubricating agents and separating agents, dispersion agents like e.g. flame dispersion silicon dioxide, disintegrants like, e.g. various types of starch, PVP, cellulose, ester as granulating or retarding agent like, e.g. waxy and/or polymeric substances based on Eudragit ® , cellulose or Cremophor ® .
  • medicaments formulated for peroral administration can comprise antioxidants, sweetening agents like, e.g. saccharose, xylite or mannite, taste correcting agents, ftavorants, preservatives, colouring agents, buffering agents, direct compression excipients, microcrystalline cellulose, starch, hydrolysed starch (e.g. Celutab ® ), lactose, polyethylene glycol, polyvinylpyrrolidone, dicalcium phosphate, lubricants, fillers like, e.g. lactose or starch, binders in the form of lactose, types of starch like e.g. wheat or corn and rice starch, respectively, derivatives of cellulose like, e.g.
  • stearate like e.g. magnesium stearate, calcium stearate, talkum, siliconised talkum, stearic acid, cetyl alcohol or hydrogenated fats etc.
  • Megace® or a therapeutically acceptable salt thereof can also be formulated as an oral therapeutic system, in particular based on osmotic principles like, e.g. GIT (gastro-intestinal therapeutic system) or OROS (oral osmotic system).
  • GIT gastro-intestinal therapeutic system
  • OROS oral osmotic system
  • Effervescent tablets or tabs are also among compressed formulations, which can be perorally administered and which are both rapidly dissolvable or suspendable in water and are rapidly drinkable instant drug formulations.
  • megestrol acetate or a pharmaceutically acceptable salt thereof is applied orally.
  • Perorally administrated formulations also include solutions e.g. drops, juices and suspension which can be produced according to methods known in the art and which can comprise - beside the already mentioned adjuvants and additives for the increase of the stability - preservatives and if desired flavouring agents for easier ingestion and colouring agents for better distinction as well as antioxidants and/or vitamins and sweetening agents like sugars or artificial sweeteners.
  • This also applies to dried juices which are prepared with water prior to use.
  • an ingestible liquid formulation can also comprise an ion exchange resin.
  • the Megace® is selected from common Megace® and/or novel Megace®, which is MegaceTMES.
  • Megestrol acetate or a pharmaceutically acceptable salt thereof is selected from common Megace® and/or novel Megace® ES (i.e. microcristalline megace).
  • Yet another preferred embodiment of the present invention is characterised in that the medicament is applied orally.
  • Megace® or a pharmaceutical acceptable salt thereof is applied in a dosage of between 30 mg/d and 2000 mg/d, preferably between 100 mg/d and 1600 mg/d, most preferred 300 to 800 mg/d.
  • the active ingredient can be administered in one or several doses per day; alternatively the active ingredient can be administered in larger time intervals.
  • Megace® or a pharmaceutical acceptable salt thereof is applied in a dosage of between 4 and 15 mg/kg/d.
  • the active ingredient can be administered in one or several doses per day; alternatively the active ingredient can be administered in larger time intervals.
  • Fig. 1 Results related to heart function, in particular LV ejection fraction when MegaceTMES or a placebo is administered.
  • Fig. 3 Results related to heart function, in particular LV endsystolic volume, when MegaceTMES or a placebo is administered.
  • Fig. 4 Results related to survival when MegaceTMES and a placebo is administered.
  • Fig. 5 Results related to body weight and body composition when MegaceTMES and a placebo is administered.
  • Fig. 6 Results related to loss of lean body mass when MegaceTMES and a placebo is administered.
  • Fig. 7 Results related to loss of fat mass when MegaceTMES and a placebo is administered.
  • Fig. 8 Results related to foot intake when MegaceTMES and a placebo is administered Fig. 9: Results related to locomotor activity when MegaceTMES and a placebo is administered
  • Heart function high resolution echocardiography was assessed before inoculation and on day 11 of the 14-day protocol.
  • Weight and body composition were assessed on day 0 and day 14 after sacrifice (without tumour)
  • the hepatoma Yoshida AH-130 cells (10 s ) were inoculated into approx. 20Og male Wistar rats. Alternatively animals received saline injection only (sham). The animals were housed in groups of three. The day after inoculation animals were randomized into various groups as described in the methods. The rats then received treatment with either placebo or MegaceES® at 100mg/kg/d (this formulation of megesterol acetate is a nano-crystalline formulation) over a period maximal 16 days.
  • the primary endpoints of the study included assessment of body weight, body composition and survival. Organ weight was assessed at the end of the study (or after death) as a secondary endpoint.
  • Heart function/LV ejection fraction Results related to heart function, in particular LV ejection fraction, are shown in Fig. 1.
  • Treatment with MegaceTMES significantly improved left ventricular ejection fraction (73.09 ⁇ 6.68% vs 49.65 ⁇ 4.87%, p 0.01) on day 11.
  • Results related to heart function, in particular LV fractional shortening, are shown in Fig. 2.
  • Treatment with MegaceTMES significantly improved left ventricular fractional shortening (45.30 ⁇ 5.53% vs 26.54 ⁇ 3.63, p 0.0075) on day 11.
  • LVEDV left ventricular enddiastolic volume
  • LVSV left ventricular stroke volume
  • LVEDD left ventricular enddiastolic diameter
  • LVESD left ventricular endsystolic diameter.
  • Table 3 shows LVmass, LV PWT dia, LV PWT sys, Septum dia, Septum sys, and Aorta diameter after treatment with Megace or Placebo.
  • LV left ventricular
  • PWT posterior wall thickness
  • dia diastole
  • sys systole
  • the ascites hepatoma Yoshida AH-130 cells (10 8 ) were inoculated into approx. 20Og male Wistar rats.
  • animals received saline injection only (sham).
  • the animals were housed in groups of three. The day after inoculation animals were randomized into various groups as described in the methods. The rats then received treatment with either placebo or
  • Tumor inoculation (10 s cell, AH-130 hepatoma) was performed in approx. 20Og male Wistar rats. Alternatively, animals were injected with saline only. One day after tumor inoculation, the animals will start to receive treatment with MegaceTMES or placebo per gavage.
  • Body weight and body composition Results related to body weight and body composition are shown in Fig. 5.
  • Food intake and spontaneous activity are generally accepted as a means of assessing the quality of life of an animal.
  • EDL extentensor digitalis longus
  • Soleus are skeletal muscles

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Abstract

La présente invention concerne le traitement de patients souffrant de cachexie comme comorbidité d'un cancer à l'aide d'acétate de mégestrol (MA), en particulier à l'aide d'une suspension d'acétate de mégestrol par voie orale (MegaceTM), plus précisément à l'aide de la préparation nanoparticulaire de pointe de la suspension par voie orale d'acétate de mégestrol présentant une solubilité et une biodisponibilité améliorées (MegaceTM ES). La présente invention concerne en outre la prévention et la réduction des problèmes cardiovasculaires chez les patients atteints d'un cancer.
PCT/EP2008/064886 2007-12-04 2008-11-03 Acétate de mégestrol pour réduire la mortalité et/ou améliorer la qualité de vie chez les patients atteints d'un cancer WO2009071405A1 (fr)

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EP07122279.8 2007-12-04
EP07122279 2007-12-04

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WO2009071405A1 true WO2009071405A1 (fr) 2009-06-11

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1669074A1 (fr) * 2004-12-01 2006-06-14 Par Pharmaceuticals, Inc. Utilisation de l'acetate de megestrol pour améliorer la fonction cardiaque et pour traiter les insuffisances cardiaques

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1669074A1 (fr) * 2004-12-01 2006-06-14 Par Pharmaceuticals, Inc. Utilisation de l'acetate de megestrol pour améliorer la fonction cardiaque et pour traiter les insuffisances cardiaques

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; 2003, TOMÍSKA M ET AL: "Palliative treatment of cancer anorexia with oral suspension of megestrol acetate.", XP002517569, Database accession no. NLM12937858 *
DATABASE MEDLINE [online] US NATIONAL LIBRARY OF MEDICINE (NLM), BETHESDA, MD, US; November 1993 (1993-11-01), KORNBLITH A B ET AL: "Effect of megestrol acetate on quality of life in a dose-response trial in women with advanced breast cancer. The Cancer and Leukemia Group B.", XP002517573, Database accession no. NLM8229122 *
FEMIA ROBERT A ET AL: "The science of megestrol acetate delivery: potential to improve outcomes in cachexia.", BIODRUGS : CLINICAL IMMUNOTHERAPEUTICS, BIOPHARMACEUTICALS AND GENE THERAPY 2005, vol. 19, no. 3, 2005, pages 179 - 187, XP009111555, ISSN: 1173-8804 *
JOURNAL OF CLINICAL ONCOLOGY : OFFICIAL JOURNAL OF THE AMERICAN SOCIETY OF CLINICAL ONCOLOGY NOV 1993, vol. 11, no. 11, November 1993 (1993-11-01), pages 2081 - 2089, ISSN: 0732-183X *
NEOPLASMA 2003, vol. 50, no. 3, 2003, pages 227 - 233, ISSN: 0028-2685 *
SALACZ MICHAEL E: "Megestrol acetate for cancer anorexia/cachexia #100.", JOURNAL OF PALLIATIVE MEDICINE JUN 2006, vol. 9, no. 3, June 2006 (2006-06-01), pages 803 - 804, XP008102108, ISSN: 1096-6218 *
SKARLOS D V ET AL: "Megestrol acetate in cancer patients with anorexia and weight loss. A Hellenic Co-operative Oncology Group (HeCOG) study.", ACTA ONCOLOGICA (STOCKHOLM, SWEDEN) 1993, vol. 32, no. 1, 1993, pages 37 - 41, XP008102133, ISSN: 0284-186X *
SWISS GROUP FOR CLINICAL CANCER RESEARCH (SAKK) THURLIMANN B ET AL: "Formestane Versus Megestrol Acetate in Postmenopausal Breast Cancer Patients After Failure of Tamoxifen: a Phase III Prospective Randomised Cross Over Trial of Second-line Hormonal Treatment (SAKK 2090)", EUROPEAN JOURNAL OF CANCER, PERGAMON PRESS, OXFORD, GB, vol. 33, no. 7, 1 June 1997 (1997-06-01), pages 1017 - 1024, XP004282796, ISSN: 0959-8049 *
YEH SHING-SHING ET AL: "Megestrol acetate in cachexia and anorexia.", INTERNATIONAL JOURNAL OF NANOMEDICINE 2006, vol. 1, no. 4, 2006, pages 411 - 416, XP008102106, ISSN: 1176-9114 *

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