*see next pages for the list of Committees and Boards Members

PAIN IN CANCER AN OUTCOME RESEARCH PROJECT EVALUATING THE EPIDEMIOLOGY AND THE EFFECTS OF DIFFERENT PHARMACOLOGICAL STRATEGIES TO TREAT PAIN IN CANCER PATIENTS The Protocol Writing Committee, on behalf of the * Cancer Pain Outcome Research Study Group Coordinating Center Dept. of Oncology Istituto di Ricerche Farmacologiche Mario Negri Via Eritrea 62, 20157 Milan, Italy apolone@marionegri.it *see next pages for the list of Committees and Boards Members 1

Advisory Board Livia Pomodoro, Vittorio Ventafridda, Umberto Veronesi Steering Committe Amadori Dino, Angelo Bianco, Apolone Giovanni, Arcuri Edoardo, Bertetto Oscar, Carbone Floriani Loredana, Aaron Goldirsch, Corli Oscar, Costa Alberto, De Conno Franco, Galanti Andrea, Inglese Stefano, La Bianca Roberto, Mosconi Paola, Mercadante Sebastiano, Nicosia Francesco, Tamburini Marcello, Zucco Furio Writing Protocol Committee Apolone Giovanni, Bertetto Oscar, Augusto Caraceni, Oscar Corli, De Conno Franco, La Bianca Roberto, Maltoni Marco, Nicora Mariaflavia, Torri Valter Coordinating Center Giovanni Apolone (Principal Investigator), Valter Torri (Statistician), Paola Mosconi (Patient-Reported Outcomes), Luca Clivio (Informatics), Cinzia Colombo (Research Assistant), Giulio Isola (Liaisons with Sponsors), Gianna Costa (Secretarial Support) 2

Protocol Writing Committee Giovanni Apolone Oscar Bertetto Augusto Caraceni Oscar Corli Franco De Conno Roberto La Bianca Marco Maltoni Mariaflavia Nicora Valter Torri Laboratorio di Ricerca Traslazionale e di Outcome, Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy Oncologia Medica, Ospedale Molinette, C.so Bramante 88, 10126, Torino, Italy Unità Operativa di Palliazione e Cure Palliative, Istituto Nazionale dei Tumori, Via Venezian 1, 20123 Milano, Italy Unità Operativa Cure Palliative, Istituti Clinici di Perfezionamento, P.O. Vittore Buzzi, Via Castelvetro 32, 20154 Milano Unità Operativa di Riabilitazione e Cure Palliative, Istituto Nazionale dei Tumori, Via Venezian 1, 20123 Milano, Italy Oncologia Medica, Ospedali Riuniti di Bergamo, Largo Barozzi 1, 24100 Bergamo Ospedale Pierantoni, Via Forlanini 34, 47100, Forlì Direzione Medica, Grunenthal-Formenti, Via Correggio 43, 20149, Milano Laboratorio di Ricerca Clinica in Oncologia, Dipartimento di Oncologia, Istituto di Ricerche Farmacologiche Mario Negri, Via Eritrea 62, 20157 Milano, Italy 3

INTRODUCTION AND PROJECT RATIONALE Pain afflicts most cancer patients, mainly in the advanced and metastatic phase of the disease (1). Recent reviews of published literature suggest that the prevalence of pain in advanced cancer is about 70 % with ample variations according to the cancer type and disease stage (2). Despite the existence of published and well-known guidelines for cancer pain management recommended by the World Health Organization (WHO) and effective treatments are available for 70-90% of cases (3), under treatment is well documented and large proportions of cancer patients (reaching in some evaluations 40%) remain intentionally under-treated (4), for several reasons, often conceptualized in terms of barriers related to health care provider, patient, family, institution and society (5). The most frequent cause of under-treatment is usually considered misconceptions about opioids. The general picture that derives from the analysis of experiences carried out in international settings does apply to Italy also, with some peculiarities: a) Opioids consumptions is ranked among the lowest in Europe until 2000, with some improvements at least in terms DDD/100000 people after the introduction of new opiods in the list of reimbursable drugs (transdermal fentanyl and morphine syrup) in 2000. A recent evaluation of the market sales indicates that all the increase in the use of opioids (now 45 DDD/100000) should be attributed to the prescription of transdermal fentanyl. The fact that the sales and prescriptions of the other opioids available in Italy for cancer patients (morphine and buprenorphine) remained constant, suggests that the increase should be attributed to the prescription of transdermal fentanyl as a first option in patients who, according the current recommendations, should have been treated with oral morphine, thus suggesting that some of these prescriptions were not appropriate, at least according to the WHO recommendations (6). b) Until January 2005, when a new bill was introduced at national level, no WHO-step II analgesic products were available in the list of reimbursable drugs in most of Italian regions, as well as some strong WHO-step III opioids, making it difficult for physicians the appropriate prescription of drugs and creating variability in drugs utilization across different Italian regions. c) A non appropriate use of FANS (mostly new and costly products) prescribed to patients requiring WHO-step II drugs can be suspected (7). d) Evidence about pain prevalence, drug utilization and quality of analgesic care are scanty being most obsolete, or from small samples, or from studies with methodological problems (8). In particular, it is not available in medical literature any large parallel randomized controlled trial conducted in advanced cancer patients suffering from severe pain (step 3 in the WHO s pain ladder), comparing any alternative opioids to oral morphine. In addition, at least in Italy, the epidemiology of cancer pain and the yield of its treatments (effectiveness) is not known. 4

THE PROJECT ON CANCER PAIN A multidisciplinary Advisory Board of experts in the field of cancer and pain treatments from Industry, Scientific Societies and Patients Associations was convened by the Mario Negri Institute on November 2003 to discuss the quality of pain management in cancer patients in Italy and, eventually, to recommend possible ameliorative educational and research strategies. Member of the Boards highlighted the lack of and the need for new empirical evidence about the epidemiology and the effectiveness of available therapeutic strategies, and called for a prospective program of research aimed at making available to treating physicians, patients and families valid information about pain management in cancer. Two main lines of activities were identified as necessary: information and education activities addressed to physicians, care givers and patients/citizens, and prospective data collection to document patterns of care and outcomes. Operationally, some working groups met several times during 2004, identified a selected sample of about 100 centers treating cancer patients with advanced/metastatic disease and pain that could be potentially eligible for a prospective study, and planned 3 types of activities to be implemented during the following 3 years (2005-2007): a) information and education: a prototipe of educational course for professionals (physicians and nurses) has been assembled and tested on a sample of participants (through a residential course approved by the Italian Committee for Medical Continuing Education with 26 and 33 credits for physicians and nurses, respectively); a critical appraisal of information available in the web (Internet) was also carried out with the preparation and publication of a meta-site that facilitates the use of selected (internet) resources for people interested and/or involved in issues related to cancer pain (www.paincare.it); b) drug utilization and appropriateness: an evaluation of the volume and quality (appropriateness) of prescription of analgesic drugs in a large administrative data base in collaboration with a local Italian Health Authority has been started to test the feasibility of the approach in a wider context (regional), c) a prospective, multicenter, nationwide effectiveness study to test the effect of different and alternatives analgesic strategies (such as oral morphine, fentanyl and buprenorphine patches, etc) on patient-reported-outcomes. In the context of the effectiveness study, in addition to a prospective and standardized data collection, a randomized controlled trial will be eventually implemented, involving large number of oncologists, palliativists and general practitioners to test the efficacy of different analgesic strategies. The objective of the comprehensive, observational, cohort prospective multi-center study will be to collect in a standardised way information about the volume, case-mix, treatments and outcomes of patients seen in a given study period at participating centers in order to describe the epidemiology, pattern of care and outcome of a large and representative cohort of cancer patients, suffering from moderate to severe pain. 5

The ongoing activities In addition to the prospective data collection that is described in details in a companion document, according to the recommendations of the Project Boards and to the preliminary results, 2 other types of activities are planned: 1) a population-based multi-modal intervention to improve the management of cancer pain patients; it will be carried out at regional level, in collaboration with the local Health Authority. The multi-modal intervention will be implemented in a intervention-region and results will be compared using the before-after approach with data from a control-region. The interventions will include media coverage, public lectures, workshops, distribution of information documents, educational and training courses. The evaluation of the effect of the interventions at population level will be carried out by using quantitative pre-planned indicators (total amount of WHO step-iii opioids, difference of prevalence prescriptions in cancer patients, proportion of different opioids, etc). Examples are present in the international literature (9-11). 2) the development, test and implementation of a series of informative and educational tools, such as training module, courses, dedicated web-sites etc, addressed to professionals and citizens in order to increase the knowledge and awareness about effective analgesic strategies and change (improve) the quality of cancer patients management. These activities will be carried out in collaboration with other initiatives at present ongoing in Italy, either in the medical or lay field (see for example: www.partecipasalute.it). The Project, fully sponsored by a pharmaceutical company (Grunenthal-Formenti, Italy) with a unrestricted educational grant, will be carried out from 2005 to 2007, in Italy, under the supervision of qualified scientific and ethics Boards. The Coordinating Center of the Project is at present located at the Mario Negri Institute (www.marionegri.it). According to the policy of the Mario Negri Institute that launched the initiative in 2003 and to the recent recommendations by the International Committee of medical Journal Editors (12,13), details of the Project and first results were published (8): further details are available on the Project web-site http://crc.marionegri.it/cancerpain or by Authors upon request. The launch of the Project is planned for May 4, 2005. 6

REFERENCES 1. Cherny N. The management of cancer pain. Cancer J Clin 2000; 50: 70-116, 2. Hearn J and Higginson IJ. Cancer pain epidemiology: a systematic review. In: Cancer Pain, Assessment and Management. Edited by Bruera ED & Portenoy RK, Cambridge University Press, 2003. 3. WHO Cancer Pain Relief: with a Guide to Opioid Availability, 2 nd Edition. WHO, Geneva, 1996. WHO, Geneva 1990 4. Cohen MZ, Easley MK, Ellis C, Hughes B. et al for the JCAHO. Cancer Pain Management and the JCAHO s Pain Standards. An Institutional Challenge. J Pain Symptom Manage 2003; 25: 519-527, 5. Ripamonti C, De Conno F, Blumbhuber H, et al. Morphine for relief of cancer pain. Lancet 1996; 347: 1262-1263 6. Chinellato A, Terrazzani G, Walley T, Giusti P. Opioids on Italy: is marketing more powerful than the law? Lancet 2003; 362: 78 7. Mannino S. (ASL Cremona, Italy): Personal Communication, 2004 8. Apolone G, Mosconi P, Colombo P and Tamburini M. Il dolore nel paziente con cancro: un progetto di ricerca. Ricerca & Pratica 2004, 20: 137-143 9. Gome-Batiste X, Porta J, Tuca A, et al. the WHO demonstration project on palliative care implementation in catalonia: results at 10 years (1991-2001). J Pain Symptom Manage 2002; 24: 239-244 10. Weisman DE, Dahl JL. Update on the cancer pain role model education program. J Pain Symptom Manage 1995; 10: 292-297. J Pain Symptom Manage 1995; 10:292-297 11.Hofman W, Munzinger H, Horstkotte E, Greiser E. A population based evaluation of an intervention to improve advanced stage cancer pain management. J Pain Symptom Manage 2004; 28 342-350. 12. De Angelis C, Drazen JM, Frizelle FA, Haug C, et al. Clinical trials registration. A statement from the International Committee of Medical Journal Editors. New Eng J Med 2004;351 1250-1251. 13. Drummond R. Trial registration. A great idea switch from ignored to irresistible. JAMA 2004, 292.1359-1362. 7