PERUGIA INTERNATIONAL CANCER CONFERENCE VII MULTINATIONAL ASSOCIATION FOR SUPPORTIVE CARE IN CANCER CONSENSUS CONFERENCE ON ANTIEMETIC THERAPY PERUGIA, March 29-31, 2004 Organizing and Overall Meeting Chairs: Richard J. Gralla, MD Fausto Roila, MD Maurizio Tonato, MD
ANTIEMETIC GUIDELINE CONSENSUS - Official Process Subscribed to by 9 International Oncology Groups - International: MASCC North America: -U.S. - Canada ASCO, ONS, NCCN CCO Europe: Africa: Australia: ESMO, EONS SASMO COSA
PARTICIPANTS IN THE PERUGIA ANTIEMETIC GUIDELINE PROCESS: 2004 Matti Aapro, MD Enzo Ballatori, PhD Sussanne Borjeson, RN, PhD Rebecca Clark-Snow, RN, BA, OCN Albano Del Favero, MD Lawrence Einhorn, MD Petra Feyer, MD Richard Gralla, MD Steven Grunberg, MD Jørn Herrstedt, MD Paul Hesketh, MD Rolf Kaiser, MD, PhD Jim Koeller, RPh, MS Mark Kris, MD Ernesto Maranzano, MD Alexander Molassiatis, RN, PhD Ian Olver, MD, PhD David Osoba, MD Bernardo Rapoport, MD Cynthia Rittenberg, RN, MN, AOCN Fausto Roila, MD Maurizio Tonato, MD David Warr, MD
PERUGIA 2004 ANTIEMETIC GUIDELINES - The Process - 1) Each committee worked on its area of concentration prior to the Perugia Meeting. At Perugia, each committee chair presented the findings of that committee to the entire group, and included the suggested rating of the level of evidence / confidence of the guideline (ASCO and MASCC criteria). 2) Group discussion and consensus voting then followed each presentation. What were the criteria for consensus? As per a prior consensus meeting*: 75% or greater agreement among the panelists was required to change a guideline. To change an existing guideline: Compelling evidence was required based on well-conducted trials, generally with a comparator felt to be consistent with guidelines and representing best practice. * Columbia Consensus antiemetic meeting 2001
PERUGIA 2004 ANTIEMETIC GUIDELINES - Committees and their Areas - I. Emetic classification of antineoplastic agents II. Acute emesis: Highly emetic chemotherapy III. Delayed emesis: Highly emetic chemotherapy IV. Acute emesis: Moderately emetic chemotherapy V. Delayed emesis: Moderately emetic chemotherapy
PERUGIA 2004 ANTIEMETIC GUIDELINES - Committees and their Areas - VI. VII. Emesis induced by minimal or low emetic risk chemotherapy Additional Issues: Refractory emesis, rescue antiemetic therapy,multiple-day chemotherapy, high-dose chemotherapy VIII. Anticipatory emesis IX. Radiotherapy-induced emesis, Antiemetics in children receiving chemotherapy X. Future Considerations: Research Directions, Study Design, Economic Considerations
ANTIEMETIC RESEARCH - General Methodology: High and Moderate Risk - In Comparison Trials: The emetic stimulus should be as similar as possible High Risk Cisplatin vs Cisplatin in similar dose and schedule Dacarbazine vs Dacarbazine in similar dose and schedule Moderate Risk AC (EC, FAC) vs AC preferred over vs all moderate risk agents Stratify (and analyze) according to known risk groups (especially: gender, age, alcohol history) - Consider validating an algorithm of patient risk factors which could be used in research and practice - The same would be of value in RT
ANTIEMETIC RESEARCH - General Methodology: Delayed Emesis (Com III & V) - In addition to controlling the emetic stimulus, the antiemetic regimen for Acute Emesis should be the same for all patients Guideline recommended regimens should be the basis for comparison studies Trials should be designed to account for the patient s response to the acute emesis regimen - Complete control vs < Complete control - The methodology needs to assist in accounting for the carry-over effect of the acute emesis regimen
ANTIEMETIC RESEARCH - Persistently Under-Addressed Areas - Low risk settings a lack of prospective trials (Com VI) - Not difficult to conduct - Optimal, economically sound regimens - Proven approaches when first-line is inadequate Pediatrics (Com IX) - Studies continue to be few in number and low in quality - Surprising given the high percentage of patients on studies Radiation Therapy (Com IX) - Specific trials continue to be necessary - Newer agents with potentially longer durations of action are particularly good study candidates - Validate risk models Antiemetic Side Effects - Do agents affecting NK 1 receptors influence blood counts?
ANTIEMETIC RESEARCH - Emerging Area of Focus: Controlling Nausea - Methodology Issues: - Do patients have the same definition of Nausea that is implied in antiemetic trials? Is nausea confused with: - Anorexia? - Fatigue? - Pyrosis? - Is this a reason why trials show poorer nausea scores? - Nausea should be a primary endpoint in many clinical trials Efficacy Issues: - This control lags behind the control of vomiting - Are other therapeutic interventions needed? Dex dose? - There is a high correlation between the control of vomiting and nausea but is another mechanism involved? - Clearly a cause of great distress and a major need
ANTIEMETIC RESEARCH - Basic Science Studies and Correlations - Investigation of new receptor families Opioid Receptors Cannabinoid Receptors Other Receptor Candidates Duration of action studies with PET Genetic / Molecular studies Gene Arrays Pharmacogenetic studies
Aprepitant Blocks Brain NK 1 Receptors in Humans Binding of PET tracer to NK 1 receptors prior to aprepitant dosing Blockade of NK 1 receptors after aprepitant dosing Low Tracer Binding Brain NK 1 Receptor Occupancy (%) 100 90 80 70 60 50 40 30 20 10 0 Mean (± SD) Plasma Trough Concentrations of the Aprepitant 3-Day Regimen 0 1 10 100 1000 10000 Aprepitant Plasma Trough Concentration (ng/ml) High Hargreaves R. J Clin Psychiatry 2002; 63( Suppl.1): 18-24.
ANTIEMETIC RESEARCH - Other Methodology Considerations - Prospective evaluation of emetic potential of: (Com I) Newer Chemotherapy Agents: oxaliplatin, pemetrexed Novel Agents: gefitinib, erlotinib, erbitux Long-term treatment studies (Com I) Oral chemotherapy RT Specific methodology in: Multiple cycle studies Rescue trials Prognostic Factor Investigation: Are these the same when NK 1 antagonists are used? Gender / hormonal effects including large data base reviews Correlation of psychologic factors / expectations with outcomes
Addressing AC * as a Separate Group Groups II - V Although not part of the official recommendations for acute emesis in MEC, the panel agreed that it should be recognized that women receiving a combination of anthracycline plus cyclophosphamide represent a situation with a particularly great risk of nausea and vomiting. Additionally, it appears that the risk of nausea and vomiting increases during multiple cycles. * AC = Anthracycline + Cyclophosphamide, includes regimens such as: AC, EC, FAC, and FEC. A = doxorubicin, E = epirubicin, C = cyclophosphamide, F = 5-FU.
ANTIEMETIC RESEARCH - Economic Considerations - Economic factors should be addressed in appropriate studies: Less costly regimens should be preferred when results are equal Generic agents will likely have an increasing role Reimbursement is a reality in regimen choice Economic studies: Should be done by independent groups The point of view ( Perspective ) should be identified Beneficial to conduct prospectively, with randomized trials More complete studies evaluate all costs
ANTIEMETIC RESEARCH - Utilization and Guideline Considerations - Guideline Use: Studies evaluating The impact on individuals with the use of guidelines When and why guidelines are not followed Successful strategies in increasing guideline use Perceived value of antiemetics (and emetic control) Oncology Professionals Patients The Public Quality of Life Studies Is there a need for further studies using a validated instrument? The impact of emetic control on quality of life vis a vis other treatment factors
ANTIEMETIC RESEARCH - Committee X Conclusions - Several areas of study in the immediate future are recommended based on: - The emergence of newer agents - Those areas with a low degree of guideline evidence - Areas of poorer control and attention to nausea issues Methodology considerations will be even more important - Better results with available regimens - Long-standing problems that are difficult to study Molecular Techniques have great potential for this field It is imperative that cooperative groups and large therapeutic trials employ and investigate supportive care: - Mandate established supportive care interventions - Perform quality supportive care trials
PERUGIA 2004 ANTIEMETIC GUIDELINES - Process for the future: Keeping the Guidelines Accurate, Up-to-Date, and Valid - Ongoing process to address emerging evidence in the future: Committees are permanent Each chair queries the committee every 6 months regarding whether there is new information which may affect the guideline A steering committee queries the chairs for these suggestions If evidence appears compelling, all group members are notified for their opinions If consensus is achieved, the Web-Guideline document (MASCC) is updated. All participating Societies are notified. Future print publications will have to be addressed this should be done in a coordinated way among the Societies