Special article. Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference

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1 Annals of Oncology 9: , Kluwer Academic Publishers. Printed in the Netherlands. Special article Prevention of chemotherapy- and radiotherapy-induced emesis: Results of the Perugia Consensus Conference Antiemetic Subcommittee of the Multinational Association of Supportive Care in Cancer (MASCC) * Seepage 816 for list of Writing Committee and investigators Summary Background: The need to review and summarize the evidence concerning preventive treatment of cancer chemotherapy- and radiotherapy-induced emesis. Design: After a survey among experts the Antiemetic Subcommittee of the MASCC planned and held a Consensus Conference on antiemetic therapy. Recommendations were provided on the basis of scientific confidence and the of consensus among the participating experts. Results and conclusions: A 5-HT 3 antagonist plus is the regimen of choice in the prevention of acute emesis induced by single high, and low and repeated doses of cisplatin, and of acute emesis induced by moderately-high emetogenic chemotherapy (i.e., cyclophosphamide, doxorubicin, epirubicin, carboplatin, used alone or in combination) in both adults and children. In the prevention of delayed emesis induced by cisplatin the most efficacious choice is a combination of with either metoclopramide or a 5-HT 3 antagonist, while in moderately-high emetogenic chemotherapy alone or a 5-HT 3 antagonist alone or their combination should be used. No evidence or consensus exists regarding antiemetic treatment for patients receiving low emetogenic chemotherapy, or about the optimal rescue treatment for patients failing antiemetic prophylaxis. The best treatment for anticipatory emesis is the best possible control of acute and delayed emesis. Although 5-HT 3 antagonists have some efficacy in the prevention of acute emesis induced by high-dose chemotherapy, more studies should be carried out to determine the best preventive treatment. For prevention of acute emesis induced by highly/moderately emetogenic radiotherapy (TBI, irradiation of the upper part of the abdomen or of the whole abdomen/radiotherapy of the thorax, pelvis and lower body half) a 5-HT 3 antagonist is the best choice. Key words: antiemetics, chemotherapy and radiotherapyinduced emesis, 5-HT 3 antagonists Introduction Nausea and vomiting are the most distressing side effects of cancer chemotherapy. A better understanding of the pathophysiology of emesis and the recent introduction of the 5-HT 3 antagonists into clinical practice have brought about substantial progress in the prevention of chemotherapy-induced nausea and vomiting. To define the optimal antiemetic treatment in patients receiving chemotherapy and radiotherapy and the best methodological approach to the still-pending problems, the sub-committee for antiemetics of the Multinational Association of Supportive Care in Cancer (MASCC) organised a Consensus Conference which was held in Perugia, Italy, April 1997 [1]. To identify the most important topics about which it might be possible to reach a consensus, the sub-committee created a questionnaire which was circulated to experts. The results of this survey were recently published [1], and eight of its major issues constituted the basis of the consensus conference. The conference dealt with clinical, methodological and neuropharmacological issues. The clinical topics were methods for the control of acute and delayed emesis caused by chemotherapy with high and moderate emetogenic potential, and the problems related to emesis induced by multiple-day chemotherapy, rescue antiemetic treatment, emesis in children and emesis due to radiotherapy. The methodological issues concerned classification of the emetogenic potential of the antineoplastic agents and the appropriate design of studies on antiemetic drugs. The neuropharmacology of the 5-HT 3 antagonists and of other antiemetic drugs was also discussed. For each of eight sessions, a written review was provided that was submitted to a respondent and to the chairman of the respective sessions. Copies of the reviews, together with the respondents' comments, were given to all meeting participants in preparation for the discussion. At the end of the discussions the panels for the respective sessions prepared consensus documents, all of which have been published in Supportive Care in Cancer (1998; 6: ). This article will review the most important conclusions about clinical issues presented at the conference. The therapeutic choices for each of the problems related to antiemetic treatment (i.e., prevention of cisplatininduced acute, delayed emesis, etc.) have been discussed

2 812 in relation to the of scientific confidence as well as to the extent of consensus among the experts. The of scientific confidence was classified as 'high' when a number of well-conducted randomized controlled trials of appropriate size were available; 'moderate' when at least one randomized clinical trial supported by wellconducted phase II trials was available; 'low' when formal clinical trials were of a less than that expressed above, and 'no confidence possible'. Characteristics of chemotherapy-induced emesis Emesis is a complex phenomenon characterized by three components: vomiting, nausea and retching, which are often, but not always, interrelated. There are three types of chemotherapy-induced emesis: acute emesis, which occurs soon after chemotherapy administration; delayed emesis, which has arbitrarily been defined as emesis beginning 24 hours after chemotherapy administration that can persist up to six to seven days, and anticipatory emesis, which can occur before a subsequent course of chemotherapy. Although these are arbitrary distinctions, the three types of emesis are probably distinct phenomena, and they give rise to different therapeutic problems. Cancer drugs differ quantitatively and qualitatively in their emetogenic potential but, at present, all of the available classifications are open to criticism because the emetogenic potential can be influenced by chemotherapy-related factors (i.e., drug combination, dose, schedule and route of administration) or by patient characteristics (sex, age, previous experience of chemotherapy, alcohol intake, experience of emesis during pregnancy and motion sickness) [2, 3]. A working classification is shown in Table 1 ( of confidence: low; of consensus: moderate). Chemotherapy with high emetogenic potential Single high-dose of cisplatin (^50 mg/m 2 ) Acute emesis Cisplatin induces acute nausea and vomiting in 98% of patients who do not receive effective prophylaxis. Prior to the availability of the 5-HT 3 antagonists the most efficacious treatment was an iv. combination of highdose metoclopramide and, plus diphenhydramine or lorazepam, which completely prevented vomiting in about 60% of patients [4, 5]. With the use of 5-HT 3 antagonists (ondansetron, granisetron, tropisetron and dolasetron) administered intravenously alone, complete protection against vomiting was achieved in 40%-60% of patients [5]; their combination with was shown to increase complete protection against vomiting in 70%-90% of patients [6]. In addition to greater efficacy, two further advantages are offered by the 5-HT 3 antagonist combinations as Table 1. Approximate emetogenic potential of single chemotherapy agents. Degree of emetogenicity -high Low-moderate Low Agent Cisplatin > 50 mg/m 2 Mechlorethamine Streptozocin Cyclophosphamide > 1500 mg/m 2 Carmustine > 250 mg/m 2 Dacarbazine Cisplatin < 50 mg/m 2 Cytarabine > 1 g/m 2 Carboplatin Ifosfamide Carmustine ^ 250 mg/m 2 Hexamethylmelamine (po) Cyclophosphamide ^1500 mg/m 2 Doxorubicin Epirubicin Topotecan Irinotecan Procarbazine (po) Methotrexate > 250 mg/m 2 Cyclophosphamide (po) Mitoxantrone Docetaxel Pachtaxel Etoposide Methotrexate > 50 mg and < 250 mg/m 2 Mitomycin Gemcitabine Fluorouracil < 1000 mg/m 2 Bleomycin Busulfan Chlorambucil (po) 2-Chlorodeoxyadenosine Fludarabine Hydroxyurea Methotrexate ^ 50 mg/m 2 L-phenylalanine mustard (po) 6-Thioguanine (po) Vinblastine Vincristine Vinorelbine opposed to the metoclopramide combinations. First, the tolerability is better, and second, the effectiveness of the antiemetic treatment is greater, and persists over the first three cycles of chemotherapy [7-9]. The combination of a 5-HT 3 antagonist with is thus the regimen of choice for the prevention of acute emesis in cisplatin-treated patients (Table 2). Preliminary data suggest that the addition of a dopamine antagonist (metopimazine) to a 5-HT 3 antagonist increases the antiemetic efficacy of the 5-HT 3 antagonist used alone [10]. These findings should be further investigated in randomized clinical trials. Despite some pharmacological differences among 5-HT 3 antagonists [11] their efficacy and tolerability have proven similar in several double-blind comparative trials [12], and aside from their respective economic costs, there is little to recommend any one of them over the others. However, this parameter is difficult to calcu-

3 813 late. Despite the fact that the optimal dose, schedule and route of administration of the 5-HT 3 antagonists have been evaluated in a number of trials [13-24], the results have been conflicting, and there is a broad variation in the 'approved' single i.v. dose (i.e., in the US the approved dose of ondansetron, 32 mg or approximately 0.45 mg/kg, is four times higher than the European one (8 mg) while the opposite is true for granisetron (1 mg or 10 ug/kg versus 3 mg or 40 ug/kg) [13-20]. Suggested therapeutically equivalent doses, schedules and routes of administration of the 5-HT 3 antagonists in the prevention of cisplatin-induced acute emesis are reported in Table 3. Preliminary data also suggest that the oral route is equivalent to i.v. administration. In two large doubleblind studies oral granisetron (2 mg) achieved results similar to those of i.v. ondansetron (32 mg) [25], and the effects of oral ondansetron (24 mg) were similar to those of i.v. ondansetron (8 mg) [26]. Furthermore, good results were shown in a pilot study using an oral combination of dolasetron and [27]. The optimal single i.v. dose of remains to be determined [28]. Delayed emesis This syndrome was first described in patients receiving high-dose cisplatin; 74% suffered vomiting and 87% nausea 24 to 120 hours following chemotherapy [29]. All patients receiving high-dose cisplatin should receive antiemetic prophylaxis for delayed emesis ( of confidence: high; of consensus: high). Worthy of note is the fact that the lower the protection against acute emesis the greater the risk of delayed emesis. The 5-HT 3 antagonists used alone failed to demonstrate a clinically meaningful benefit [30, 31] while the combinations of oral (8 mg twice daily on days 2-3 and 4 mg twice daily on days 4-5) plus metoclopramide (0.5 mg/kg four times a day on days 2-5) [32, 33] or intramuscular (8 mg twice daily on days 2-3 and 4 mg on day 4) plus oral ondansetron (8 mg twice daily on days 2-4) [34] have proven efficacious, although even with these combinations, about 50% of patients continue to suffer delayed vomiting and/or nausea [35]. The combination of with either metoclopramide or a 5-HT 3 antagonist, beginning 24 hours after chemotherapy for a minimum of 72 hours, is the most effective regimen for preventing delayed emesis following treatment with cisplatin (Table 2). Chemotherapy with moderate-high emetogenic potential Single i. v. dose of cyclophosphamide, doxorubicin, epirubicin, carboplatin Most of these drugs are given in combination rather than as single agents and such combinations of moder- Table 2. Level of scientific confidence and consensus among experts related to main problems of chemotherapy-induced emesis. Problems Cisplatin single high dose (>50mg/m 2 ) Acute emesis Delayed emesis of carboplatin, doxorubicin, epirubicin and cyclophosphamide Acute emesis Delayed emesis Cisplatin low and repeated doses (20-40 mg/m 2 /day for three to five days) Oral C.M.F. a Treatment of choice Dexamethasone + metoclopramide or 5-HT 3 antagonist Dexamethasone or 5-HT3 antagonist or on each day Dexamethasone + metoclopramide If not tolerated: 5-HT3 antagonist Confidence Consensus high 3 for patients treated with curative intent, high for palliative intent. This because, although rare, serious side effects have been described after high-dose corticosteroids. Table 3. Dosage and schedule of 5-HT3 antagonists in cisplatininduced emesis. Agent Ondansetron Granisetron Tropisetron Dolasetron Daily dose 8mg 24 mg 10 ug/kg 2mg 5 ing 1.8 mg/kg 200 mg Schedule Abbreviation: i.v. = intravenously. Route i.v. Oral i.v. Oral l.v. i.v. Oral Confidence Low Low Consensus ately emetogenic drugs results in a rather highly emetogenic regimen. Acute emesis Corticosteroids such as (8 mg i.v. before chemotherapy plus 4 mg orally, given every six hours, repeated four times) or methylprednisolone ( mg i.v. or intramuscularly starting before chemotherapy and continued every six hours for three times) can provide complete protection from vomiting in about 60%-80% of patients [5]. Contrasting results have been achieved in

4 814 Table 4. Dosage and schedule of oral 5-HT 3 antagonists in moderatehigh emetogenic chemotherapy. Agent Ondansetron Granisetron Tropisetron Dolasetron Daily dose mg 2mg a mg Schedule TID (or BID) OD (or BID) a OD Confidence a Consensus a Abbreviations: OD = single dose daily; BID = twice daily; TID = three times daily. a Insufficient data available. all studies comparing the efficacy of corticosteroids to that of metoclopramide but corticosteroids were always found to be better tolerated [5]. The development of 5-HT 3 antagonists was the impetus for a number of comparative trials. When used alone, these compounds have shown superior antiemetic efficacy compared to older drugs such as metoclopramide [36-40], alizapride [41, 42], and phenothiazines [43-45], and similar efficacy to that of (8 mg i.v. plus 4 mg orally every six hours starting contemporarily with chemotherapy) [46, 47], although the percentage of complete protection from vomiting varied among studies from 50% to 70%. Interestingly, one of these studies demonstrated that the combination of a 5-HT 3 antagonist with was significantly more efficacious than or granisetron alone (complete protection from acute vomiting being achieved in 93%, 71% and 72% of patients, respectively) and its antiemetic activity persists through three consecutive cycles of chemotherapy [47, 48]. In two further trials ondansetron combined with proved superior to the combination of metoclopramide and [49, 50]. Thus, the combination of a 5-HT3 antagonist plus can provide optimal prevention of acute emesis in these patients (Table 2). Oral 5-HT 3 antagonists are also appropriate in this setting. The optimal oral dose and schedule of the 5-HT 3 antagonists is shown in Table 4 [51-58]. The optimal dose and schedule of corticosteroids remain to be determined. Delayed emesis Only a few studies have been specifically planned to investigate methods for prevention of delayed emesis induced by cyclophosphamide, carboplatin, epirubicin or doxorubicin. Oral ondansetron (8 mg twice a day) as well as oral (4 mg twice a day) and oral dolasetron (200 mg once daily) with or without corticosteroids on days 2-5 after chemotherapy have proven efficacious, with prevention of delayed emesis in approximately 40%-60% of patients [53, 59, 60]. In these patients the degree of protection against acute emesis has a great deal of influence on the occurrence of delayed emesis. In fact, in one study the overall incidence of delayed vomiting and moderate-to-severe nausea was less than 20% in patients with no acute vomiting and moderate-to-severe nausea, and about 55%-75% in those with acute vomiting and moderateto-severe nausea [61]. Thus, if patients have a significant probability of suffering delayed emesis, prophylactic treatment should be administered ( of confidence: low; of consensus: high). In such case, oral alone, a 5-HT 3 antagonist, or their combination, beginning 24 hours after chemotherapy and continuing for a minimum of 72 hours, should be administered (Table 2). Low and repeated doses of cisplatin (20-40 mg/m /day for 3-5 days) Only a few small studies have been carried out with this type of chemotherapy [62-67]. The i.v. combination of a 5-HT 3 antagonist plus has been shown to induce about 55% 83% complete protection from vomiting during the three tofivedays of cisplatin administration, and this combination has proven superior to i.v. high-dose metoclopramide plus [65], alizapride plus [66] and to a 5-HT 3 antagonist alone [67]. Thus, this combination, administered on each day of cisplatin chemotherapy, should be considered the treatment of choice (Table 2). The optimal dose of the 5-HT 3 antagonist as well as that of remains to be clarified. Oral cyclophosphamide in combination with i.v. methotrexate-fluorouracil (C. M. F.) Despite the widespread use of this regimen, only two controlled studies have been published on prevention of emesis [68, 69]. A combination of, as a single i.v. dose (10 mg) on days 1 and 8, plus a 14-day oral metoclopramide (10 mg three times daily) administration, has been shown to be the treatment of choice (Table 2) [68]. A 5-HT 3 antagonist is an alternative regimen in patients who do not tolerate this combination [69]. Chemotherapies with low-to-moderate or low emetogenic potential Very few controlled studies have been carried out in patients treated with low-to-moderate (i.e., fluorouracil, methotrexate) and low (i.e., bleomycin, vinblastine, vinorelbine) emetogenic chemotherapy. It is thus impossible to identify the patients who require antiemetic prophylaxis and the optimal antiemetic treatment ( of confidence: no confidence possible, of consensus: high). Refractory emesis and rescue antiemetic therapy There are no clear-cut definitions of the terms 'rescue antiemetic therapy' and 'refractory emesis'. Rescue antiemetic treatment is generally understood to be anti-

5 815 Table 5. Level of scientific confidence and consensus among experts related to main problems of chemotherapy-induced emesis. Problems Refractory emesis in cisplatin patients failing optimal therapy Anticipatory emesis -dose chemotherapy Radiotherapy ly emetogenic ly emetogenic Chemotherapy in children ly and moderately emetogenic Treatment of choice + metopimazine Alprazolam Systemic desensitization and hypnosis 5-HT 3 antagonist 5-HT 3 antagonist 5-HT3 antagonist 5-HT3 antagonist + Abbreviation: NP = not possible. Confidence Low NP Consensus emetics given on demand to a patient with emesis. No randomized double-blind trials have investigated antiemetics in this setting. A few trials have investigated patients with refractory emesis denned as emesis in the previous cycle of chemotherapy, but without emesis before the subsequent cycle of chemotherapy (no anticipatory emesis). In two randomized trials, metopimazine improved the efficacy of ondansetron [70] and of ondansetron plus methylprednisolone [71] in patients with refractory emesis, but more data are needed before firm conclusions can be drawn (Table 5). Anticipatory emesis Anticipatory emesis does not develop unless frequent and/or severe post-treatment nausea and vomiting have occurred. Therefore, the best treatment for anticipatory emesis is optimal control of post-chemotherapy emesis. In a study evaluating 1385 patients prior to the fourth chemotherapy cycle, the prevalence of anticipatory nausea was around 20%, with approximately 1/3 of all patients experiencing symptoms at least once by the fourth treatment. Approximately 8% of patients had at least one episode of anticipatory vomiting during this period [72]. Contrasting data have been published on the incidence and severity of anticipatory nausea and vomiting before and after the introduction of the 5-HT 3 antagonists in clinical practice [73, 74]. Currently available pharmacological agents are incapable of providing complete protection from anticipatory nausea and vomiting. A potentially useful treatment is low-dose oral alprazolam (0.5 mg to 2 mg) which, taken daily in a double-blind, placebo-controlled study of 57 women with breast cancer, significantly reduced (from 18% to 0%) the occurrence of anticipatory nausea [75]. Unfortunately, the efficacy of treatment tended to decrease as chemotherapy treatment continued (Table 5). Systematic desensitization and hypnosis have proven effective against anticipatory nausea and vomiting in several studies (Table 5) [76, 77]. The best approach, however, is still a multidisciplinary one that includes the best possible pharmacological control of acute and delayed nausea and vomiting, drugs as needed to decrease anxiety, and adjunctive behavioural treatment (systematic desensitization, hypnosis), ideally given prophylactically. Emesis induced by high-dose chemotherapy -dose chemotherapy followed by hematopoietic stem cell transplantation provides a unique approach to the prevention and management of emesis. Only a few published data describe the magnitude of this problem or indicate effective interventions for its prevention. Three small randomized trials involving the 5-HT 3 antagonists have been published. In one, ondansetron was shown to be superior to metoclopramide and droperidol [78]. In another, continuous infusion of chlorpromazine was comparable to continuous infusion of ondansetron, with ondansetron proving significantly less toxic [79]. The third study showed no statistically significant difference between granisetron and 'standard' antiemetic therapy in the control of emesis [80]. Although the 5-HT 3 antagonists have some efficacy in the prevention of acute emesis, further studies are needed to determine their optimal dosage and timing as well as their combination with or other drugs (Table 5). At present, no therapy has been convincingly shown to control high-dose chemotherapyinduced delayed emesis. Radiotherapy-induced emesis The incidence and severity of radiotherapy-induced emesis are related to the site, the field size and the dose of radiotherapy. Total body irradiation and irradiation of the upper part of the abdomen or of the whole abdomen are considered the most emetogenic regimens in radiotherapy, while the emetogenic potential is considered moderate in radiotherapy of the thorax, pelvis and lower half-body, and low in radiotherapy of head and neck, extremities, brain and skin. Before the advent of the 5-HT 3 antagonists the few trials carried out demonstrated only a moderate control of emesis with older antiemetic drugs (complete protection from vomiting in approximately 50% of patients

6 816 submitted to moderately emetogenic radiotherapy but only poor control for highly emetogenic radiotherapy). Convincing data exist from comparative studies that the 5-HT 3 antagonists have antiemetic efficacy superior to that of placebo, metoclopramide, prochlorperazine and a combination of metoclopramide, and lorazepam in the prevention of emesis induced by moderately- and highly-emetogenic radiotherapy (Table 5) [81-88]. It is possible that antiemetic efficacy increases when 5-HT 3 antagonists are combined with corticosteroids (complete control of emesis in 86% of cases) [89], but the data are too preliminary to serve as a basis for definitive conclusions regarding this drug combination (Table 5). Rescue therapy with 5-HT 3 antagonists is effective for moderately emetogenic daily fractionated radiotherapy but must be administered as soon as symptoms (usually nausea) develop [90]. Further studies are needed to determine optimal dosing and timing of the 5-HT 3 antagonists as well as their most effective combination with other antiemetic drugs. There is no data on the incidence, severity or treatment of radiotherapy-induced delayed emesis. Antiemetics in children receiving cancer chemotherapy Only a few studies have been carried out in children on the prevention of chemotherapy-induced emesis and it is inappropriate to assume that all results obtained in adults can be directly applied to children, since metabolism and side effects of drugs may be different. Before the introduction of 5-HT 3 antagonists only nine comparative studies using different antiemetics (metoclopramide, phenothiazines and cannabinoids) were reported in the literature but the data are difficult to interpret. In fact, these trials were poorly designed, did not take into account the different emetogenic potency of the cytotoxic agents and the differences between acute and delayed emesis. Finally, many of the trials were too small to permit adequate statistical analysis [91-98]. Overall, metoclopramide, phenotiazines and cannabinoids had only moderate efficacy and significant side effects, most notably marked sedation and extrapyramidal reactions. Four comparative studies with 5-HT 3 antagonists have been published [99-102]. Ondansetron and granisetron have been shown to be superior to chlorpromazine and to metoclopramide combined with and were less toxic [100,101]. As in the adult population, the combination of a 5-HT 3 antagonist with was shown to be more efficacious than a 5-HT 3 antagonist alone [99, 102]. Therefore, all pediatric patients receiving chemotherapy of high or moderate emetogenic potential should receive antiemetic prophylaxis with a combination of a 5-HT 3 antagonist and (Table 5), but the optimal dose and scheduling of these compounds has not been studied in depth. No studies have specifically evaluated antiemetic drugs in the prevention of chemotherapy-induced delayed and anticipatory emesis in the pediatric population. Conclusions The introduction of the 5-HT 3 antagonist antiemetics has rendered it possible to dramatically reduce the incidence of chemotherapy- and radiotherapy-induced nausea and vomiting. To obtain optimal control, however, the results from antiemetic research studies must be transferred to clinical practice. The success of antiemetic therapy depends on an awareness of the type of the emesis in question, the prognostic or risk factors for emesis and the choice of the most appropriate scheme and schedule of antiemetic treatment. Unfortunately, many problems related to cancer chemotherapy-induced emesis have not yet been satisfactorily resolved (i.e., rescue treatment, necessity of preventive treatment in patients receiving chemotherapy with low-to-moderate emetogenic potential, anticipatory emesis, emesis induced by high-dose chemotherapy) and further research is needed in these fields. However, new drugs are currently being developed (i.e., neurokinin inhibitors) [103] which promise to expand our therapeutic arsenal. * Appendix Writing Committee F. Roila, MD, A. Del Favero, MD, R.J. Gralla, MD, M. Tonato, MD. Participating investigators M. S. Aapro, MD, Institute Multidisciplinaire d'oncologie, Genolier, Switzerland; P. L. R. Andrews, PhD, St. George's Hospital Medical School, London, UK; E. Ballatori, PhD, University of L'Aquila, L'Aquila, Italy; P. H. M. De Mulder, MD, University Hospital Nijmegen, Nijmegen,The Netherlands; A. Del Favero, MD, University of Perugia, Perugia, Italy; M. A. Dicato, MD, Centre Hospitalier, Luxembourg, Luxembourg; A. du Bois, MD, St. Vincentius Hospital, Karlsruhe, Germany; P. C. Feyer, MD, Humboldt University Berlin, Germany; D. R. Gandara, MD, University of California, Davis, Sacramento, USA; R. J. Gralla, MD, Ochsner Clinic, New Orleans, USA; S. Groshen, MD, University of Southern California, Los Angeles, USA; S. M. Grunberg, MD, University of Vermont, Burlington, USA; J. Herrstedt, MD, Copenhagen University Hospital Herlev, Denmark; P. J. Hesketh, MD, St. Elizabeth's Medical Center, Boston, USA; R. A. Joss, MD, Kantonsspital Luzern, Luzern, Switzerland; M. G. Kris, MD, Memorial Sloan-Kettering Cancer Center, New York, USA; M. M. Marty, MD, Hopital Saint Louis, Paris, France; G. R. Morrow, PhD, University of Rochester Cancer Center, Rochester, USA; R. J. Naylor, MD, University of Bradford, Bradford, UK; I. N. Olver, MD, Royal Adelaide Hospital, Adelaide, Australia; F. Roila, MD, Policlinico Monteluce, Perugia, Italy; J. F. Smyth, MD, Western General Hospital, Edinburgh, UK; Th. R. Spitzer, MD, Massachusetts General Hospital, Boston, USA; A. Stewart, MD, Christie Hospital, Manchester, UK; M. Tonato, MD, Policlinico Monteluce, Perugia, Italy; D. Warr, MD, Princess Margaret Hospital, Toronto. Canada.

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J Natl Cancer Inst 1997; 89: Received 13 May 1998; accepted 9 June Correspondence to: F. Roila, MD Medical Oncology Division Policlinico Hospital Perugia Italy oncmedpg@krenet.it

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