Helsinn Healthcare Exhibit 2035
`Dr. Reddy's Laboratories, Ltd., et al. v. Helsinn Healthcare S.A.
`Trial PGR2016-00007
`
`Page 1 of 9
`
`

`
`
`
`,
`
`
`
`
`
`European Journal of Cancer
`
`Aims and Scope
`
`
`
`
`
`The European Journal of Cancer is an international comprehensive oncology journal that publishes original research, editorial comments,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`review articles and news on experimental oncology, clinical oncology (medical, paediatric, radiation, surgical) and on cancer epidemiology
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and prevention. Letters that comment on an article previously published in the European Journalof Cancerare also welcomed.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Publishing & Advertising Olfices:Eisevier Science Ltd,The Boulevard, Langford Lane, Kidlington, Oxford OX51GB, UK. (01865 843000).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Advertising iniormaiion. Advertising orders and enquiriescan be sent to: USA and Canada: Eisevier Science lnc., MrTino Decario, 655 Avenue
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`of the Americas, New York, NY 100105107, USA; phone: +1 212 633 3815; fax: +1 212 633 3820; e—mali: t.decarlo@elsevier.com. Japan: The
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Advertising Department, Elsevier Science K.K., 9-15 Higashi-Azabu 1—chome, Minato~ku,Tokyo 106-0044, Japan; phone: +813 5561-503.3; fax:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`+81 3 5561 5047. Europe and ROW: Rachel Leveson-Gower, Eisevier Science Ltd, Advertising Department, The Boulevard, Larigford Lane,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Kidlington,Oxiord OX51GB. UK; tel: +44 (0)1865 843565; fax; +44 (0)1865 848976; e-mail: r.ieveson—gower@elsevier.co.uk.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Subscription rates (2002): Annual Institutional Subscription Rate to the European Journal of Cancer: Europe, The CIS and Japan €1968.00. All
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`other countries US$ 2200.00. Combined institutional Rate to the European Journal of Cancer and Oral Oncology: Europe,The ClS and Japan
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`€2375.00. All other countries US$ 2656.00. For more information go to www.ejcon|ine.com. Personal Print and Online Subscription Rate for the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`European Journal of Cancer: Europe,The CiS and Japan €85.00. All other countries US$ 95.00. Online only €41.00 Dutch Guiiders or US$ 46.00.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Dutch Guilder prices exclude VAT. Non-VAT registered customers in the European Community will be charged the appropriate VAT in addition to
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the price listed. Prices include postage and insurance and are subject to change without notice.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Orders, claims, and product enquiries: please contact the Customer Support Department at the Regional Sales Office nearest you:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`NewYork: Eisevier Science, PO Box 945, NewYork, NY10159-0945, USA; tel: +1212 633 3730 [toll free number for North American customers:1
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`888-4ES—lNFO (437-4636)}; fax: +1212 638 8680; e—mali: usinfo~f@elsevier.com.
`'
`
`
`
`
`
`
`
`
`Amsterdam: Elsevier Science, PO Box 211,1000 AE Amsterdam, The Netherlands; tel: +31 20 4853757; fax‘: +31 20 4853432; e—mali: n|into-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`f@e|sevier. nl.
`
`Tokyo: Eisevier Science, 9-15 Higashi—Azabu 1—chome, Minato-ku, Tokyo 106~0044, Japan; tel: +81 8 5561 5033; fax: +81 3 5561 5047; e—mali:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`info@eisevier.co.jp.
`-
`
`
`Singapore: Elsevier Science, No.1 Temasek Avenue, #17-01 Mllienla Tower, Singapore 039192; tel: +65 434 3727; fax: +65 337 2230; e—mali:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`asiainio@elsevier,c0m.sg.
`
`
`
`Rio de Janeiro: Eisevier Science, Rua Sete de Setembro 111/16 Andar, 20050-002 Centro, Rio de Janelro - RJ, Brazil; tel: +55 (21) 509 5340; tax:
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`+55 (21) 507 1991; e—mali: e|sevier@campus.com.br [Note (Latin America): for orders, claims and help desk intormatlon, please contact the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Regional Sales Otiice in New York as listed above].
`
`
`
`
`
`
`
`
`PERIODICALS POSTAGE PAID AT RAHWAY, NEW JERSEY European Journal of Cancer (ISSN 0959-8049) is published in 18 issues by
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Eisevier Science Ltd,The Boulevard, Langford Lane, Kidlington, Oxford OX51GB, UK.The annual subscription in the USA is $2200.00.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`European Journal of Cancer is circulated by Mercury international Limited, 365 Blair Road, Avenel, NJ 07001, USA.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`POSTMASTER: Please send address corrections to: European Journal of Cancer, clo Customer Services, Elsevier Science lnc., 655 Avenue of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`the Americas, NewYork, NY10010, USA.
`
`
`
`
`
`
`
`
`
`
`
`Copyright © 2001 Elsevier Science Ltd, All rights reserved
`
`
`
`
`
`
`
`
`
`
`This Journal and the individual contributions contained in it are protected under copyright by Elsevier Science Ltd and the following terms and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`conditions apply to their use:
`
`
`
`
`
`Photocopying. Single photocopies of single articles may be made for personal use as allowed by national copyright laws. Permission of the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`publisher and payment of a fee is required for all other photocopying, including multiple or systematic copying, copyingfor advertising or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`promotional purposes, resale, and all forms of document delivery. Special rates are available for educational institutions that wish to make
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`photocopies ior non-profit educational classroom use.
`
`
`
`
`
`
`Permissions may be sought directly from Eisevier Science Global Rights Department, PO Box 800, Oxford OX51DX, UK; phone: +44 (0)1865
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`843830; fax: +44 (0)1865 853333, e—mali: permlssions@eisevier.co.uk.You may also contact Global Rights ciirectlylthrough Eisevier's home
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`page (http://www. elsevier.com), selecting ‘Obtaining Permissions’.
`
`
`
`
`
`
`In the USA, users may clear permissions and make payments through the Copyright Clearance Center, lnc., 222 Rosewood Drive, Danvers, MA
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`01923, USA; phone: +1 (978) 7508400, fax: +1 (978) 7504744, and in the UK through the Copyright Licensing Agency Rapid Clearance Service
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(CLARCS), 90 Tottenham Court Road, London W1P OLP, UK; phone: +44 020 7531 5555; fax: +44 020 7631 5500. Other countries may have a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`local reprographic rights agency for payments.
`
`
`
`
`
`
`Derivative works. Subscribers may reproduce tables of contents or prepare lists oi articles including abstracts for internal circulation within
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`their institutions. Permission of the publisher is required for resale or distribution outside the institution.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Permission of the publisher is required for all otherderivative works, including compilations and translations.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Electronic storage or’ usage. Permission of the publisher is required to store or use electronically any material contained in this journal,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`including any article or part of an article.
`
`
`
`
`
`
`
`
`Except as outlined above, no part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`means, electronic, mechanical, photocopying, recording or otherwise, without prior permission of the publisher.
`
`
`
`
`
`
`
`
`
`
`
`
`
`Address permissions requests to: Eisevier Science Global Rights Department, at the mail, fax and e—mail addresses noted above.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Notice. No responsibility is assumed by the Publisher for any injury and/or damage to persons or property as a matter of products liability, negli-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`gence or otherwise, or from any use or operation of any methods, products, instructions or ideas contained in the material herein. Because of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`guarantee orendorsement of the quality or value of such product or of the claims made of it by its manufacturer.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`The ltem—Fee Code for this publication is: 0959-8049/01 S20.00+0.00.
`
`
`
`
`
`
`
`
`
`®”‘ The paper used in this publication meets the requirements of ANSl/NISO Z3948-1992 (Permanence oi Paper). .
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`'
`
`,
`i
`
`1
`
`-
`
`',
`‘i
`
`Page 2 Of 9
`
`DTX-0047-0003
`
`
`
`Page 2 of 9
`
`

`
`
`
`PERGAMON
`
`
`
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`
`
`
`
`
`
`
`
`
`
`
`
`i
`
`European Journal of Cancer 37 (2001) 23984404
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`European
`
`
`Journal of
`Cancer
`
`
`www .ejconline.com
`
`
`
`
`
`
`
`
`Randomised comparison of ondansetron plus dexamethasone
`
`
`
`
`
`
`
`
`with dexamethasone alone for the control of delayed
`
`
`cisplatin—induced emesis
`
`
`
`
`
`
`
`
`
`
`H. Tsul<ada*, T. Hirose, A. Yokoyama, Y. Kurita
`Depczrtment ofIntemal Men'1'cine, Niigata Cancer Center Hospital, 2-15-3 Kuwagis/zz‘-c/10, Niigata, 951-8566, Japan
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Received 6 February 2001; received in revised form l2 July 2001; accepted 12 September 2001
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`._._....._.-...-.-..aau.aw—w.—.---
`
`Abstract
`
`
`The role of 5-hy[li.‘OKytl'y]I)t21I11ll1€3 (HT3) antagonists in the treatment of delayed emesis is still controversial. To evaluate whether
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`5—HT3 antagonists can add to the efficacy of corticosteroids in controlling delayed emesis, we performed a randomised, prospective,
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`open study comparing ondansetron plus dexamethasone with dexamethasone alone in cisplatin—treated patients, 149 cisplatin-naive
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`patients with lung cancer received at least 60 mg/m2 of cisplatin and were treated with dexamethasone 32 ‘mg intravenously (iv)
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and granisetron 3 mg i..v. on day 1. Patients were randomly assigned to receive either dexamethasone 16 mg i.v. alone (arm A) or
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`dexamethasone plus ondansetron 8 mg daily (arm B) on days 24. None of the efficacy variables related to control of delayed emesis
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`differed significantly between the two arms. In conclusion, there does not appear to be stiificieiit evidence to support the prolonged
`use of 5—l-IT3 receptor antagonists after 24 h of cisplatin-containing chemotherapy. © 2001 Elsevier Science Ltd. All rights reserved.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Keyword.s'.' Delayed emesis; Antiemetics; Cisplatin; Ondansetron; Dexamethasone; 5-HT3—recepto1‘ antagonists
`
`
`
`
`
`
`
`
`
`
`
`1. Introduction
`
`
`
`
`
`
`
`
`
`
`
`Nausea and emesis are among the most distressing
`adverse effects of cancer chemotherapy. The control of
`
`
`
`
`
`
`nausea and cmcsis has a remarkable effect on the
`
`
`
`
`
`patient’s quality of life and willingness to complete their
`
`
`
`
`
`
`
`
`
`course of treatment.
`
`
`
`Acute emesis after cisplatin administration has been
`
`
`
`
`
`
`
`
`
`
`
`widely studied, and following the introduction of
`
`
`
`
`5-hydroxytryptamineg (5-HT3)
`receptor antagonists,
`
`
`
`
`
`
`
`
`
`significant advances have been made. in its control [I-4].
`Furthermore, large multicentre randomised trials have
`
`
`
`
`
`
`
`
`
`
`
`the combination of a 5-HT3 receptor
`shown that
`
`
`
`
`
`antagonist plusza corticosteroid is significantly more
`
`
`
`
`
`
`
`effective than a 5-HT3 antagonist alone. In these trials,
`
`
`
`
`
`
`the combination of a 5-HT3 receptor antagonist plus a
`
`
`
`
`
`
`
`
`corticosteroid has been shown to yield an approximately
`75% (range 58-96%) complete control rate of acute
`
`
`
`
`
`
`
`
`
`
`
`
`
`emesis after a high-dose eisplatin—based regimen [5—9].
`
`* Corresponding author. Tel.: + 81-25-266-5111; fax: + 81-25-233-
`
`
`
`
`
`
`
`3849.
`
`E-mail add/‘es.r.' htsukada@niigata-cc.niigata.niigata.jp
`
`
`
`(II. Tsukada).
`
`
`
`
`
`However, the success achieved in the prevention of
`
`
`
`
`
`
`acute emesis has not been extended to the control of the
`
`
`
`
`
`
`
`
`
`
`
`delayed cmcsis induced by cisplatin. Delayed emesis,
`
`
`
`
`
`
`although less intense than acute emesis, is still a major
`
`
`
`
`
`
`
`
`problem for many patients, and its incidence varies, but
`
`
`
`
`
`
`
`
`
`can be as high as 80% [l0,l 1]. Since the neuropharmaco-
`
`
`
`
`
`
`
`
`
`
`logical mechanism of delayed emesis is not well under-
`
`
`
`
`
`
`
`
`stood, preven-tion of this problem has been based on
`
`
`
`
`
`
`
`empirical results [12]. In the clinical practice guidelines
`
`
`
`
`
`
`
`developed by the American Society of Clinical Oncol-
`
`
`
`
`
`
`
`
`
`
`
`
`
`ogy (ASCO), a corticosteroid plus metoclopramide -or a
`5—HT3 antagonist is recommended for the prevention of
`
`
`
`
`
`
`
`delayed emesis [12]. Although the combination of corti-
`
`
`
`
`
`
`
`
`costeroid and metocloprznnide has been shown to be
`
`
`
`
`
`
`superior to placebo, and also to dexamethasone alone
`
`
`
`
`
`
`[ll,l3], it is controversial whether continuation of a 5-
`
`
`
`
`
`
`
`
`
`
`
`
`HT3 antagonist after acute control of emesis prevents
`
`
`
`
`
`
`the development or reduces the frequency of delayed
`emesis [l4—20,23].
`
`
`
`
`
`
`
`
`
`
`To evaluate the role of a 5—HT3 antagonist, in parti-
`
`
`
`
`
`
`cular oral ondansetron,
`in the prevention of delayed
`
`
`
`
`ernesis, we planned a single-institution randomised,
`
`
`
`
`
`
`prospective, open study comparing ondansetron plus
`
`0959-8049/Ol/$ - see front matter © 2001 Elsevler Science Ltd. All rights reserved.
`
`
`
`
`
`
`
`
`
`
`
`PII: SO959—8049(0l)00326-4
`
`
`
`
`
`
`in
`
`Page 3 of 9
`
`DTX-0047-0004
`
`
`
`Page 3 of 9
`
`

`
`
`
`H. Tsukada et al. / European Journal of Cancer 37 (2001) 2398-2404
`
`
`
`
`
`
`
`
`
`
`
`
`
`2399
`
`
`
`
`
`
`
`dexamethasone with dexamethasone alone in cisplatin-
`
`
`treated patients,‘
`
`2. Patients and methods
`
`
`
`
`
`
`2.]. Patient selection
`
`
`
`
`
`
`
`
`
`Eligibility criteria included pathologically—ccnfirmed
`
`
`
`
`
`
`
`
`lung cancer, age between 15. and 80 years, performance
`
`
`
`
`
`
`
`status of 3 or less according to the Eastern Cooperative
`
`
`
`
`
`Oncology Group (ECOG)
`scale and chemotherapy
`
`
`
`
`
`including cisplatin at a dose of at
`least 60 mg/m2.
`
`
`
`
`
`
`Patients meeting any of the following criteria were
`
`
`
`
`
`
`excluded: primary brain tumour or symptomatic brain
`
`
`
`
`
`
`metastases, prior treatment with cisplatin, presence of
`
`
`
`
`
`
`
`nausea and/or vomiting before the cisplatin treatment,
`current use of corticosteroids, recent changes in the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`doses of major tranquilisers or sleeping pills habitually
`used, clinically significant gastrointestinal disease, or
`
`
`
`
`
`evidence of severe uncontrollable diabetes. Written
`
`
`
`
`
`
`
`
`
`
`
`
`informed consent was obtained from all patients, and
`the study-was approved by the Institutional Review
`
`
`
`
`
`
`Board of our hospital.
`
`
`
`
`
`2 .2. Treatment protocol
`
`
`
`
`Patients were randomly assigned to receive either
`
`
`
`
`
`
`
`
`
`
`
`
`dexamethasone alone (arm A) or dexamethasone plus
`
`
`
`
`
`
`
`
`ondansetron (arm B). All the patients received cisplatin
`
`
`
`
`
`
`
`
`
`
`
`treatment (60 or 80 mg/m2) only on the first day (day 1)
`of treatment, either alone or in combination with other
`
`
`
`
`
`
`
`
`
`chemotherapeutic agents. On days 2-4, either no
`
`
`
`
`
`
`
`
`
`
`chemotherapy or only agents with low emetogenicity
`
`
`
`
`
`
`
`were administered. On day 1, patients received prophy-
`
`
`
`
`
`
`lactic treatment with granisetron 3 mg intravenously
`
`
`
`
`
`
`
`(i.v.) and dexamethasone 32 mg i.v. in four separate
`doses (8 mg each). Then patients assigned to treatment
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`arm A received dexamethasone 8 mg iv. twice daily on
`days 2-4. The treatment for arm B consisted of oral
`
`
`
`
`
`
`
`
`ondansctron 8 mg daily in the morning on days 2-4, in
`
`
`
`
`
`
`
`
`addition to dexamethasone at the same dose and on the
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`same schedule as arm A. If more than two episodes of
`severe nausea or vomiting were observed, patients
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`received a standard dose of metoclopramide (10 mg per
`body i.v. or intramuscularly) or domperidone (60 mg
`
`
`
`
`
`
`
`
`
`
`per body suppository). Requirement of any other
`antiemetic treatment necessitated withdrawal from the
`
`
`
`
`
`
`study;
`
`
`
`2.3. Assessment ofejficacy
`
`
`
`
`
`
`
`
`
`
`
`The protocol-specified primary end-points were com-
`
`
`
`
`
`
`
`
`
`
`plete control of emesis (CCE), defined as no emetic epi-
`' Ksodcs, no use of rescue medication, and no missing data
`
`
`
`
`
`
`
`
`
`
`during the 4-day period; complete control of nausea
`
`
`
`
`
`
`
`
`(CCN), defined as no nausea, no use of rescue medica-
`
`
`
`
`
`
`
`
`
`tion, and no missing data during the 4-day period; and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`total control of emesis (TCE), defined as no vomiting;
`no nausea, no use of rescue medication, and no missing
`
`
`
`
`
`
`
`
`
`
`data during the 4-day period.
`
`
`
`
`
`immediately after
`randomisation (baseline period)
`
`
`
`
`
`and at the end of each day (days 1-4), all patients were
`
`
`
`
`
`
`
`
`
`
`
`asked to complete a daily diary. These diaries consisted
`
`
`
`
`
`
`
`
`of the number of emetic episodes, the intensity of nau-
`
`
`
`
`
`
`
`
`
`
`sea,
`their assessment of global satisfaction with the
`
`
`
`
`
`
`antiemetic treatment, and general mood at that time.
`
`
`
`
`
`
`
`Since all the patients were inpatients over the 4-day
`
`
`
`
`
`
`
`
`study period, monitoring by direct observation and
`
`
`
`
`
`
`interview was also used. Anemetic episode was defined
`
`
`
`
`
`
`
`
`
`as any episode of vomiting or dry retching. .
`
`
`
`
`
`
`
`
`The patients assessed the intensity of nausea accord-
`
`
`
`
`
`
`
`
`ing to a graded scale: none, mild (did not interfere with
`
`
`
`
`
`
`
`
`
`normal daily life), moderate (interfered with normal
`
`
`
`
`
`
`
`daily life) and severe (bedridden due to nausea).
`
`
`
`
`
`
`
`
`Patient’s global satisfaction with antiemetic treatment
`
`
`
`
`
`
`was assessed using the visual analogue scale (VAS). The
`
`
`
`
`
`
`
`
`
`patient was asked to place a mark on a 100-mm line
`
`
`
`
`
`
`
`where 100 mm was ‘not at all satisfied’ and 0 mm was
`
`
`
`
`
`
`
`
`
`
`‘totally satisfied’.
`
`
`Each patient reported subjective assessment of general
`
`
`
`
`
`
`
`mood day-by-day using a five-point face scale from
`
`
`
`
`
`
`
`“QOL assessment of cancer patients receiving chemo-
`
`
`
`
`
`
`therapy” reported by Kurihara and colleagues [30].
`
`
`
`
`
`
`
`We plotted the daily VAS score and daily face scale
`
`
`
`
`
`
`
`
`
`
`score on a time curve for each patient. The VAS and
`
`
`
`
`
`
`
`
`
`
`face scale profiles were then evaluated on the basis of
`
`
`
`
`
`
`
`
`area under curve (AUC) over the 4-day period calcu-
`
`
`
`
`
`
`
`
`
`lated by trapezoidal summation, and the difference
`
`
`
`
`
`between the baseline score and worst score during the
`
`
`
`
`
`
`
`
`
`study period.
`
`
`
`2.4. Assessment ofscgfetiy
`
`
`
`
`
`
`All adverse events were documented throughout the
`
`
`
`
`
`
`
`study period. Vital signs were recorded before and after
`
`
`
`
`
`
`
`
`
`the administration of the antiemetic or cytostatic ther-
`
`
`
`
`
`
`
`
`apy. Routine haematological and biochemical tests were
`
`
`
`
`
`
`
`performed at
`the same times. The severity of each
`
`
`
`
`
`
`adverse event and its relationship to the study treatment
`
`
`
`
`
`
`
`
`
`was assessed by the investigator.
`
`
`
`
`
`
`
`
`
`'2.5. Statistical analysis
`
`The sample size was calculated assuming that 40% of
`
`
`
`
`
`
`
`
`
`patients assigned to arm A, and at least 65% of the
`
`
`
`
`
`
`
`patients of arm B would achieve total control of emesis.
`
`
`
`
`
`
`
`
`
`With type 1 and 2 errors of 5 and 20%, respectively, it
`
`
`
`
`
`
`
`
`was calculated that 61 patients should be included in
`
`
`
`
`
`
`each arm. To ensure there would be at least 61 patients
`
`
`
`
`
`
`
`
`
`
`assessable for analysis, we decided to include 70 patients
`
`
`
`
`
`
`
`
`
`in each arm.
`
`
`
`
`Page 4 of 9
`
`DTX-0047-0005
`
`
`
`Page 4 of 9
`
`

`
`2400
`
`
`
`‘ii
`
`
`
`H. Tsukadu at (11. / European Journal of Cancer 37 (2001) 2398-2404
`
`
`
`
`
`
`
`
`
`
`
`Recruited or accrued patients
`(n=149)
`
`
`
`
`sidered significant. Received standard Intervention
`
`3. Results
`
`
`
`3.]. Patients’ characteristics
`
`
`
`
`
`
`
`
`
`
`
`
`
`A total of 149 patients entered the study, and 141
`
`
`
`
`
`
`patients were evaluated for eflicacy according to the
`
`
`
`
`
`
`
`intention-to-treat principle. 8 were lost to follow-up and
`
`
`
`
`
`
`
`
`excluded from the analysis (Fig. 1). Toxicity was also
`
`
`
`
`
`
`
`evaluated in these 141 patients. Of the assessable and
`
`
`
`
`
`
`
`eligible patients, 70 received dexamethasone alone (arm
`
`
`
`
`
`
`A) and 71 received ondansetron plus dexamcthasone
`
`
`
`
`
`
`(arm B) as a maintenance treatment. Treatment groups
`
`
`
`
`
`
`
`
`
`were well balanced for sex, age, daily alcohol consump-
`
`
`
`
`
`
`
`
`
`tion, performance status and for cisplatin dose (Table 1).
`
`Received test Intervention
`as allocated
`as allocated
`
`
`
`(I1-=73)
`(n=7G)
`
`Did not receive standard
`
` Did not receive test
`intervention as allocated
`Intervention as allocated
`
`
`
`
`
`(n=0)
`(n=0l
`
`
`
`
`
`
`
`
`
`
`
`
`
`Followed-up (n=73)
`
`Followedup (n=76)
`
`
`
`
`Withdrawn (n=3)
`Intervention lnetieotive (n=0)
`Last to ioliow-up (n=0)
`
`Other (n:-.0)
`
`
`
`
`
`
`
`
`Withdrawn (n=5)
`
`Intervention lnellectlva (n=0)
`Lost to ioliow-up (n=5)
`
`
`Other (n=D)
`
`
`
`
` Completed trial (n—~70)
`
`
`
`
`
`
`
`
`Completed trial (n=T1)
`
`Fig. 1. ‘Flow chart of the progress of patients through the trial (adap-
`
`
`
`
`
`
`
`
`
`
`
`ted from Ref. [29]).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.2. Control of acute emesis (day 1)
`
`
`
`
`
`
`
`
`Analysis of nausea and emesis was performed sepa-
`
`
`
`
`
`
`
`
`
`
`rately for day 1 (acute emesis) and for each day, from
`
`
`
`
`
`
`
`day 2 to day -4, considering the overall results between
`
`
`
`
`
`
`
`
`days 2 and 4 as an evaluation of delayed emesis.
`Fisher’s Exact test was used to evaluate the balance of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`prognostic factors between the two groups, and to
`
`
`
`
`
`examine differences in eflicacy and the incidence of
`
`Overall, complete control of emesis was observed in
`
`
`
`
`
`
`93% and control of nausea was observed in 82% of
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`patients. Between the two randomised groups, no sig-
`
`
`
`
`
`
`
`nificant differences were observed in the complete con-
`trol of vomiting (arm A versus arm B; 93% versus
`
`
`
`
`
`
`
`’93%),'of nausea (84% versus 80%), or of both nausea
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`and vomiting (84% versus 79%). Mean number of
`
`
`
`
`
`
`
`
`
`emetic episodes (0.1 versus 0.1), mean score of maximum
`
`
`
`
`
`
`
`
`
`intensity of nausea (0.2 versus 0.3), and the number of
`
`NS
`
`NS
`
`NS
`
`NS
`
`
`
`V
`
`NS
`
`
`NS
`
`
`NS
`
`
`
`
`1
`
`71
`
`53/13
`
`
`63 (2(F72)
`
`
`
`
`21/46
`
`
`
`66/5
`
`
`
`14
`57
`
`
`
`
`25/46
`
`
`42/29
`
`
`Table 1
`
`Patients’ characteristics
`
`
`
`
`_
`
`Number of patients
`
`
`
`
`
`70
`
`
`
`
`55/15
`
`65 (40-74)
`
`
`
`Sex: male/female
`
`
`
`
`Median age (years) (range)
`Habitual alcohol intake"
`
`
`
`No/Yes
`
`Performance status (ECOG)
`
`
`0-1/2—3
`
`Cisplatin dose (mg/mi)
`
`
`
`< 80
`
`
`
`> 30
`Histological type
`
`
`SCLC/NSCLC
`16/54
`
`Clinical stage
`
`
`I-III/IV
`
`
`
`
`28/37
`
`
`
`63/7
`
`
`
`13
`57
`
`
`
`
`
`
`44/26
`
`
`Dexamethasone alone
`
`
`
`
`Ondansetron plus dexamethasone
`
`
`
`
`
`P value
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`SCLC, small cell lung cancer; NSCLC, non-small cell lung cancer; ECOG, Eastern Co-operative Oncology Group; NS, non significant.
`“ , there are missing data in some categories.
`
`
`
`
`
`
`
`
`
`
`Page 5 of 9
`
`DTX-0047-0006
`
`
`
`adverse events. Mann—Whitney’s U-test was performed
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`to compare treatment groups with respect to intensity of
`
`
`
`
`
`
`nausea, global satisfaction with antiemetic treatments,
`and ‘number of emetic episodes. All P values refer to
`
`
`
`
`
`
`
`two-tailed tests, and P values less than 0.05 were con-
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fiandornised patients
`
`Not randomised (n=O)
`Reasons (give all violation
`
`
`
`of inclusion criteria)
`
`
`
`
`
`
`
`
`
`
`
`
`Page 5 of 9
`
`

`
`'
`
`
`87% 86°/o
`
`
`
`
`(l.96
`
`-74% 75%
`
`“fl
`
`(a) 100
`
`"
`
`
`
`
`
`
`
`P=0.97
`84% 84%
`
`30
`
`
`
`H. Tsu/cada er al. /European Journal of Cancer 37 (2001) 2398-2404
`
`
`
`
`
`
`
`
`
`
`0.81
`90% 89%
`
`
`
`
`2401
`
`
`
`(b) 100
`
`
`
`
` 30
`
`
`
`P=0.76
`0.67
`
`6 0-95 67% 70%
`
`69% 66%
`
`
`
`
`
`
`
`
`
`
`0.94
`
`54% 55%
`
`
`
`
`
`
`
`60
`
`40
`
`Percent
`
`
`
`
`
`20
`
`
`
`Percent
`
`60
`
`40
`
`20
`
`Day 2
`Day 3
`
`
`
`Days 2-4
`Day 4
`
`
`
`
`
`
`
`
`
`
`
`Days 2-4
`
`
`
`
`i,
`
`;
`
`-.-I:--‘1-;1-:~
`
`El ArmA - ArmB
`
`
`
`Fig. 2. Percentages of complete control of delayed (a) ernesis and (b) nausea.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`patients receiving rescue medication (54 versus 55) were
`nearly identical in the two groups.
`
`
`
`
`
`
`
`3 .3 . Comm] of delayed emesis
`
`
`
`
`
`
`The percentages of CCE or CCN on a daily basis over
`
`
`
`
`
`
`
`
`
`
`days 2-4 are shown in Fig. 2. None of the pairwise
`
`
`
`
`
`
`
`
`treatment comparisons of efficacy revealed a statistically
`
`
`
`
`
`
`significant difference. We also found no significant dif-
`
`
`
`
`
`
`
`
`fcrence between the two arms in either total number of
`
`
`
`
`
`
`
`
`
`vomiting episodes per patient during days 2-4
`
`
`
`
`(P=0.8716) or worst grade of nausea intensity duri11g
`
`
`
`
`
`
`days 24 (P = 0.9474).
`
`
`
`
`
`
`As shown in Fig. 3a, TCE rates for the entire study
`
`
`
`
`
`
`
`
`
`
`period (days 2-4) were approximately 50%. TCE rates on
`
`
`
`
`
`
`
`
`
`the individual days and over days 2-4 in the two compar-
`
`
`
`
`
`
`
`
`
`
`
`able arms did not differ significantly. Irrespective of the
`
`
`
`
`
`
`
`
`
`anticmctic treatment received, TCE was achieved in 70
`
`
`
`
`
`
`
`of 115 patients (61%) who did not suffer from emesis on
`
`
`
`
`
`
`
`
`
`
`
`day 1 and in 2 of 26 patients (8%) who suffered from
`
`
`
`
`
`
`
`
`emesis on day 1. This difference was highly significant
`
`
`
`
`
`
`
`
`(P<0.000l). In the subgroup of patients who did not
`
`
`
`
`
`
`
`sufler from either vomiting or nausea on day 1, there
`
`
`
`
`
`
`
`
`were no significant differences in the TCE rates (Fig. 3c).
`
`
`
`
`
`
`
`
`
`
`TCE rates of those who suffered from emesis on day 1
`
`
`
`
`
`
`
`
`
`were also similar in the two treatment groups (Fig. 3b).
`
`
`
`
`
`
`
`
`
`
`
`(b) 100
`
`
`
`
`
`
`
`80
`E so
`8
`
`3 4°
`
`20
`o
`
`
`(0) 100
`an
`
`E 60
`8
`E 40
`20
`
`
`
`(a) 100
`
`
`
`
`30
`
`
`'P=0.52
`
`69% 63%
`
`
`
`0.68
`
`66% 69%
`
`
`
`
`66% 65%
`0-91
`
`
`
`0.67
`
`53% 49%
`
`
`
`
`
`E 6°
`8
`
`ii.’
`
`40
`
`20
`
`0
`
`
`Day 2
`
`
`Day 3
`
`
`Day 2
`
`
`Day 3
`
`
`Days 2-4
`Day 4
`
`
`
`0
`
`Days 2-4
`Day 4
`
`
`
`Fig. 3. Total control rates over days 24 for delayed emesis among (a) total population, (b) the patients who suffered from emesis on day l and
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(c) the patients who did not suffer from emesis on day l.
`
`
`
`
`
`
`
`
`
`
`
`
`|:| Arm A - Arm B
`
`
`
`
`Page 6 of 9
`
`DTX-0047-0007
`
`
`
`Page 6 of 9
`
`

`
`2402
`
`
`
`
`
`H. Tsu/coda et al. /European Journal of Cancer 37 (2001) 23984404
`
`
`
`
`
`
`
`
`
`
`5
`
`
`
`
`
`Face scale
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Baseline
`
`Day 1
`Day 2
`Day 3
`Day 4
`
`
`Baseline Day 1
`Day 2
`Day 3
`
`
`Day 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Fig. 4. Visual analogue scale (VAS) and face scale score profile over the study period. Open circles indicate each scale score profile for the patients
`assigned to arm A and closed circles indicate those for the patients assigned to arm B.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`3.4. Patienzs’ global satisfaction
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Profiles of the mean daily VAS and face scale scores
`
`
`
`
`
`
`
`
`are shown in Fig. 4. Error bars represent the standard
`
`
`
`
`
`
`
`errors. 28 patients were excluded from these analyses
`
`
`
`
`
`because the investigators failed to deliver
`the ques-
`
`
`
`
`
`
`
`tionnaires to 21 of them and because 7 patients stopped
`
`
`
`
`
`
`
`
`filling out the questionnaires halfway through the study
`‘
`period.
`'
`
`
`
`
`
`
`
`
`There was no difference between the groups in the
`
`
`
`
`
`proportion of patients excluded. No statistically sig-
`
`
`
`
`
`
`
`
`nificant differences were recorded between the groups in
`
`
`
`
`
`
`
`
`
`the VAS or face scale score on any one of days 2—4.
`
`Table 2
`
`Adverse events (days 24)
`
`
`
`
`
`
`Dexaincthasone Ondausetron plus
`
`
`dexamethasonc
`alone
`
`
`
`
`
`Pvalue
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`When we calculated the AUC over the 4-day period and
`the difference between baseline and the worst score on
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`these two scales during the study period, no significant
`
`
`
`
`
`
`
`
`
`differences were found between the two arms (Fig. 4),
`
`3.5. Safety
`
`
`
`
`
`
`
`
`
`
`
`No severe or unexpected adverse events were repor-
`
`
`
`
`
`
`ted. Adverse events of grade 3 or 4 were also not
`
`
`
`
`
`
`
`reported. Adverse events of grade 1 or 2 occurred in 34
`
`
`
`
`
`
`
`
`
`
`(49%) of the 70 patients for arm A and in 46 (§5,%) of
`
`
`
`
`
`
`
`
`71 for arm B (P=0.06). Epigastric pain, constipation,
`
`
`
`
`
`
`
`asthenia, heartburn, and insomnia occurred with greater
`
`
`
`
`
`
`
`
`frequency with arm B (8, 23, 27, 6 and l7 %, respec-
`
`
`
`
`
`
`tively) compared with arm A *(l, 21, 21,
`1 and 9%,
`
`
`
`
`
`
`
`respectively). However, there were no significant differ-
`
`
`
`
`
`
`
`
`
`
`
`ences in the rates of each adverse event from days 2 to 4
`
`
`
`
`
`
`
`between the two treatment groups (Table 2).
`
`Number of patients 70
`
`
`
`71
`NS
`
`
`Number (%) of patients suffering adverse event
`
`
`
`
`
`
`
`9 (13)
`4 (6)
`NS
`
`
`
`
`771 (1)
`6 (8)
`NS
`
`
`
`
`
`9 (13)
`7 (10)
`NS
`
`
`
`
`
`IO (14)
`7 (10)
`NS
`
`
`
`
`
`15 (21)
`16 (23)
`NS
`
`
`
`
`
`15 (21)
`19 (27)
`NS
`
`
`
`
`
`1 (1)
`4 (6)
`NS
`
`
`
`
`
`6 (9)
`12 (17)
`NS
`
`
`
`
`4 (6)
`4 (6)
`NS
`
`
`
`
`
`36 (51)
`25 (35)
`NS
`
`
`
`
`Adverse effects“
`
`
`Headache
`
`Epigastric pain
`
`
`Rush
`
`Abdominal gas
`
`Constipation
`
`Asthcnia
`
`Heartburn
`Insomnia
`
`I-Iot flashes
`
`
`None
`
`NS, non significant.
`
`
`
`“ All events were grade 1 or 2.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4. Discussion
`
`
`
`
`
`
`
`
`
`The combination of a corticosteroid plus a 5-HT3
`
`
`
`
`
`
`
`
`antagonist is one of the recommended regimens for cis-
`
`
`
`
`
`platin-induced delayed emesis in the ASCO Clinical
`
`
`
`
`
`
`
`practice guidelines [12]. Several randomised trials have
`
`
`
`
`
`
`shown that the addition of corticosteroids to 5-HT3
`
`
`
`
`antagonists
`significantly improved the
`control of
`
`
`
`delayed emcsis [16,21—23].
`
`
`
`
`
`
`
`
`
`However, there was very limited data on the efficacy
`
`
`
`
`
`
`of dexamethasone alone without 5—HT3 antagonists as
`I
`
`
`
`
`
`
`
`
`background therapy [24]. None of the trials comparing
`
`
`
`
`
`Page 7 of 9
`
`DTX-0047-0008
`
`
`
`Page 7 of 9
`
`

`
`
`
`H. Tsukada at al. / European Journal ofCzmcer 37 (2001) 2398-2404
`
`
`
`
`
`
`
`
`
`
`
`
`2403
`
`
`
`the combination of corticosteroid plus a 5—HT3 antago-
`
`
`
`
`
`
`
`nist with corticosteroids alone determined the benefit of
`
`
`
`
`
`
`
`
`adding 5-HT3 antagonist to corticosteroids in the con-
`
`
`
`
`
`
`trol of delayed emesis [l8—20]. These studies employed
`
`
`
`
`
`
`
`granisetron or tropisetron as a 5—HT3-receptor antagonist.
`
`
`
`
`
`
`Although the majority of multiple, randomised stud-
`
`
`
`
`
`
`
`ies have demonstrated that the four currently available
`
`