,
`
`Vol.28A No.6/7
`Published in May 1992
`
`ISSN 0964--1947
`
`IN THIS ISSUE
`
`Comments and Critique
`
`Papers
`
`Feature Articles
`
`Book Reviews
`
`News
`
`Letters
`
`1009
`
`1014
`
`1182
`
`1282
`
`1284
`
`' I
`
`1293
`
`The Official Journal of:
`
`EORTC - European Organization for Research and Treatment of Cancer
`ESQ
`- European School of Oncology
`EACR - European Association for Cancer Research
`- Federation of European Cancer Societies
`FECS
`
`I
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`Celltrion, Inc., Exhibit 1029
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`

`

`Alms end Scope
`The ~vropean Joumaf of Cancer (EJC) rs an international 1ournal lhal publishes
`Oftg1nal research, editorial commenl. re111ew articles. book reviews news. and
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`1 Jiang FN. Liv DJ. Neyndorff H. ChPsle-r M Jiang S· Y Luy JG Photodynamrc
`k1llmg or hl~man squamous cell carcinoma cell~ usmg a monoclonal antibody·
`photosens1hzercon1u gate J Nari Cancer Ins t 1991 83. 121 8 1225
`Gulhck WJ. Venter DJ The c·er-b62 and its expression m human tumours. In
`Waxman J, Sikora K, eds The Molecular 81ufogy nf C.1nc('r 0 1dord Blackwell
`Sc.ent1~c Pubhca11ons 1989 38 53
`Lumley JSP, Green C J Lear P, Angell-James JE Essen11a1s ol EKpenmemaJ
`Surgery. London Butterworths 1990
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`The European Journal of Cancer
`
`Volume 28A, Number 617
`
`Comments and Critique
`A. P. M. Heintz
`
`B. Modan
`
`0. Bang
`
`CONTENTS
`
`HXl9
`
`Sequential cisplatin - doxorubicin, early debulking in advanced ovarian cancer
`
`1010
`
`Low-dose radiation carcinogenesis
`
`1012
`
`EC proposal for directive can destroy the possibili ties of eaneer research
`
`I. S. Fcntiman and U. Chetty
`
`1013
`
`Axillary surgery in brea;t cancer-is there still a debate?
`
`Papers
`M. D. Brooks, S. R . Ebbs, A . A. Colletta
`and M. Ba um
`
`1014
`
`Desmoid tumours treated with triphenylethylenes
`
`K. Bremer on behalf or che Graniserron Study Group
`
`1018
`
`A single-blind study of the efficacy and safely of intravenous granisetron
`compared with alizapride plus dexamethasone in the prophylaxis and control of
`emesis in patienh receiving 5-day cytostatic therapy
`
`M.A. Richards, P . Hopwood , A. J. Ramirez,
`C. J . Twelves, J . Ferguson, W. M. Gregory,
`R . Swindell , W. Scrivener, J. Miller, A. Howell and
`R . D . Ruben;
`
`1023
`
`Doxorubicin in advanced breast cancer: influence of schedule on response, survival
`a nd quality o f life
`
`D . A. Vernier~. R . B. Keus. P. F. Schouwenburgand
`H. Bartclink
`
`1028
`
`Radiation therapy, an important mode of treatme nt for head and neck
`ehemodectomas
`
`M. Bilous. J . Milliken a nd J .-M . Mathij;
`
`P.A. Palmer. J . Vinke, P. Evers. C. Pourreau,
`R. Oskam , G. Rocst, F. Vlems, L. Becke r, E. Loriaux
`and C. R . Fra nks
`
`J. Richner, R . A. Joss, A. Goldhirsch and
`K . W. Brunner
`
`H . Thomas, C. Barto n, A. Sa ini. A . Dalgleish and
`.I. Waxman
`
`M. G. Leahy. D . Pitfield , S . Popen, C. J. Gallaghe r
`a nd R. T . D . Oliver
`
`1033
`
`1038
`
`1044
`
`1047
`
`1049
`
`lmmunocytochemistryand in .1iru hybridisa tion of epidermal growth factor receptor
`and relation to prognostic factor~ in breast cancer
`
`Continuous infusion of recombinant interleukin-2 with or without autologous
`lymphokine activated kille r cells for the treatment or advanced renal cell ca rcino ma
`
`Phase II study of eontinuo u; subcutaneous interferon-al fa combined with eisplatin
`in advanced maligna nt me lanoma
`
`Sequential inte rleukin-2 and alpha interferon for renal cell ca rcinoma and
`melanoma
`
`Phase I study compa ring continuous infusion o f recombinant inierle ukin-2 by
`subcutaneous o r intraveno us administration
`
`M. Bolla, M. C hedin , M. Colonna, J . Marron.
`B. Rostaing-Puissani and E. C hambaz
`
`1052
`
`Prognostic value of epidermal grow1h factor receptor in a series of 303 breast
`cancers
`
`G. Ciccone, P . Vineis, A. Frigerio and N . Segnan
`
`1054
`
`Inte r-observer and intra-observer variability of mammogram interpretation:
`a field study
`
`K. Miyauehi, H. Koyama, S . Noguchi , H . Inaji ,
`H . Yamamoto, K. Kodama and T. lwa naga
`
`M. Omne-Ponten, L. Holmberg . T . Burns,
`H . 0. Adami and R. Bergstrom
`
`R. Mondina, G. Borsellino, S. Pom a, M. Baroni.
`B. Di Nubila and P . Sacchi
`
`J . H e rrsredt. P. Clcmentsen and 0 . P . Hansen
`
`G . P . van dcr Schelling, J. N . M. IJze rmans, T . C.
`Kok , M. Schcringa . R . L. Ma rque t , T. A. W. Splinte r
`and J. Jcekcl
`
`A. Alama, F. Merlo, S. Chiara , M. P. Muttini,
`T. Guido, G. Nicolo , P . F. Conte and N. Ragni
`
`D . Tummarello, P. lsidori, F. Pasini. G. Cctto and
`R. Ccllc rino
`
`1059
`
`Surgical treatment for chest wall recurrence of breast cancer
`
`1062
`
`Determinants of the psycho-social outcome after operation for breast cancer.
`Results of a prospective comparat.ivc interview study following mastectomy and
`breast conservation
`
`1068
`
`Breast carcinoma and skele tat formation
`
`1070
`
`1073
`
`1079
`
`1081
`
`Increased myelosupprcssion during cywstatic treatment and pleural effu~ion in
`patients with small cell lung cancer
`
`A phase I study o f local treatment of liver metastases with recombinant tumour
`necrosis fact.o r
`
`Pred iction o f survival by thymidine labelling index in patients with rcsistan1 ovarian
`carcinoma
`
`Teniposidc as single drug therapy for elderly patients affected by small cell lung
`cancer
`
`Pnnre>c1 in ( lrf>~t Rnl ~in hv liPCC Wlw>:tlnn'> I ril F.Y~t~r
`
`Comirwed o verleaf
`
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`

`Conrirmed from previous page
`
`Z. Agnr, R. Amon and B. Schechter
`
`M. D. Mason and M. F. Pera
`
`M. Boiocchi and G. Toffoli
`
`T. G. Baier, W-D. Ludwig, D. Schiinherg and
`K. K. P. Hartmann
`
`A . M. E. Nouri. R. F. Hussain, A. V. L. Do' Santo,,
`D. J. Gillott and R. T. D. Oliver
`
`L. Losi, J. Ben haltar and J. Costa
`
`1085
`
`1090
`
`HJ99
`
`1105
`
`Effeet of the dosing interval on myclotoxicity and snrvival in mice treated hy
`eytarahine
`
`ln1111unohistoehe111ical and biochemical characlcnsalion o f the cxpres,ion of a
`hun1an emhryonal carcinoma cell protcoglycan antigen in human germ cell tumours
`and other tissues
`
`Mechanism of multidrug resistance in human tumour cell line>. and complete
`reversion of cellular resistance
`
`Characterisa1ion of insulin-like growth factor l recepto" of human acute
`lymphoblastic leukaemia (ALL) cell lines and primary ALL cells
`
`1110
`
`Induction of MHC antigens by tumour cell lines in respo n'e lo interferons
`
`1115
`
`Stahility of K-rm mutation' throughout che natural history of human colorcctal
`cancer
`
`M. Rof\,'iel, E . Seilles, J-J. Voigt. D. Yuitton, N. Legait 1120
`and J-P. Revillard
`
`Polymeric Tg receptor expression in hcpatocdlular carcmom<1
`
`S. K. Das, T. Z. Jia. A. M. Bandyopadhyay and
`M. R. Banerjee
`
`1124
`
`~-Caro1ene-mediated inhibition of a DNA adduct induced by 7.12-dimethylhenz
`(a)anthracene and 7-hydroxymcthyl-12-mclh} lhcnz(a)anthraccnc in mome
`mammary gland in vitro
`
`C. Chauzy, B. Delpech, A. Olivier, C. Bastard,
`N. Girard, M-N. Couret, C. Maingonnat, T. Frebourg,
`J . Tayot and P. Creissard
`
`S. A. Copland, K. C. McHardy. K. W. J. Wahle and
`A. W. Hutcheon
`
`R. Yan Ginckel, W. Di,telmans, M. De Brabander,
`M. Callens, B. Janssens, E. Jagers, L. Wouters.
`R. De Coster a nd P . A. J. Janssen
`
`P. Sminia, G. Los, J. J. G. W. Hendriks,
`M. J. H. van Vugt, J. Haveman and D. Gonzalez
`Gonzalez
`
`1129
`
`Establishment and characteri;acion of a human glioma cell line
`
`11)5
`
`Ahered plate lei sccaric to oleic acid ratio m malignancy
`
`I lJ7
`
`Levami,olc plus 5-ftuorouracil inhibit; the grnwth of human colorcclal xcnogram
`in nude mice
`
`1139
`
`The influence of hypenhermia 011 chc uptake of cisplatin in the rat cervical spinal
`cord
`
`B. F. Fermor, J. R. W. Masters, C. B. Wood, J. Miller. 1143
`K. Apostolov and N. A. Habib
`
`Fatty acid compo;ition of normal and malignant cell> and cytotoxicily of 'ccaric.
`oleie and ;terculie acid; in viiro
`
`L. J. Yatcen and S. Kvinnsland
`
`1148
`
`Pregnancy-re lated factor' and risk of breast cancer in a prospective 'Ludy of 29981
`Norwegian women
`
`D. M. Ingram, A. Robercs and E. M. Nottage
`
`1153
`
`Ho't factors and breast cancer growth characteristic'
`
`D. W. Wilson, A. Turkes, R. Jones, Y. Danutra.
`G. F. Read and K. Griffiths
`
`1162
`
`A comparison of menstrual cycle profiles of salivary progc,tcrone in B ritish and
`Thai adolescent girls
`
`E. Negri, C. La Vecchia, S. Franceschi, A . Decarli
`and P. Bruzzi
`
`1167
`
`Attributable risks for oeso phageal cancer in northern Italy
`
`R. Zanetci, S. Franceschi, S. Rosso , S. Colonna and
`E. Bidoli
`
`1172
`
`Cutaneous melanoma and sunburn; in childhood in a So uthern European
`population
`
`M. Ewe rtz
`
`1176
`
`Oral contraceptive' and breast cancer risk in Denmark
`
`Feature Articles
`M. Marselos and L. Tomatis
`
`P. Workman, M. D'Incalci, W . E. Berdel.
`M. J. Egorin, C. Hele ne, J . A. Hickman, M. Jarman,
`G . Schwansmann and K. Sikora
`
`1182
`
`Diethybtilboe,trol: I. pharmacolog}, toxicology and carcinogenicity in humam
`
`1190
`
`New approaches in cancer pharmacology: drug design and development
`
`0. H . Iversen
`
`1200
`
`Cell kinetic alterations during epidermal carcinogenesis
`
`C. La Vecchia, F. Lucchini, E . Negri. P. Boyle ,
`P. Maisonneuve and F. Levi
`
`1210
`
`Trends of cancer mortality in Europe , 1955-1989: IV, urinary tract . e ye . brain and
`nerves, and thyroid
`
`Pnn1cd 111 Grc;u Rnr<tUI hy HP(.T Wtic;-110n~ Ltd. Exeter
`
`Co 111rrwed o verleaf'
`
`298
`
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`

`Co111inued f rom p revwus page
`
`Book Reviews
`F. Rilke
`
`D . Neal
`
`G . E. Adams
`
`News
`
`Letters
`H. D. Preisler and A. R aza
`
`S. Lowry
`
`1282
`
`Tumour.1Structure 111111 Dw11nosis b} R. C. Curran a nd E . L. .lone'
`
`Essay.1 j (Jr the Urolo~i>f. Um'.ogicu/ Oricoloi;y- Dilemmas uml l>n•t•lopme111s by
`A. R. Aldc l'son, R. I . D. Ohvc r. I. W. F. Ha nham a nd Ii . .I . G. Bloom
`
`Pho!O.\emitisi11g Compounds: Their Chem istry, Biology a11d Clinical use by T. J .
`Dougherty
`
`1282
`
`1283
`
`1284
`
`1293
`
`Problem s associated with the stud y of cytokincs in patie nts with leukaemia
`
`1293
`
`Handedness and breast cancer
`
`A. 0 rbo and E . Simo nsen
`
`1294
`
`Cispla tin-induced sodium and magnesium wastage
`
`G. Falkson and B. L. Rapoport
`
`1294
`
`Lethal toxic epide rma l nccrolysis during suramin treatment
`
`S. J. H arla nd and G. M. D uchesne
`
`I 295
`
`Suramin and prostate cancer: the role of hyd rocortisone
`
`W. de Riese, E . A llhoff, S. Liedke , M. Werner, H.
`Kirchner a nd J. Atzpodien
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`12% Compari,;on of growth fractio n with tumou r stage and grade in rena l cell ca rcinoma
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`D . G he rsi. M. K. B. Pa rmar, L.A. Stewart, S. Marsoni 1297
`and C. J. W''liams
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`Early ovarian cancer a nd the Icon trials
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`1298
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`Sociocultural habits and urological malignancies in Ibadan, Nigeria
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`M . Hadjiyanni, K. Valianato u, M . T~ilianos a nd
`6. ~eitan idis
`
`1299
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`Prolonged thrombocytopenia afte r procarbazinc "overdose'
`
`J.WilsandH.O.Klcin
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`1299
`
`MMAF for advanced gastric cancer
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`E. N. Imyanitov, 0. I. C he rnitsa. 0. M. Scrova and P.
`G. Knyazev
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`1300
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`R are occurrence of amplification of HER-2 (erb B-2/neu ) oncogene in ovarian
`cancer patie nts
`
`Indexed/Abstracted in: Current Contenls; Excerpla Medica;
`index Medicus; MED LIN E; CABS; B IOSIS Database;
`PASCA L-CNRS Database
`
`/SSN0964-1947
`EJCO DS 28A(617) 1009- 1300(1992)
`
`Published by
`PERGAMON PRESS Oxford · New York · Seoul · Tokyo
`
`5 of 11
`
`Celltrion, Inc., Exhibit 1029
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`

`

`E"'J Canar, Vol. Z8tl, No 617,pp IOZJ-/OZ8, 199Z
`Pn.!fttd m Grf'al Bnra1n
`
`Doxorubicin in Advanced Breast Cancer: Influence
`of Schedule on Response, Survival and Quality of
`Life
`M.A. Richards, P. Hopwood, A.J. Ramirez, C.J. Twelves, J. Ferguson,
`W.M. Gregory, R. Swindell, W. Scrivener,}. Miller, A. Howell
`and R.D. Rubens
`
`The influence of scheduling of doxorubicin on response, survival and quality of life was assessed in a randomised
`trial in patients with advanced breast cancer, none of whom had previously received cytotoxic chemotherapy for
`advanced disease. 28 patients received 75 mg/m2 doxorubicin every 3 weeks for four courses (arm 1) and 31
`patients received 25 mglm2 weekly for 12 courses (arm 2). Response rates and median time to progression were
`similar in the two arms and median survival was 8 months in both arms. However, amongst patients receiving
`treatment every 3 weeks, psychological distress measured using the Rotterdam symptom checklist feU significantly
`over the course; no such change was observed in those treated weekly. Physical symptoms related to cancer
`improved during treatment similarly for both groups.
`Eur J Cancer, Vol. 28A, No. 617, pp. 1023-1028, 1992.
`
`INTRODUCTION
`THE MANAGEMENT of patients with metastatic breast cancer is
`essentially palliative in intent. Breast cancer is moderately
`sensitive to several cytotoxic agents, of which doxoru bicin is
`generally considered to be the most active, with response rates
`between 40 and 57% when given at doses of 60-75 mg/m2 every
`3 weeks to previously untreated patients (1, 2]. The optimum
`dose and schedule of administration for doxorubicin has, how(cid:173)
`ever, not been established [3]. The importance of dose was
`shown in a randomised study, in which patients who received
`70 mg/m2 doxorubicin every 3 weeks had a higher response rate
`and a longer median survival than those receiving 35 mg/m2
`every 3 weeks [4]. Dose intensification has recently been investi(cid:173)
`gated as a possible way of increasing the efficacy of ueaunent
`[5-9). Response rates up to 85% have been reported for patients
`receiving doxorubicin at doses between 75 and 135 mg/m2
`, given
`at monthly intervals [6]. These high doses of doxorubicin are
`associated with marked toxicity including severe myelosuppres(cid:173)
`sion, stomatitis and potential cardiotoxicity, but there is no
`definite evidence that such high dose intensity treatment pro(cid:173)
`longs survival.
`Although doxorubicin is conventionally given every 3 weeks,
`weekly treatment is also effective and may reduce the incidence
`of cardiotoxicity [10]. The efficacy and toxicity of weekly and
`every 3 weeks doxoru bicin treatment given at equal planned dose
`intensities (mg/m 2/week) have not, however, been compared in
`a prospective trial. In this study patients with metastatic breast
`cance'r who had not previously received cytotoxic chemotherapy
`for advanced disease were randomised between two regimens
`
`Correspondence to M.A. Richards.
`M.A. Richards, A.J. Ramirez, C. J. Twelves, W.M. Gregory, W.
`Scrivener and R.D. Rubens are ac the Imperial Cancer Research Fund,
`Clinical Oncology Unit, Guy's Hospical, London SEl 9RT, U.K. and
`P. Hopwood, J . Ferguson, R. Swindell, J. Miller and A. Howell are ac
`the Cancer Research Campaign, Department of Medical Oncology,
`Chriscie Hospital and Holt Radium Instimte, Manchester, U.K.
`Revised 13 Nov. 1991; accepted 28 Jan. 1992.
`
`with the same planned dose intensity: doxorubicin 25 mg!m2
`weekly or 75 mg/m 2 every 3 weeks. The efficacy of the two
`treatment schedules was compared using the standard par(cid:173)
`ameters of response and survival. An important feature of this
`trial was an attempt to compare the quality of life for patients
`receiving the cwo different schedules. At present there is no
`single agreed approach to the measurement of quality of life
`[11). For the purposes of rhis study, assessment of qualicy
`of life involved patients' reports of psychological symptoms,
`physical symptoms, levels of physical activity, practical diffi(cid:173)
`culties associated with treaunent and a global evaluation of
`quality of life. In this paper, aspects of che Rotterdam symptom
`checklist (RSCL) (12] concerning psychological adjustment and
`physical symptoms are presented. Full results of the quality of
`life assessments will be reported elsewhere. Pharmacokinetic
`studies were undertaken during the first cycle of treatment in a
`subset of these patients [13].
`
`PATIENTS AND METHODS
`Between July 1987 and June 1989, 59 patients were entered
`into this randomised phase III study at Guy's Hospital and the
`Christie Hospital. All patients had histologically proven breast
`cancer witb either metastatic (11 = 53) or locally recurrent
`disease which was not considered curable (11 = 6). None had
`received previous cytotoxic chemotherapy for advanced disease.
`Patients who had received prior adjuvant chemotherapy were
`eligible provided this had not included an anthracycline. Other
`eligibility criteria were as follows: age less tban or equal to 75
`years; measurable or evaluable disease; a life expectancy of at
`least 3 months and a performance score of 0-2 on the WHO
`scale [14]. Patients with a performance score of 3 due solely to
`immobility resulting from the presence of bone metastases were
`also eligible. Approval was obtained from local committees on
`ethical practice and all patients gave informed consent.
`count
`a
`peripheral white
`blood
`Patients with
`(WBC) < 3.0 x 109/l or a platelet count < 70 x 109/l were
`excluded as were those with a serum bilirubin > 25 µmol/l or
`
`1023
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`Celltrion, Inc., Exhibit 1029
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`1024
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`M.A. Richards el al.
`
`an aspanate transaminase level greater than twice the upper limit
`of normal. Other exclusion criteria were as follows: symptomatic
`cerebral metastases confirmed by compmer tomography (CT)
`or MRI; prior or concomirant malignancy (with the exception
`of adequately treated carcinoma in situ of the cervix or non(cid:173)
`melanomatous skin cancer); any condition preventing adequate
`follow up or weekly attendance at the hospital; active uncon(cid:173)
`trolled infection; a history of congestive cardiac failure, signifi(cid:173)
`cant arrhythmias or bifascicular bundle branch block.
`
`Trealment
`Patients were randomly allocated to receive either four courses
`of doxorubicin 75 mg/m2 given by slow intravenous bolus injec(cid:173)
`tion every 3 weeks (arm l)or 12 courses of doxorubicin 25 mg/m2
`given weekly (arm 2). For patients in arm 1, the second, third
`and fourth cycles of chemotherapy were given only if the blood
`count on day 21 showed WBC > 3.0 x 109/I and platelets
`> 100 x 109/l. If the blood counts had not recovered to these
`levels, treatment was delayed until these values were reached.
`During the first cycle of chemotherapy a nadir blood count was
`measured on day 10 and the dose of doxorubicin was modified
`for subsequent courses according to these results. For patients
`in arm 2 of the study no such dose reductions were made.
`Treatment was given each week if the WBC was > 2.0 x 109/I
`and platelets were > 70 x 109/l on the day chemotherapy was
`due. If the blood count was below these levels trearment was
`deferred for one week or until these values were attained.
`At the completion of planned treatment patients who had
`stable disease or had responded were observed without specific
`therapy until there was objective evidence of disease progression.
`Treatment on relapse varied, but patients who had shown a
`good response to doxorubicin generally received this again.
`
`lnvestigalions and assessment of relapse
`Before starting treatment a full medical history was taken
`from each patient and a clinical examination was performed.
`Performance status was graded by WHO criteria [14). Tbe
`dimensions for all measurable sites of disease were recorded and
`all visible lesions were photographed. A full blood count,
`biochemieal screen, chest radiograph, ECG and radionuclide
`bone scan were performed on all patients. Plain radiographs
`were taken of all suspicious lesions detected on bone scan.
`Ultrasound or radionuclide liver scans were undertaken in
`patients with hepatomegaly or abnormal liver biochemistry.
`Responses were assessed according to UICC criteria [IS].
`Clinical assessment of response was made every 3 weeks. In
`patients with pulmonary or pleural disease, chest radiographs
`were repeated at 6 week intervals . Plain radio graphs of evaluable
`bone lesions were performed every 3 months and at the time
`of clinical progression. Liver metastases were also reassessed
`radiologically at 3 month intervals.
`
`Quality of life assessmenl
`Quality of life was assessed using a 30 item version of the
`RSCL [12]. Eaeh item is scored between 0 (not at all) and 3
`(very much). Seven of the items within the RSCL are concerned
`with psychological symptoms. These are: worrying; feeling
`irritable; feeling nervous; feeling depressed; feeling anxious;
`feeling tense; feeling despondent about the furnre. Possible
`scores on this 7 item psychological subscale range from 0 to 21.
`The RSCL was administered before treatment, at the midpoint
`of treatment and at the completion of trearment. Providing there
`were no delays in therapy, the second and third assessments
`
`were performed 6 weeks and 12 weeks afcer starting treatment.
`Toxicity for each cycle of rreatmenc was graded according to
`WHO criteria [14].
`
`Statistical analysis
`Response to the two treatments was compared using the x2
`test. Time to progression and survival from the date of first
`treatment with doxorubicin were calculated by the Kaplan and
`Meier method [16), the treatments being compared by the log(cid:173)
`rank test. Quality of life scores for patients in the two arms of
`the study at individual time points were compared using the
`Wilcoxon rank sum test. Changes in quality of life scores over
`time in each arm of the study were assessed by Friedman's 2-
`way analysis of variance. Quality of life data were analysed on