:‘PClinica terapeutica.
`. DUP — General Collection
`_W1 CL582
`gv, 150, no. 1
`“ Jan-Feb 1999
`
`
`
`
`
`
`
`
`
`Editoriali
`The first year
`M. Lopez
`
`Gene therapy: Where are we going?
`A. Giordano c G. Romano
`1
`1
`.
`.
`II ruolo della gemcnabma nel trattamento de tumore de -
`1a vescica
`E. Cortcsi e R. Gareri
`
`Resoconto
`215‘ Annual San Antonio Breast Cancer Symposium.
`12-15 dicembre 1998, San Antonio, Texas
`G. Tuvcri
`
`1
`
`3
`
`5
`
`Opinione
`Aspetti bioetici del Viagra T”
`M. Soldini,
`
`Rassegnc
`Dexrazoxane. Attualita e prospettive nella protezio-
`ne dalla cardiotossicita indotta da chemioterapia
`M. Lopez
`
`Ruolo della TC e della RM nella identificazione, ca—
`ratterizzazione e stadiazione deIIa patologia neoplasti-
`ca della colonna vertebrale
`G.F. Gun/(1i, E. Casciani, C. Di Biasi, er a].
`
`7
`
`Dispepsia ed IIelicobactcr pylori
`AM. Care/[(1, G. Bionco, V. D'Alcssandro. et al.
`
`Articoli originali
`Single-agent 2’,2’-difluorodeoxycytidine in the treatment
`of metastatic urothelial carcinoma: A phase II study
`V. 001111111, A- Tcsm, N. BorscllinO. er ('1‘
`
`Gemcitabina nei sarcomi dei tessuti n1011i in fuse avan-
`zata: studio di fase II
`A. Amodio, S. C(IVIWIO, C- Manfredi' 6’ “1-
`
`Age-related changes in blood pressure twenty-four—hour
`pattern in normotensive subjects of two populations cha-
`racterized by “non-salt” and “salt” cultures in their ha-
`bituaI diet
`P. Cugini, T. Kawasaki, P. Lucia, era].
`
`Bowel function in runners after ingestion of sweeteners
`A. D’Alcssandro c S. Scri
`
`1 1
`
`17
`
`21
`
`29
`
`Caso Clinico
`Docetaxel nel trattamento del carcinoma metastatico del-
`Ie ghiandole salivari: presentazione di un caso clinico
`F. Belli, L. Di Lauro, A. Zappanico c S. Giunra
`
`Pietro Miliari nella Riccrca Biomedicz
`La terapia della malaria tra i1 XIX e il XX secolo
`A. M0lfcSe
`
`Novitfi
`P. FoggieA./1nmdio
`
`33
`
`37
`
`51
`
`67
`
`77
`
`81
`
`87
`
`,§W I’%7///ll\\\\§
` NATIONAL
`
`mm
`[mmvalet-n mmum ol mum
`
`PROPERTY OF THE
`
`LIBRARY OF
`MEDICINE
`
`
`
`Contiene 1.1’.
`
`
`Societa Editrice Universo — Roma
`Via G.B. Morgagni I
`- 00161 Roma
`ALVOGEN, Exh. 1020. p. 0001
`
`7......
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`ALVOGEN, Exh. 1020, p. 0001
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`

`
`
`La Clinica Terapeutica
`
`Volume 150, N. 1
`
`
`Gennaio-Fcbbraio 1999
`
`Sommario/Contents
`
`Editoriali/Editorials
`
`The first year
`M. LOPEZ
`
`Bowel function in runners after ingestion of
`sweeteners
`A. D’ALESSANDRO AND S. SERI
`
`Gene therapy: Where are we going?
`A. GIORDANO AND G. ROMANo
`
`I] ruolo della gemcitabina ncl Irattamcnto dcl
`lumorc dclla vcscica
`.
`The role of gemcitabine in the treatment of
`urothelial carcinoma
`E. CORTESI E R. GARERI
`
`Resoconto/Commentary
`21° Simposio Annualc di San Antonio sul Can—
`cro dclla mammella. 12-15 Diccmbrc 1998, San
`Antonio, Texas
`21st Annual San Antonio Breast Cancer Sym-
`posium. 12-15 December I 998, San/\ntonio, Texas
`G. TUVERI
`
`Articoli originali/Original articles
`Single—agent 2’,2’-difluorodeoxycytidine in the
`treatment ofmetastatic urothelial: A phase II study
`V. GEBEIA, A. TESTA, N. BORSELLINO, G. MAU—
`CERI, F. VARVARA, M.L. TIRRITO, D. SAMBATARO
`AND G. FALLICA
`
`Gcmcitabina nci sarcomi dei tcssuti molli in fasc
`avanzata: studio di fasc II
`
`Gemcitabine in the treatment ofsoft tissue sar-
`comas: A phase II trial
`A. AMODIO, S. CARPANO, C. MANFREDI, G. DEL
`MONTE, L. DI LAURO, T. GIONFRA, F. CONT], G.
`PAOLET'I‘I E M. LOPEZ
`
`Age-related changes in blood pressure IWC’NI)“
`four-hour pattern in normotensive subjects of
`two populations
`P. CUGINI, T. KAWASAKI, P. LUCIA, G. LEONE, A.
`FELOSIO AND K. UEZONO
`
`11
`
`17
`
`21
`
`Opinione/Opinion
`Aspctti bioclici dc] ViagraTM
`Bioethics aspects ofViagraTM
`M. SOLDINI
`
`Rasscgnc/Rcviews
`Dcxrazoxanc. Attualitz‘l c prospcuivc nclla pro—
`lczionc dalla cardiotossicitfi indotta da chcmio-
`
`terapia
`Dexrazoxane. Present status and perspectives
`in amelioration of chemotherapy induced car-
`diotoxicity
`M. LOPEZ
`
`Ruolo dclla TC e della RM nclla idcntificazio-
`no, caratlcrizzazionc c sladiazionc della pato—
`logia neoplastica della colonna vcrtebralc
`CT and MRI ofthe tumors of the spine
`G.F. GUALDI, E. CASCIANI, C. D1 BIASI, G. TRASI-
`MEN] E F. POSTACCIHNI
`
`Dispepsia ed Helicobacter pylori
`Dyspepsia and Helicobacter pylori
`A.M. CARELLA, G. BIANCO, V. D’ALESSANDRO, M.
`VILLELLA, G. D’AMICO, G. MAZZOCCOLI, M. SPE-
`RANDEO, M.A. ANNESE E G. SABELLA
`
`Caso clinico/Clinical case
`Docctaxcl ncl trattamcnto dcl carcinoma meta-
`statico dellc ghiandolc salivari: prcscnlazionc
`di un caso clinico
`Docetaxel in the management of metastatic
`carcinoma of the salivary glands: A case
`report
`F. BELLI, L. D1 LAURO, A. ZAPPANICO E S. GIUNTA
`
`29
`
`33
`
`37
`
`51
`
`67
`
`75
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`ALVOGEN, Exh. 1020, p. 0002
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`ALVOGEN, Exh. 1020, p. 0002
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`

`

`
`
`Pietro Miliari nclla Riccrca BiomedicalMile-
`
`Novitix/Ncws
`
`stones in Biomedical Research
`La tcrapia dclla malaria Ira i1 XIX e il XX sccolo
`The therapy of malaria between 19’“ and 20’“
`century
`A. MOLFESE
`
`81
`
`P. F000] 13 A. AMODIO
`
`85
`
`Istruzioni per gliAutori/Instructions to Authors
`
`m S
`
`ISSN 0009 - 9047
`
`ocicu‘l Edilricc Universo (S.E.U.)
`La Clinica Terapeutica é pubblicata bimcslralmcntc.
`La corrispondcnza cditorialc v21 indirizzula a: Massimo Lopez, La Clt'nica Terapeutica, Via G.B. Morgagni,
`Roma
`
`Le richicstc di abbonamcnto vzmno inviatc alla Socictfi Editricc Univcrso, Via G.B. Morgagni, 1 - 00l61 Roma.
`[1 costo dcll’abbonamcnto annuo é di fl. 100.000 pcr l’ltalia e di £. 200.000 per l’Estcro. Pcr 1a pubblicitz‘i, ordini di numcri
`arrctrati cd altrc infornmzioni. rivolgcrsi a: Sociclfi Editricc Univcrso s.r.l., Via G.B. Morgagni, 1
`- Roma.
`Tel. (06) 4402053 - 4403054 - 4423117] - Fax (06) 4402033 - E-Mail: SEUCOM@pclagus.it
`
`ALVOGEN, Exh. 1020, p. 0003
`
`l
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`- 00161
`
`ALVOGEN, Exh. 1020, p. 0003
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`

`

`La Clinica Terapeutica
`
`
`
`La Clinica Terapculica e una rivista multidisciplinare ehe pubblica articoli e rassegne (in italiano e inglese) con implicazioni
`prevalentemcnte tcrapcutiche. Sono, tuttavia, presi in considerazione anche lavori increnti la ricerea di base purehé orientati in
`senso clinico terapeutico.
`
`Direttorc scientifico/ Scientific Director
`
`Massimo Lopez, Roma, ltalia/Rome, Italy
`
`Direttore Associato per la Medicina Molecolare/ Associate Director for Molecular Medicine
`Antonio Giordano, Filadelfia, USA/Philadelphia, USA
`
`Comitato Scientifico/ Scientilic Committee
`
`Giorgio Areangeli Roma, ltalia/Rome, ltaly
`Edoardo Arcuri Roma, ltalia/Rome, ltaly
`
`Tullio Battelli Ancona, Italia/ Ancona, Italy
`
`Pietro Bria Roma, ltalia/ Rome, ltaly
`Paolo Brunctti Perugia, Italia/ Perugia, Italy
`Cesare Bumma Torino, ltalia/ Turin, Italy
`
`Lucio Capurso Roma, ltalia/ Rome, Italy
`Renato Cavalicre Roma, ltalia/ Rome, ltaly
`
`Giuseppe Colucci Bari, ltalia/ Bari, Italy
`Mario Condorelli Napoli, ltalia/ Naples, Italy
`Pietro Cugini Roma, Italia/ Rome, Italy
`Franco Dammacco Bari, ltalia/ Bari, ltaly
`Carlo Maria Foggi Roma, ltalia/ Rome, Italy
`Zvi Fuks New York, USA
`
`Nicola Gebbia Palermo, ltalia/Palermo, ltaly
`
`Paolo Gentilini Firenze, ltalia/Florence, ltaly
`
`Ezio Giovannini Roma, ltalia/Rome, ltaly
`
`Fiorella Guadagni Roma, ltalia/Rome, ltaly
`Giuseppe Guarini Roma, ltalia/Rome, ltaly
`Carlo Ludovico Maini Roma, ltalia/Rome, ltaly
`
`Enrico Malizia Roma, ltalia/Rome, ltaly
`
`Carmine Melino Roma, ltalia/Rome, ltaly
`
`Piergiorgio Natali Roma, ltalia/Rome, ltaly
`Eugenio Paroli Roma, ltalia/ Rome, Italy
`Ada Sacchi Roma, ltalia/ Rome, Italy
`Eugenio Santoro Roma, ltalia/ Rome, Italy
`Jamey Sclilom Bethesda, USA
`Gabriella Zupi Roma, ltalia/ Rome, Italy
`
`Comitato di Redazione/ Editorial Committee
`
`Antonella Amodio Roma, Italia/ Rome, Italy
`Mauro Antimi Roma, ltalia/ Rome, Italy
`Carlo Barone Roma, Italia/ Rome, Italy
`
`Vittorio Gebbia Palermo, ltalia/ Palermo, ltaly
`Carlo Federico Perno Roma, ltalia/ Rome, Italy
`
`Redazione/ Editorial Office
`
`- 00161 Roma, ltalia
`Paola Pironti - Societa Editrice Universo, Via G.B. Morgagni, l
`Tel. (06) 44231 171 - 4402053 - 4402054 — Fax (06) 4402033
`E-Mail: SEUPUB@pelagus.it
`
`_——__—’_—__——__—_——
`
`La Clinica Tcrapcutica e citata in: INDEX MEDlCUS - MEDLINE - EMBASE/Excerpta mediea
`
`ALVOGEN, Exh. 1020, p. 0004
`
`ALVOGEN, Exh. 1020, p. 0004
`
`

`

`Original article
`
`Clin Ter 150: 11-15, 1999
`
`Single agent 2’,2’-difluorodeoxycytidine in the treatment of
`metastatic urothelial carcinoma: a phase II study
`
`V. Gebbia, A. Testa‘, N. Borsellinoz, G. Mauceri, F. Varvara‘, M.L. Tirrito3, D. Sambataro and G. Fallica
`
`Division Medical Oncology, Centro Catanese di Oncologia, Catania, ’Division ofOncology, Clinica Macchiarella, Palermo. 2 Division
`ofMedical Oncology, Dipartimento Oncologico ad Alta Specialita, La Maddalena, 3 Service ofOncology, Clinica Torina, Palermo, Italy
`
`Abstract
`
`Riassunto
`
`Purpose: To evaluate the therapeutic activity and toxicity of
`gemcitabine in the treatment of metastatic urothelial carcinoma.
`Patients and Methods: TWenty—four consecutive patients with
`recurrent- and/or metastatic urothelial carcinoma pretreated with first
`line cisplatin-based chemotherapy were treated with gemcitabine
`1000 mg/m’lweck intravenously diluted in 250 cc of normal saline
`as 20 minutes infusion for 3 consecutive weeks followed by a 1 week
`
`rest period. Chemotherapy was repeated every 28 days.
`Results: All enrolled patients were evaluable for objective
`response accordingly to an intent-to-trcat analysis. A complete re-
`sponse was achieved in 1 patient (4%) and a partial response in 6
`cases (25%) for an overall response rate of 29% (confidence limits
`18%-39%). The median duration of objective responses was 7.4+
`months (range 3.0+/12.8). Six patients showed no change (25%) with
`a median duration of 4.0 months. A subjective improvement in tumor-
`related symptoms was reported by all responding patients, and in 3
`patients with no change. Six out of 9 patients with symptomatic bone
`lesions had a subjective improvement with reduction in analgesic
`drugs consumption. Objective responses were observed at all sites
`of disease. The median overall survival was l3.0+ months (range
`4.0/162+). Over a total of 76 cycles (a mean of 3.1 cycles/patient),
`grade 1-2 leukopenia was seen in 9 patients (37%), grade 1-2
`thrombocytopcnia in 4 patients (17%), and grade 1 anemia in only 2
`03505 (8%). Grade 3 leukopenia was seen in 3 cases (12.5%). Grade
`4 leukopenia or grade 3-4 thrombocytopcnia were not seen. Gastro-
`intestinal toxicity was very mild.
`Conclusions: Single agent gemcitabinc at the dose of 1000 mg/
`m2 on a weekly schedule is active, at least in terms of objective
`response rate and tumor-related symptoms palliation. against
`pretreated urothelial carcinoma with good tolerability. These results
`compare favorably with those achieved with the most active drugs
`such as cisplatin and methotrexatc.
`
`Obiettivo: Lo scopo principale di questo studio era di valuta-
`re l’efficacia terapeutica e la tossicita della gemcitabina nel trat-
`tamento dei carcinomi uroteliali metastatici.
`
`Pazienti e Metodi: Ventiquattro pazienti (pz) consecutivi con
`carcinoma uroteliale recidivato e/o metastatico pretrattati con
`
`chemioterapia di 1“ linea a base di cisplatino sono stati trattati
`con gemcitabina 1000 mg/ml/sett. diluita in 250 cc di soluzione
`fisiologica e somministrata come infusione ev di 20 minuti per 3
`settimane consecutive seguite da 1 settimana di intervallo ogni
`28 giorni.
`Risultati: Tutto i pz arruolati crano valutabili per risposta sc-
`condo un’analisi intent-to-trcat. Una RC e stata ottenuta in 1 pz
`
`(4%), una RP in 6 casi (25%) per un tasso di risposta obiettiva
`complessivo del 29% (limiti di confidenza 18%-39%). La durata
`mediana della risposta obiettiva era di 7.4+ mesi (range 3.0+/
`12.8). Sci pz hanno ottenuto una SD (25%) con una durata mediana
`di 4.0 mesi. Tutti i pz in risposta obiettiva e 3 con SD hanno
`ottenuto un miglioramento soggettivo con riduzione del consu-
`mo di analgesici. Una risposta obiettiva e stata osservata in tutti i
`siti di malattia. La sopravvivenza mediana é stata di 13.0+ mesi
`(range 4.0/162+). Su un totale di 76 cicli (media 3.1 cicli/pz). 9
`pz hanno mostrato una leucopenia di grado 1-2 (37%). 4 pz una
`piastrinopenia di grado 1-2 (17%), e 2 pz un’anemia di grado 1.
`Una leucopenia di grado 3 e stata registrata in 3 casi (12.5%).
`Conclusioni: La gemcitabina somministrata come agente sin-
`golo alla dose di 1000 mg/mzlsctt. a: attiva, almcno in termini di
`risposta obiettiva e di palliazione dei sintomi legati al tumore,
`nei confronti dei carcinomi uroteliali pretrattati con buona tol-
`lerabilita. Questi risultati sono paragonabili a quelli riportati per
`altri farmaci attivi quali il cisplatino ed il methotrexatc.
`
`Key words: Chemotherapy, gemcitablne, metastases, urothelial
`cancer
`
`Parole chlave: Carcinoma uroteliale, chemioterapia, gemcitabina,
`metastasi
`
`Introduction
`
`Urothelial carcinoma is one of the leading most
`common types of cancer in Western countries (1).
`
`Although several patients with muscle-invading disease
`can be cured by locoregional therapies, however a
`significant percentage of patients will develop pelvic
`recurrence and/or distant metastatic disease (1,2). Once
`
`Correspondence: Vittorio Gebbia MD, PhD, Division Medical Oncology, Ccntro Catanese di Oncologia, Via V.E. Dabormida n. 64,
`95100 Catania, Italy. Fax. : 095-336989
`
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`

`
`
`12 V. Gebbia et al.
`
`metastatic disease is found the prognosis of patients in
`term of overall survival usually is less than 9 months
`(1-3).
`For these obvious reasons many medical oncologists
`have shown considerable interest
`in developing newer
`and more active therapies for advanced urothelial
`carcinoma. Results achieved by Sternberg et a]. (4,5)
`with the chemotherapeutic combination of methotrexate,
`vinblastine, doxorubicin, and cisplatin, the so called M-
`VAC regimen, in metastatic urothelial carcinoma have
`been outstanding. However, although the M-VAC regi-
`men has been shown to be able to improve survival of
`patients with metastatic urothelial carcinoma, the use of
`such schedule is often associated to severe and poten—
`tially life-threatening side effects. Patients treated with
`full-dose M-VAC regimen experience some degree of
`vomiting and complete alopecia in almost all cases,
`neutropenia in 25-60% of cases with febrile neutropenia
`in 10-25%, and grade 3—4 mucositis in 15% of patients
`(4-6). The M-VAC related toxicities, mainly myelosup—
`presion and mucosal damage, have been reduced with
`the use of hematopoietic growth factors, such as granu-
`l0Cytc - or granulocyte/macrophage colony stimulating
`factors (7-9). Although the incidence and severity of
`chemotherapy-related side—effects, use of antibiotics, and
`length of hospitalization have been significantly reduced
`by the use of colony stimulating factors, however it was
`not possible to increase dosage of M-VAC (7,8). There-
`fore, benefits in term of survival an disease control
`should be weighted against number and degree of side-
`effects. Patients who reach complete objective response
`show a maximal benefit, but the incidence of complete
`regression is low and is usually seen in patients with
`low metastatic burden. Moreover, objective response rate
`and duration of response in patients with bone and liver
`metastases is far to be satisfactory (10,11). A recent
`prospective study (5), comparing the M—VAC regimen
`to single agent cisplatin in a large number of patients,
`showed a clear advantage of the combination regimen
`over single-agent chemotherapy in terms of objective
`response rate (39.5% versus 12%). However, the overall
`response rate was not satisfactory as well as the median
`survival of only 8.2 and 12.5 months for patients treated
`with cisplatin alone or with M-VAC regimen respectively.
`2’.2’-Difluorodeoxycytidine (gemcitabine, GEM) is
`a new dcoxycytidine analogue with structural and meta—
`bolic similarities to arabinosylcytosine (cytarabine,
`ARA-C) (13). The two compounds differ from the parent
`nucleoside for a modification at the 2’ position of their
`structure (13). GEM has been shown to be more active
`than ARA-C against a wide range of malignant neopla-
`sms, with a particular schedule dependency with
`Intermittent administration being superior to continuous
`exposure (13,14). This peculiar activity may be related
`to the cellular pharmacokinetics of GEM whose 5'-
`triphosphate form intracellular concentration may be 20
`fold greater that that observed for ARA-C (14). These
`differences may be explained by gemcitabine increased
`cellular membrane penetration, higher affinity for the
`enzyme dcoxycytidine kinase, and a longer intracellular
`retention due to a series of self-potentiating mechanisms
`
`(14). GEM exerts its antineoplastic activity inhibiting
`DNA synthesis.
`In this paper we report pour experience with GEM
`monochemotherapy in a small series of patients with
`chemotherapy-pretreated, recurrent and/or metastatic
`urothelial carcinoma. Results in terms of response rate,
`duration of response, overall survival and toxicity pattern
`are reported.
`
`Materials and Methods
`
`Entry criteria
`
`Before entry into the study all patients had to fulfill the foll-
`owing inclusion criteria: histological diagnosis of urothelial
`carcinoma previously treated with chemotherapy and not more
`amenable with surgery; age S 75 years; performance status
`according to Karnofsky Index 2 60; life expectancy 2 3 months;
`clinically measurable disease according to W110 criteria (14);
`adequate bone marrow function (WBC Z 4,000/mmc, platelets
`2 120.000/mmc); serum bilirubin S 1.2 mg/dl; serum creatinine
`S 1.2 mg/dl and BUN S 50 mg/dl o clinically detectable brain
`metastases; no second malignant neoplasm, except adequately
`treated in situ carcinoma of the cervix and cutaneous basal cell
`carcinoma; at least 4 week interval since last antineoplastic
`treatment; no sign of severe chemotherapy-related toxicities that
`could be worsened by subsequent chemotherapeutic treatment;
`no severe and/or uncontrolled concomitant cardiovascular,
`
`respiratory, metabolic or neurological disease. Informed consent
`was required from all patients due to the investigative nature of
`the study.
`
`Staging procedures
`
`Before starting chemotherapy all patients were extensively
`staged with physical examination, medical history, chest X—ray,
`abdominal sonograms, 99Tc bone scan, hematological and routine
`chemistry tests, ECG, and CT scan of the involved sites. Most of
`the above mentioned procedures were used to define the objective
`response at restaging after 2 complete cycles of chemotherapy.
`
`Treatment plan
`
`Eligible patients were treated as follows: GEM 1000 mg/m/
`week was given intravenously diluted in 250 cc of normal saline
`as 30 minutes infusion once a week for 3 weeks followed by a 1
`
`week rest period. Chemotherapy was repeated every 28 days.
`Metoclopramide was employed as antiemetic therapy 15 minutes
`before starting chemotherapy, and subsequently as needed. In
`selected cases methylprednisolone 125 mg iv was employed to
`enforce antiemetic therapy. Duration of chemotherapy was
`strictly dependent on type of objective response :
`if partial
`response or stable disease were achieved chemotherapy was
`continued until progressive disease or unacceptable toxicity
`ensued. In case of complete regression of all signs and symptoms
`chemotherapy was stopped after 6 months. In case of progressi- .
`ve disease, third line chemotherapy or best supportive care were
`given as needed.
`
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`13
`2’,2’-Difluor0dcoxycytidinc in urothelial cancer
`___—____—____________________._—__———-—-——
`
`Response assessment and statistics
`
`Table 1. Patients characteristics
`
`Patients were evaluated for objective response after a minimum
`of 2 cycles according to the WHO criteria (14). Briefly. complete
`response was the complete disappearance of all signs of at least 4
`weeks; partial response as a 2 50% n the sum of the products of
`the major perpendicular diameters of all measurable lesions for
`at east 4 weeks without the appearance of any new lesions; no
`change or stable disease as a < 50% reduction or < 25% increase
`in the size of tumoral lesions; and progression is the appearance
`of new tumoral deposits or a 2 25% increase in the size of pre-
`existing lesions. Responses have been reported as relative rates
`with 95% confidence limits.
`
`Duration of response was calculated from the day when
`chemotherapy was started until the date of documented pro-
`gression. Survival was calculated from the day of registration until
`last follow—up or death. Univariatc analysis ofduration ofresponse
`and overall survival was calculated employing the product-limit
`estimate of Kaplan and Meier (15). All statistical analysis were
`performed with the IMPD Statistical Software (Cork, Ireland) and
`an IBM personal computer.
`
`Side-effects
`
`Chemotherapy - related toxicity was reported accordingly to
`the W.H.O. criteria. A detailed interview of enrolled patients and
`
`complete hemat010gical and laboratory chemistry tests were
`obtained before each administration of GEM. In case of hemato-
`logical toxicity, GEM dosage was reduced accordingly to the
`degree of toxicity. Briefly. for WHO grade 3 leukopenia and/or >
`grade 2 thrombocytopenia GEM dosage was reduced to 75% of
`the initial dosage. In case of prolonged myclosuppression GEM
`was omitted for 1 week. Any > grade 3 extra —- hematological
`toxicity caused patient withdrawal from the study.
`
`Results
`
`Patients population
`
`Twenty-four consecutive patients with recurrent and/
`or metastatic urothelial carcinoma pretreated to first line
`chemotherapy were enrolled into the study. The patients‘
`main clinical characteristics are shown in table 1. Briefly,
`enrolled patients had a median age of 61 years (range
`40-75) with a median performance status according to
`the Karnofsky Index of 80 (range 60-90). Fifteen patients
`had previously received surgery (62%), 4 patients had
`radiotherapy (17%), 13 patients Chemotherapy adjuvant
`‘0 surgery (54%) and 14 (58%) for advanced disacase.
`Among the latter group, 10 patients had M-VAC regimen
`and 4 cisplatin plus methotrexate. Most patients (71%)
`had multiple sites of disease which included liver, lung,
`bone, nodes.
`
`Objective response and survival
`
`Types and duration of objective response are shown
`in Table 2. All enrolled patients were evaluable for
`
`No. of enrolled patients
`
`Median age (range)
`
`Sex
`
`Male
`Female
`
`Median PS (Karnofsky Index)
`
`Histology
`Transitional cell carcinoma
`— well dilterentiated
`— moderate
`-— poorly differentiated
`Unditlerentiated carcinoma
`
`‘Previous treatments
`
`surgery
`radiotherapy
`chemotherapy
`adjuvant therapy
`advanced disease
`
`Sites of disease
`
`bone
`node
`liver
`lung
`pelvis
`
`Number of involved sites
`
`24 (100%)
`
`61 (40-75)
`
`19 (79%)
`05 (21%)
`
`80 (60-90)
`
`22 (83%)
`03
`08
`to
`02 (17%)
`
`15 (62%)
`04 (17%)
`
`13 (54%)
`14 (58%)
`
`09 (37%)
`10 (42%)
`(37%)
`08 (33%)
`08 (33%)
`
`07 (29%)
`single
`17 (71%)
`multiple
`_______________________————-——
`
`Table 2. Type of objective response
`_______________.._._____._———————
`
`Median duration
`N. of patients
`Response
`(months)
`(percent)
`_______________________‘_._—————
`
`Complete response
`
`01 (04%)
`
`Partial response
`
`Overall response
`
`Stable disease
`
`06 (25%)
`
`07 (29%)
`
`06 (25%)
`
`7.4+ months
`
`4.0 months
`
`not applicable
`11 (46%)
`Progression
`__________________._._’—~—-—
`
`objective response accordingly to an intent-to-treat
`analysis One complete response was achieved. A partial
`response was achieved in 6 cases (25%) for an overall
`response rate of 29% (95% confidence limits 18%-39%).
`The median duration of objective responses was 7.4+
`months (range 3.0+/12.8). Six patients showed no change
`(25%) with a media duration of 4.0 months, I 1 patients
`progressed (46%). A subjective improvement in tumor—
`related symptoms was reported by all responding
`patients, and in 3 patients with no change. Several
`patients (6/9) with symptomatic bone lesions had a
`subjective improvement with reduction in analgesic
`
`ALVOGEN, Exh. 1020, p. 0007
`
`ALVOGEN, Exh. 1020, p. 0007
`
`

`

`14
`V. Gebbia et al.
`
`drugs consumption. Objective responses were observed
`at all sites of disease.
`In fact responses were seen in at
`liver, lung, bone and nodal metastases. The median
`overall survival was l3.0+ months (range 4.0/16.2).
`
`Toxicity
`
`Over a total of 76 cycles (a mean of 3.2 cycles/
`patient), grade l-2 leukopenia was seen in 9 patients
`(37%), grade 1-2 thrombocytopenia in 4 patients (17%),
`and grade 1 anemia in only 2 cases (8%). Grade 3
`leukopenia was recorded in 3 cases (12.5%); grade 4
`leukopenia or grade 3-4 thrombocytopenia were not seen.
`Grade 1-2 non infectious fever was recorded in 8 patients
`(33%) and was easily controlled by steroid parenteral
`administration. Alopecia was virtually absent. Gastro-
`intestinal toxicity was very mild with 9 patients (37%)
`suffering from grade 1-2 nausea/vomiting, 2 patients
`(17%) complaining of grade l-2 diarrhea, and 2 patients
`with grade 1-2 stomatitis (17%). No cases of grade 3-4
`gastrointestinal toxicities have been observed. No cases
`of cardiotoxicity and/or neurotoxicity were recorded.
`
`Discussion
`
`Recurrent and/or metastatic urothelial carcinoma is
`considered a chemotherapy-sensitive malignancy even
`if clinical results in terms of duration oftumor regression
`and overall survival are still considered unsatisfactory.
`To date, the standard regimen, i.e. the combination of
`methotrexate, vinblastine, doxorubicin, and cisplatin (M-
`VAC), is able to induce a major objective response is
`35-60% of treated patients, but the overall long-term
`survival has been disappointing while toxicity has been
`severe in a significant percentage of cases. Therefore,
`search for newer active, and tolerated antineoplastic
`drugs is a primary goal for investigative oncologists.
`Gemcitabinc has been tested in advanced urothelial
`carcinoma with excellent tolerability and interesting
`actrvrty as reported in two small phase I—II trials (17,18).
`In the trial carried out by Pollera et al. (17) a 27% overall
`response rate has been observed in a series of 14
`prevrously treated patients receiving gemcitabine 1200
`mg/m2/week. In the phase II trial by Stadler et al. (18) 5
`out of 9 previously untreated patients achieved a major
`response phase II studies, while in the study reported by
`Moore et al. a 38% overall response rate has been yield
`in a series of 21 patients (19).
`In our trial 24 consecutive patients with recurrent and/
`or metastatic urothelial carcinoma pretreated with first
`line etsplatin-based chemotherapy were treated with
`gemcitabine 1000 mg/m2/weck for 3 consecutive weeks
`followed by a 1 week rest period. In our hands this
`schedule was able to yield a complete response in 1
`patient (4%) and a partial response in 6 cases (25%) for
`an overall response rate of 29% (confidence limits 18%-
`39%) with a median duration of7.4+ months (range 3.0+/
`12.8) and a median overall survival of 130+ months. A
`subjective improvement in tumor-related symptoms was
`
`reported by all responding patients, and in 3 patients with
`no change. Six out of9 patients with symptomatic bone
`lesions had a subjective improvement with reduction in
`analgesic drugs consumption. This schedule was very
`well tolerated by most patients with grade 1-2 leukope-
`nia, thrombocytopenia, and nausea/vomiting being the
`most frequent side-effects. Grade 3-4 toxicity was vir-
`tually absent. These data are in the range reported in
`medical literature on recurrent and/or metastatic uro—
`
`thelial carcinoma (17-19), and compare favorably with
`data achieved with other active drugs such as cisplatin,
`methotrexate, and anthacyclines.
`In conclusion clinical data above—presented strongly
`suggest that gemcitabine is a very active antineoplastic
`drug against advanced urothelial carcinoma and may be
`considered as one of the most effective antitumoral
`
`agents. Moreover, gemcitabine may be safely admini-
`stered even to previously treated patients with good tole-
`rability. These characteristics may be important for the
`treatment of those patients with recurrent an/or meta-
`static urothelial carcinoma which are not suitable for ag-
`gressive chemotherapy such as the M-VAC — like regi-
`mens. Further. clinical investigations with gemcitabine
`in combination with other active drugs are warranted.
`
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`