“Clinica terapeutica.
`- DUP - General Collection
`W111 CL582
`Vv, 150, no. 4
`™ Jan-Feb 1999
`
`
`
`
`
`
`Editoriali
`The first year
`M. Lopez
`
`Genetherapy: Where are we going?
`A. Giordano e G, Romano
`a.
`Il ruolo della’ gemcitabinaneltrattamento del tumore del-
`la vescica
`E. Cortesi e R. Gareri
`
`Resoconto
`21" Annual San Antonio Breast Cancer Symposium.
`12-15 dicembre 1998, San Antonio, Texas
`G. Tuveri
`
`Articoli originali
`Single-agent 2’ 2’-difluorodeoxycytidine in the treatment
`of metastatic urothelial carcinoma: A phaseIT study
`V. Gebbia,A. Testa, N. Borsellino, et al.
`
`Gemcitabina nei sarcomi dei tessuti molli in fase avan-
`zata: studio di fase II
`A. Amodio, S. Carpano, C. Manfredi, et al.
`
`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-
`bitual diet
`P. Cugini, T. Kawasaki, P. Lucia, etal.
`
`Bowel function in runnersafter ingestion of sweeteners
`A. D’ Alessandro e S. Seri
`
`l
`
`3
`
`5
`
`7
`
`11
`
`17
`
`21
`
`29
`
`Opinione
`Aspetti bioetici del Viagra™
`M.Soldini.
`
`Rassegne
`Dexrazoxane. Atiualita e prospettive nella protezio-
`ne dalla cardiotossicita indotfa da chemioterapia
`M. Lopez
`
`Ruolo della TC e della RM nella identificazione, ca-
`ratterizzazione e stadiazione della patologia neoplasti-
`ca della colonna vertebrale
`G.F. Gualdi, E. Casciani, C. Di Biasi, et al.
`
`Dispepsia ed Helicobacter pylori
`A.M. Carella, G. Bianco, V. D’ Alessandro, et al.
`
`Caso clinico
`Docetaxelneltrattamento del carcinoma metastatico del-
`le ghiandole salivari: presentazione di un caso clinico
`F. Belli, L. Di Lauro, A. Zappanicoe S. Giunta
`
`Pietre Miliari nella Ricerca Biomedics
`La terapia della malaria tra il XIX e il XX secolo
`A. Molfese
`
`Novita
`P. Foggi e A. Amodio
`
`33
`
`37
`
`51
`
`67
`
`77
`
`8]
`
`87
`
`
`
`PROPERTY OF THE
`SVvzFis
`NATIONAL
`LIBRARY OF
`|MEDICINE] MATIONAL [XSTITUTED OF HEALTH
`MEDICINE
`
`LIBRARY OF}
`
`‘‘ontiene LP.
`
`
`
`Societa Editrice Universo — Roma
`Via G.B. Morgagni 1 - 00161 Roma
`ALVOGEN, Exh. 1020, p. 0001
`
`—
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`ALVOGEN, Exh. 1020, p. 0001
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`

`

`
`
`La Clinica Terapeutica
`
`Volume 150, N. 1
`
`
`Gennaio-Febbraio 1999
`
`Sommario/Contents
`
`Editoriali/Editorials
`The first year
`M. Lorez
`
`Gene therapy: Where are we going?
`A. GIORDANO AND G. ROMANO
`
`Il ruolo della gemcitabina nel trattamento del
`tumoredella vescica
`The role of gemcitabine in the treatment of
`urothelial carcinoma
`E. Correst & R. GARERI
`
`Resoconto/Commentary
`21° Simposio Annuale di San Antoniosul Can-
`cro della mammella. 12-15 Dicembre 1998, San
`Antonio, Texas
`21st Annual San Antonio Breast Cancer Sym-
`posium, 12-15 December1998, San Antonio, Texas
`G. TUVERI
`
`Articoli originali/Original articles
`Single-agent 2’ ,2’-difluorodeoxycytidine in the
`treatmentofmetastatic urothelial: A phase I study
`V. Gepaia, A. Testa, N. BORSELLINO, G. Mau-
`CERI, F. Varvara, M.L. Tirrito, D, SAMBATARO
`AND G. FALLICA
`
`Gemcitabina nei sarcomi dei tessuti molli in fase
`avanzata: studio di fase II
`Gemcitabine in the treatment of soft tissue sar-
`comas: A phase II trial
`A. Amonio, S. Carrano, C. Manrrepl, G. DEL
`Monte, L. Di Lauro, T. Gionrra, F. ConTI, G.
`PAOLETTI E M. Lopez
`
`Age-related changesin blood pressure twenly-
`four-hour pattern in normotensive subjects of
`nwo populations
`P. Cucint, T, Kawasaki, P. Lucia, G. LEONE, A.
`PELOSIO AND K. UEzONO
`
`21
`
`Bowel function in runners after ingestion of
`sweeteners
`A. D’ ALESSANDRO AND S. SERI
`
`Opinione/Opinion
`Aspetti bioctici del Viagra™
`Bioethics aspects of Viagra™
`M. SOLDINI
`
`Rassegne/Reviews
`Dexrazoxane. Attualita e prospettive nella pro-
`tezione dalla cardiotossicita indotta da chemio-
`terapia
`Dexrazoxane. Present status and perspectives
`in amelioration of chemotherapy induced car-
`diotoxicity
`M. Lopez
`
`Ruolo della TC ¢ della RM nella identificazio-
`ne, caratterizzazione ec stadiazione della pato-
`logia ncoplastica della colonna vertebrale
`CT and MRIof the tumors of the spine
`G.F. Guatot, E. Casciant, C. Di Biasi, G. TRAS!-
`MENI E F, POSTACCHINI
`
`11
`
`Dispepsia ed Helicobacter pylori
`Dyspepsia and Helicobacter pylori
`A.M. Care.La, G. Bianco, V. D’ALESSANDRO, M.
`VILLELLA, G. D’Amico, G. Mazzoccoul, M. SPE-
`RANDEO, M.A. ANNESE E G. SABELLA
`
`Caso clinico/Clinical case
`Docetaxel nel trattamento del carcinoma meta-
`statico delle ghiandole salivari: presentazione
`di un caso clinico
`Docetaxel in the management of metastatic
`carcinoma of the salivary glands: A case
`report
`F. Bett, L. Di Lauro, A. Zappanico ES. GIUNTA
`
`29
`
`33
`
`37
`
`51
`
`67
`
`715
`
`ALVOGEN, Exh. 1020, p. 0002
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`ALVOGEN, Exh. 1020, p. 0002
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`

`

`
`
`Pietre Miliari nella Ricerca Biomedica/Mile-
`stones in Biomedical Research
`La terapia della malaria tra il XIX ¢ il XX secolo
`The therapy of malaria between 19" and 20"
`century
`A. MOLFESE
`
`81
`
`Novita/News
`P. Foca! & A, AMopio
`
`85
`
`Istruzioni per gli Autori/Instructions to Authors
`
`eee
`
`ISSN 0009 - 9047
`
`Socicta Editrice Universo (S.E.U.)
`La Clinica Terapeutica & pubblicata bimestralmente.
`Lacorrispondenzaeditoriale va indirizzata a: Massimo Lopez, La Clinica Terapeutica, Via G.B. Morgagni,
`Roma
`Le richieste di abbonamento vanno inviate alla Societa Editrice Universo, Via G.B. Morgagni, | - 00161 Roma.
`Il costo dell’abbonamento annuoé di £. 100.000 perI'Italia ¢ di £. 200.000 perI’Estero.Perla pubblicita, ordini di numeri
`arretrati ed altre informazioni, rivolgersi a: Societa Editrice Universos.r.1., Via G.B. Morgagni, |
`- Roma.
`Tel. (06) 4402053 - 4403054 - 44231171 - Fax (06) 4402033 - E-Mail: SEUCOM@pelagus.it
`
`1
`
`- 00161
`
`ALVOGEN, Exh. 1020, p. 0003
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`

`

`La Clinica Terapeutica
`
`
`
`La Clinica Terapeutica & una rivista multidisciplinare che pubblica articoli ¢ rassegne (in italiano ¢ inglesc) con implicazioni
`prevalentemente terapeutiche. Sono, tuttavia, presi in considerazione anche lavori inerenti la ricerca di base purchéorientati in
`senso clinico terapeutico.
`
`Direttore scientifico/ Scientific Director
`Massimo Lopez, Roma,Italia/Rome,Italy
`
`Direttore Associato per la Medicina Molecolare/ Associate Director for Molecular Medicine
`Antonio Giordano, Filadelfia, USA/Philadelphia, USA
`
`ComitatoScientifico/ Scientific Committee
`
`Giorgio Arcangeli Roma,Italia/Rome,Italy
`Edoardo Arcuri Roma,Italia/Rome,Italy
`Tullio Battelli Ancona, Italia/ Ancona,Italy
`Pictro Bria Roma,Italia/ Rome, Italy
`Paolo Brunetti Perugia,Italia/ Perugia,Italy
`Cesare BummaTorino, Italia/ Turin, Italy
`Lucio Capurso Roma,Italia/ Rome, Italy
`Renato Cavaliere Roma, Italia/ Rome, Italy
`Giuseppe Colucci Bari, Italia/ Bari, Italy
`Mario Condorelli Napoli, Italia/ Naples, Italy
`Pietro Cugini Roma,Italia/ Rome, Italy
`Franco DammaccoBari, Italia/ Bari, Italy
`Carlo Maria Foggi Roma,Italia/ Rome,Italy
`Zvi Fuks New York, USA
`
`Nicola Gebbia Palermo, Italia/Palermo, Italy
`Paolo Gentilini Firenze,Italia/Florence, Italy
`Ezio Giovannini Roma,Italia/Rome, Italy
`Fiorella Guadagni Roma,Italia/Rome, Italy
`Giuseppe Guarini Roma,Italia/Rome, Italy
`Carlo Ludovico Maini Roma,Italia/Rome, Italy
`Enrico Malizia Roma, Ialia/Rome, Italy
`Carmine Mclino Roma, Italia/Rome, Italy
`Piergiorgio Natali Roma, Italia/Rome, Italy
`Eugenio Paroli Roma,Italia/ Rome, Italy
`AdaSacchi Roma,Italia/ Rome,Italy
`Eugenio Santoro Roma,Italia/ Rome, Italy
`Jeffrey Schlom Bethesda, USA
`Gabriclla Zupi Roma,Italia/ Rome, Italy
`
`Comitato di Redazione/ Editorial Committee
`
`Antonella Amodio Roma,Italia/ Rome,Italy
`Mauro Antimi Roma, Italia/ Rome,Italy
`Carlo Barone Roma,Italia/ Rome,Italy
`
`Vittorio Gebbia Palermo,Italia/ Palermo,Italy
`Carlo Federico Perno Roma,Italia/ Rome, Italy
`
`Redazione/ Editorial Office
`
`- 00161 Roma, Italia
`Paola Pironti - Socicta Editrice Universo, Via G.B. Morgagni, |
`Tel. (06) 44231171 - 4402053 - 4402054 - Fax (06) 4402033
`E-Mail: SEUPUB@pclagus.it
`
`EET
`
`LaClinica Terapeutica & citata in: INDEX MEDICUS - MEDLINE - EMBASE/Excerpta medica
`
`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 phaseII study
`
`V. Gebbia,A. Testa!, N. Borsellino?, G. Mauceri, F. Varvara’, M.L. Tirrito’, D. Sambataro and G,Fallica
`Division Medical Oncology, Centro Catanese di Oncologia, Catania, ' Division ofOncology, Clinica Macchiarella, Palermo,?Division
`ofMedical Oncology, Dipartimento Oncologico ad Alta Specialita, La Maddalena, ? Service ofOncology, Clinica Torina, Palermo,Italy
`
`Abstract
`
`Riassunto
`
`Purpose: To evaluate the therapeutic activity and toxicity of
`gemcitabinein the treatment of metastatic urothelial carcinoma.
`Patients and Methods: Twenty-four consecutive patients with
`recurrent- and/or metastatic urothelial carcinomapretreated withfirst
`line cisplatin-based chemotherapy were treated with gemcitabine
`1000 mg/m’/week intravenously diluted in 250 cc of normal saline
`as 20 minutesinfusion 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-treat 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% (confidencelimits
`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 wasreported by all responding patients, and in 3
`paticnts with no change.Six outof 9 patients with symptomatic bone
`lesions had a subjective improvement with reduction in analgesic
`drugs consumption. Objective responses were observedatall sites
`of disease. The median overall survival was 13.0+ months (range
`4.0/16.2+), Over a total of 76 cycles (a mean of3.1 cycles/paticnt),
`grade 1-2 leukopenia was scen in 9 patients (37%), grade 1-2
`thrombocytopeniain 4 patients (17%), and grade | anemia in only 2
`cases (8%). Grade 3 leukopenia was seen in 3 cases (12.5%). Grade
`4 leukopenia or grade 3-4 thrombocytopenia were not scen. Gastro-
`intestinal toxicity was very mild.
`Conclusions: Single agent gemcitabineat the dose of 1000 mg/
`m? on a weekly schedule is active, at least in terms of objective
`response rate and tumor-related symptoms palliation, against
`pretreated urothelial carcinoma with goodtolerability. Theseresults
`compare favorably with those achieved with the most active drugs
`such ascisplatin and methotrexate.
`
`Obiettivo: Lo scopo principale di questo studio era di valuta-
`re l’efficacia terapeutica ¢ la tossicita della gemcitabina nel trat-
`tamento dei carcinomi urotcliali metastatici.
`Pazienti e Metodi: Ventiquattro pazienti (pz) consecutivi con
`carcinoma uroteliale recidivato c/o metastatico pretrattati con
`chemioterapia di 1* linea a base di cisplatino sono stati trattati
`con gemcitabina 1000 mg/m*sett. diluita in 250 cc di soluzione
`fisiologica e somministrata comeinfusione ev di 20 minuti per 3
`settimane consecutive scguite da 1 settimana di intervallo ogni
`28 giorni.
`Risultati: Tutto i pz arruolati crano valutabili per risposta se-
`condo un’analisi intent-to-treat. Una RC é stata ottenuta in | pz
`(49%), una RP in 6 casi (25%) per un tasso di risposta obicttiva
`complessivo del 29% (limiti di confidenza 18%-39%). La durata
`mediana della risposta obiettiva era di 7.4+ mesi (range 3.0+/
`12.8). Sei pz hanno ottenuto una SD (25%) con una durata mediana
`di 4.0 mesi. Tutti i pz in risposta obicttiva ¢ 3 con SD hanno
`ottcnuto un miglioramento soggettivo con riduzione del consu-
`mo di analgesici. Una risposta obicttiva ¢ stata osservata in tutti i
`siti di malattia. La sopravvivenza mediana é stata di 13.0+ mesi
`(range 4.0/16.2+). 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 é stata registrata in 3 casi (12.5%).
`Conclusioni: La gemcitabina somministrata comeagente sin-
`golo alla dose di 1000 mg/m?/sctt.¢ attiva, almenoin termini di
`risposta obiettiva ¢ 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 methotrexate.
`
`Key words: Chemotherapy, gemcitabine, metastases, urothelial
`cancer
`
`Parole chiave: Carcinomauroteliale, 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 discase
`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, Centro Catanese di Oncologia, Via V.E. Dabormidan. 64,
`95100 Catania, Italy. Fax. : 095-336989
`
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`
`
`12 V. Gebbia et al.
`
`metastatic disease is found the prognosis ofpatients 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 al. (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-VACregi-
`men has been shownto 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-VACrelated toxicities, mainly myelosup-
`presion and mucosal damage, have been reduced with
`the use of hematopoietic growth factors, such as granu-
`locyte - or granulocyte/macrophage colonystimulating
`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, howeverit was
`not possible to increase dosage of M- VAC(7,8). There-
`fore, benefits in term of survival an discase control
`should be weighted against number and degreeofside-
`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
`Mctastases is far to be satisfactory (10,11). A recent
`Prospective study (5), comparing the M-VAC regimen
`to single agent cisplatin in a large numberof patients,
`Showed a clear advantage of the combination regimen
`Over single-agent chemotherapy in terms of objective
`responserate (39.5% versus 12%). However, the overall
`responserate was notsatisfactory as well as the median
`survival of only 8.2 and 12.5 monthsfor patients treated
`with cisplatin alone or with M-VACregimen respectively.
`2’,2’-Difluorodeoxycytidine (gemcitabine, GEM)is
`anew deoxycytidine analogue with structural and meta-
`bolic similarities to arabinosylcytosine (cytarabine,
`ARA-C)(13). The two compoundsdiffer from the parent
`nucleoside for a modification at the 2’ position of their
`Structure (13). GEM has been shownto be moreactive
`than ARA-Cagainst 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, higheraffinity for the
`enzyme deoxycytidine kinase, and a longer intracellular
`retention duc to a seriesof 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 responserate,
`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 inclusioncriteria; histological diagnosis of urothelial
`carcinoma previously treated with chemotherapy and not more
`amenable with surgery; age $ 75 years; performance Status
`according to Karnofsky Index > 60;life expectancy 2 3 months;
`clinically measurable disease according to WHO criteria (14);
`adequate bone marrow function (WBC 2 4,000/mmc,platelets
`> 120.000/mmc); serum bilirubin < 1.2 mg/dl; serum creatinine
`< 1.2 mg/dl and BUN < 50 mg/dl 0 clinically detectable brain
`metastases; no second malignant neoplasm, except adequately
`trated in situ carcinoma of the cervix and cutaneous basal cell
`carcinoma; at Ieast 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 duc 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 bonescan, hematological and routine
`chemistry tests, ECG, and CTscan ofthe involvedsites. Mostof
`the above mentioned procedureswereused to define the objective
`responseat restaging after 2 complete cycles of chemotherapy.
`
`Treatment plan
`
`Eligible patients were treated as follows: GEM 1000 mg/m/
`week wasgiven intravenously diluted in 250 cc of normalsaline
`as 30 minutesinfusion 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 discase were achieved chemotherapy was
`continued until progressive disease or unacceptable toxicity
`ensued. In case of complete regressionof all signs and symptoms
`chemotherapy was stopped after 6 months. In case of progressi- .
`ve disease, third linc chemotherapy or best supportive care were
`given as needed.
`
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`13
`2’ ,2’-Difluorodeoxycytidine in urothelial cancer
`i
`
`Response assessmentandstatistics
`
`Table 1. Patients characteristics
`
`Patients were evaluated for objective responseafter a minimum
`of 2 cycles according to the WHOcriteria (14). Briefly, complete
`response was the complete disappearanceofall 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 Icsions for
`at east 4 weeks without the appearance of any new lesions; no
`changeorstable discase as a < 50% reduction or < 25% increase
`in the size of tumorallesions; and progressionis the appearance
`of new tumoral deposits or a = 25% increasein 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 wasstarted until the date of documented pro-
`gression. Survival was calculated from the dayof registration until
`last follow-up or death. Univariate analysis of duration of response
`and overall survival was calculated employing the product-limit
`estimate of Kaplan and Meier (15). All statistical analysis were
`performed with the IMPDStatistical 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 ofenrolled patients and
`complete hematological and laboratory chemistry tests were
`obtained before cach 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 weck. Any > grade 3 extra — hematological
`toxicity caused patient withdrawal from the study.
`
`Results
`
`Patients population
`
`No.of enrolled patients
`
`Median age (range)
`
`Sex
`
`Male
`Female
`
`Median PS (Karnofsky Index)
`
`Histology
`Transitional cell carcinoma
`~ well differentiated
`— moderate
`~ poorly differentiated
`Undifferentiated carcinoma
`
`‘Previous treatments
`surgery
`radiotherapy
`chemotherapy
`adjuvant therapy
`advanced disease
`
`Sites of disease
`
`bone
`node
`liver
`lung
`pelvis
`
`24 (100%)
`
`61 (40-75)
`
`19 (79%)
`05 (21%)
`
`80 (60-90)
`
`22 (83%)
`03
`08
`10
`02 (17%)
`
`15 (62%)
`04 (17%)
`
`13 (54%)
`14 (58%)
`
`09 (37%)
`10 (42%)
`(37%)
`08 (33%)
`08 (33%)
`
`Number of involved sites
`07 (29%)
`single
`17 (71%)
`multiple
`ven
`
`Table 2. Type of objective response
`gn
`Response
`N. of patients
`Median duration
`(percent) (months)a
`
`Complete response
`01 (04%)
`
`Partial response
`
`Overall response
`
`Stable disease
`
`06 (25%)
`
`07 (29%)
`
`06 (25%)
`
`7.4+ months
`
`4.0 months
`
`Twenty-four consecutive patients with recurrent and/
`or metastatic urothelial carcinomapretreatedtofirstline
`chemotherapy were enrolled into the study. The patients’
`mainclinical characteristics are shownin table 1. Briefly,
`enrolled patients had a median age of 61 years (range
`not applicable
`11 (46%)
`Progression
`nna
`40-75) with a median performancestatus 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
`to surgery (54%) and 14 (58%) for advanced disacase.
`Amongthelatter group, 10 patients had M-VAC regimen
`and 4 cisplatin plus methotrexate. Mostpatients (71 %)
`had multiple sites of disease which includedliver, lung,
`bone, nodes.
`
`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
`responserate of 29% (95% confidence limits 18%-39%).
`The median duration of objective responses was 7.4+
`months (range 3.0+/12.8). Six paticnts showed no change
`(25%) with a media duration of 4.0 months, | 1 patients
`progressed (46%). A subjective improvement in tumor-
`related symptoms was reported byall 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
`
`Objective response and survival
`
`Types and duration of objective response are shown
`in Table 2. All enrolled patients were evaluable for
`
`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 13.0+ months (range 4.0/16.2).
`
`Toxicity
`
`Over a total of 76 cycles (a mean of 3.2 cycles/
`patient), grade 1-2 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 werenotseen.
`Grade 1-2 non infectious fever was recorded in 8 patients
`(33%) and waseasily controlled by steroid parenteral
`administration. Alopecia wasvirtually absent. Gastro-
`intestinal toxicity was very mild with 9 patients (37%)
`suffering from grade 1-2 nausea/vomiting, 2 patients
`(17%) complaining of grade 1-2 diarrhea, and 2 patients
`with grade 1-2 stomatitis (17%). No cases of grade 3-4
`gastrointestinal toxicities have been observed. Nocases
`of cardiotoxicity and/or neurotoxicity were recorded.
`
`Discussion
`
`Recurrent and/or metastatic urothelial carcinomais
`considered a chemotherapy-sensitive malignancy even
`if clinical results in terms of duration of tumor 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% oftreated patients, but the overall long-term
`survival has been disappointing while toxicity has been
`severe in a significant percentageof cases. Therefore,
`search for newer active, and tolerated antineoplastic
`drugs is a primary goal for investigative oncologists.
`Gemcitabine has been tested in advanced urothelial
`Carcinoma with excellent tolerability and interesting
`activity as reported in two small phase I-IItrials (17,18).
`In thetrial carried out by Polleraet al. (17) a 27% overall
`response rate has been observed in a series of 14
`previously treated patients receiving gemcitabine 1200
`mg/m2/week.In the phaseIItrial by Stadler ct al. (18) 5
`out of 9 previously untreated patients achieved a major
`responsephaseII studies, while in the study reported by
`Moore ct al. a 38% overall responserate has been yield
`in a scries of 21 patients (19).
`In our trial 24 consecutive patients with recurrent and/
`Or metastatic urothelial carcinomapretreated withfirst
`line cisplatin-based chemotherapy weretreated with
`gemcitabine 1000 mg/m2/weckfor 3 consecutive weeks
`followed by a 1 week rest period. In our handsthis
`schedule was able to yield a complete responsein 1
`patient (4%) and a partial responsein 6 cases (25%)for
`an overall response rate of 29% (confidencelimits 18%-
`39%) with a median durationof 7.4+ months (range 3.0+/
`12.8) and a median overall survival of 13.0+ months. A
`subjective improvementin tumor-related symptoms was
`
`reported byall 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. 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 suchas 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 goodtole-
`rability. These characteristics may be important for the
`treatment of those patients with recurrent an/or meta-
`static urothelial carcinoma whichare notsuitable 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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`ALVOGEN, Exh. 1020, p. 0009
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`