Clinical Study
`
`Oncology 1996;53:476-481
`
`Experimental and Clinical Efficacy
`of 2' ,2' -Difluorodeoxycytidine
`(Gemcitabine) against Renal Cell
`Carcinoma
`
`Abstract
`P reclinical and clinical studies have been performed to evaluate the efficacy of
`gemcitabine (2',2'-difluorodeoxycytidine; dFdC) in human renal cell carcino(cid:173)
`ma. Experimental data corroborated dFdC as an effective drug against cell
`lines from renal cell carcinomas (ACHN, A-498, SN12C) at concentrations
`much below clinically achievable doses. ACHN-bearing nude mice showed an
`overall response rate of 27% to dFdC (3 mice with complete response, I with
`partial response, 3 with stable and 8 with progressive disease). Objective
`response from 37 evaluable patients was 8. 1 % (I patient with complete
`response and 2 patients with partial response). Gemcitabine was well tolerated
`thus, although gemcitabine at the dosage and schedule chosen had only small
`activity, the observed toxicity may permit further dose escalation or a more
`frequent administration of the drug.
`
`ONCOLOGY
`
`D. Rohde•
`P.H.M De Mulderb
`L. W eissbach c
`R. Osiekad
`J. Blatter•
`G. Jakse•
`
`a Department of Urology, Technical
`University of Aachen, Germany;
`b Department oflnternal Medicine, Division
`of Medical Oncology, University Hospital
`Nijmegen, The Netherlands;
`c Department of Urology, K.rankenhaus am
`Urban, Berlin,
`d Department of Clinical Oncology,
`Technical University of Aachen,
`e Lilly Deutschland, Bad Homburg, Germany
`
`Key Words
`2',2'-Difluorodeoxycytidine
`Renal cell carcinoma
`In vitro studies
`Xenografts
`Phase II trial
`
`Introduction
`
`Metastatic renal cell carcinoma (RCC) has been
`treated with monochemotherapy with variable success.
`Among a panel of more than 30 different drugs, fludara(cid:173)
`bine, lomustine, vinblastine, ifosfamide or bisantrene did
`show some activity. Response rates did vary between 3
`and 34% [I]. Overall, the results with chemotherapy have
`been disappointing, with most studies revealing response
`rates below I 0%. Several forms of immunotherapy with
`interferons and interleukin-2 have been applied, resulting
`in a limited number of durable responses [2]. Therefore,
`further studies with new agents are warranted. Gemcita(cid:173)
`bine (2',2'-difluorodeoxycytidine; dFdC; LY 18801 I) is
`a novel nucleoside analogue that inhibits DNA synthe(cid:173)
`sis and repair, leading to cell death. For activation, the
`
`drug requires an intracellular phosphorylation to tri
`(dFdCTP )-, di (dFdCDP)- or mono (dFdCMP)-5'-phos(cid:173)
`phorylated metabolites. The modes of action have been
`described in detail elsewhere [3-5]. Briefly, DNA elonga(cid:173)
`tion is inhibited by incorporation of wrong nucleosides [3,
`4] or by direct inhibition of DNA polymerases [5]. Inter(cid:173)
`estingly, the cytotoxicity of the drug is enhanced by sever(cid:173)
`al self-potentiating mechanisms [4].
`In vitro dFdC has already been found to be cytotoxic
`against human leukemia cells [5-7], ovarian cancer cells
`[8], colon carcinoma [9] or squamous cell carcinoma cells
`[IO].
`Therefore, we performed preclinical studies and a clin(cid:173)
`ical trial to evaluate the efficacy of gemcitabine in human
`RCC.
`
`216.185.156.28 - 1/31/2017 3:19:17 PM
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`KARGER
`E-Mail karger@kargcr.ch
`Fax+4161 3061234
`ht1p:/lwww.karger.eh
`
`© 1996S. Karger AG, Basel
`0030-2414196105 36- 04 76$10.0010
`
`Dr. D. Rohde
`Depanment of Urology
`Technical University of Aachen
`Pauwelsst rassc 30
`D-52057 Aachen (Germany)
`
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`Patients, M aterials and Methods
`
`Cell Culture. The cell lines derived from human RCC: SN l 2C,
`(II ], ACHN (intrinsically vincristine resistant; ATCC CRL I 6 I I ,
`American Type C ulture Collection, Rockville, Md., USA) and A-498
`( I 2] were grown under cell culture conditions in (D)MEM standard
`cell culture medium (GIBCO, Grand Island, N.Y., USA) at 37°C
`and a humidified atmosphere of6% CO2. Media were supplemented
`with I 0% (v/v) heat-inactivated fetal calf serum, penicillin ( 100 JU/
`ml) and streptomycin ( I 00 µg/ml).
`Colorimetric C)'lotoxicity Assay. The cytotoxicity of gemcitabine
`for ACHN, A-498 and SN I 2C cells was measured by use of the sul(cid:173)
`forhodamine B assay [ 13]. In brief, 25,000 tumor cells were seeded
`per well of a microtiter plate. After I 8 h incubation, cells were
`exposed to gemcitabine for 48 h (0.1-1,000 ng/ml). Controls received
`supplemented media. Fixation, staining and washing steps have been
`described elsewhere [ 14]. Bound stain was solubilized with 50 µI Tris
`buffer (pH 10.5). Optical densit ies were read at a single wavelength of
`530 nm o n an automated spectrophotometric plate reader (EAR 400
`AT, SLT-Labinstruments, Crailsheim, Germany). Results from du(cid:173)
`plicates per microtiter plate were repeated at least twice. Cytotoxicity
`was expressed as arbitrary TIC percent values (optical density of
`treated cells/optical density of control cells x I 00).
`Animal Experiments. 5 x 106 tumor cells were subcutaneously
`injected in 3- to 4-week-old male balb/c nu/ nu mice. T herapy was
`initiated at tumor volumes of I 00 1111113• Test group animals received
`_gemcitabine (40 mg/kg body weight intraperitoneally; Lilly Deutsch(cid:173)
`land, Giessen, Germany) compared to controls that received NaCl
`0.9% intraperitoneally (n = 11-15).
`One course of therapy ( 4 weeks) included intraperitoneal injec(cid:173)
`tions once a week for 3 weeks followed by I week rest. A complete
`therapy schedule consisted of four courses. Tumor size was measured
`with calipers; tumor volume was calculated as tumor length x
`(width)2/2. Tumor volumes after 16 weeks of therapy were compared
`using the Wilcoxon test. A p value <0.05 was designated statistically
`significant.
`Clinical Trial. A multicenter study group conducted a phase II
`nonrandomized clinical trial to treat patients with advanced RCC
`with gemcitabine monotherapy. Details have been described else(cid:173)
`where [ I 5]. Briefly, patients (18-75 years) with a histologically or
`cytologically confirmed metastatic or inoperable advanced RCC
`were eligible, if they had no previous chemotherapy, a WHO perfor(cid:173)
`mance status of 0-2 and a life expectancy of at least 3 months. Pre(cid:173)
`vious therapy with biological response modifiers was allowed (>4
`weeks before therapy), as well as palliative radiotherapy if the mea(cid:173)
`surable lesion remained non irradiated. Exclusion criteria were: bilat(cid:173)
`eral RCC, bony lesions only, second malignancies, CNS envolvement
`or any serious systemic disorder.
`Treatment was performed in accordance with the declaration of
`Helsinki, and informed consent of the patients was obtained.
`800 mg/1112 body surface gemcitabinc was administered once weekly
`for 3 weeks followed by I week rest. Patients who completed a cycle
`of therapy could have a dose escalation up to 20% in each subsequent
`cycle (maximum: 1,200 mg/m2). A 50% dose reduct ion was adminis(cid:173)
`tered if white blood cell counts >2 but <3 giga/1 leukocytes and 50-
`99 giga/1 platelets or if nonhematologic toxicity WHO grade Ill
`occurred. Any disease progression led to withdrawal from the treat(cid:173)
`ment with gemcitabine.
`
`Efficacy was examined in each patient before each therapy cycle
`and additionally in 8-week intervals (chest X-ray, CT scan if appro(cid:173)
`priate).
`Efficacy analysis included tumor response rate and 95% confi(cid:173)
`dence intervals. Each investigator-determined responder was reeval(cid:173)
`uated by independent experts. T he duration of a partial response
`(PR) was measured from the time of the first administration of the
`drug u ntil progressive disease was documented. The duration of a
`complete response (CR) was measured from the time of a docu(cid:173)
`mented CR unt il the first observation of disease progression. Surviv(cid:173)
`al was measured from the time the first dose gemcitabine was admin(cid:173)
`istered until death or the patient was last known to be alive.
`
`Results
`
`In vitro Studies
`The growth of all three tumor cell lines was inhibited
`by treatment with gemcitabine (fig. l). ACHN cells were
`inhibited more effectively than A-498 cells. SN12C cells
`were nearly 25 times less sensitive than ACHN cells. T he
`drug concentrations that led to a 50% reduction in cell
`proliferation compared to controls were approximately
`2 ng/ml (0.0076 µmol/1) for ACHN cells, 10 ng/ml
`(0.038 µmol/1) for A-498 and 45 ng/ml (0.17 11 µmol/1)
`gemcitabine for SN 12C cells (fig. I).
`
`Xenogra/ts
`Xenografts of SN l 2C cells did not respond to treat(cid:173)
`ment with gemcitabine (p < 0. 1 ). In contrast, the growth
`of tumors induced by ACHN cells was statistically signifi(cid:173)
`cantly inhibited by gemcitabine (p < 0.0014; fig. 2). Inter(cid:173)
`estingly, late responses have been observed even weeks
`after the end of therapy. Table l summarizes the best
`responses. The overall response rate was 4/15 (27%) for
`ACHN xenografts (3 CR; l PR and 3 whith stable dis(cid:173)
`ease).
`
`Clinical Data
`39 patients with measurable metastatic RCC were
`enrolled. Their characteristics are listed in table 2. 34
`have been subjected to previous surgery, 5 to previous
`radiotherapy and 20 have had prior treatment with inter(cid:173)
`feron-a and/or interferon-y.
`37 patients were eligible for evaluation of efficacy (29
`males, 8 females). T he age range was 38-74 years (median
`56.6). The WHO performance statuses were O in 15
`patients, I in 19 patients and 2 in 2 patients. There was I
`patient with a WHO performance status of 3 who,
`although this was a protocol violation, qualified for effica(cid:173)
`cy analysis. Metastatic sites were mainly located in the
`lung (81.1 %) and lymph nodes (40.5%).
`
`Gemcitabine against Renal Cell Carcinoma
`
`Oncology I 996;53:476-481
`
`477
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`

`• SN12C
`0 A-498
`D ACHN
`
`100
`
`90
`
`_ 80
`J!l ·c
`::, 70
`~
`.!c: 60
`,:,
`'" ; 50
`·;;;
`ai 40
`u
`~ 30
`li
`O 20
`
`10
`
`Fig. 1. Growth inhibition of three differ(cid:173)
`ent human RCC cell lines (SN I 2C, A-498,
`ACHN) by gemcitabine compared to unex(cid:173)
`posed tumor cells (REF).
`
`0 -'----,-----,----,---..--..--..-- . . -- . . - - - . ---,----,----,
`0. 1
`0.5
`1.0
`5.0
`10.0 50.0 100.0 500.0 1,000.0
`REF
`ng/ml gemcitabine
`
`2,000
`
`1,500
`
`(cid:127) Controls (n = 15)
`O GEM (n = 15)
`
`..,E
`
`.s .,
`~ 1,000
`~
`0
`E
`,2
`
`500
`
`Fig. 2. G rowth inhibition of xcnografts
`derived from ACHN cells by treatment with
`gemcitabine (GEM) compared to untreated
`animals (cont rols).
`
`4
`
`6
`
`10
`8
`lime (weeks)
`
`12
`
`14
`
`16
`
`18
`
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`39 patients received at least one dose of gemcitabine.
`The mean number of cycles was 3. 7 (0-1 6). 1.6% of all
`injections were omitted, only 12.8% reduced in dose.
`Most dose reductions (70%) occurred in the first three
`cycles, usually due to leukopenia. 4.6% of injections could
`be subsequently escalated.
`At present, 37 of 39 patients are evaluable, with 3
`patients being independently confirmed as responders ( I
`CR; 2 PR) giving a response rate of 8.1 % (95% confidence
`interval: 1.7-2 1.9%). Responses lasted 32, 12 and I 9
`months, respectively. Table 3 gives a summary of best
`
`tumor responses. The median time to disease progression
`was 3.7 months (0.7-33.9). The median survival was 12.3
`months (0.7-33.9). In 13 patients disease progressed. The
`major sites of metastases were the lung in 23 patients, fol(cid:173)
`lowed by the lymph nodes in 4 patients and the brain in 3
`patients.
`Overall, the drug was well tolerated. A toxicity of
`WHO grade III due to leukopen ia was seen in 5.3% of
`infusions as well as <8% grade III toxicity in liver func(cid:173)
`tion tests. No grade IV changes in laboratory parameters
`occurred.
`
`478
`
`Oncology 1996:53:476- 481
`
`Rohde/De Mulder/Weissbach/Osicka/
`Blatter/Jaksc
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`Table 1. Response ofxenografts derived from SN 12C or ACHN
`cells during therapy (0-16 weeks) and during follow-up (17-32
`weeks)
`
`Cells
`
`SN12C
`CO (n; 15)
`GEM (n; 11)
`
`AGIN
`CO (n; 15)
`GEM (n; 15)
`
`0- 16 weeks
`
`PD
`
`SD
`
`17- 32 weeks
`
`PD
`
`R+SD
`
`15
`II
`
`15
`13
`
`2
`
`15
`I I
`
`15
`8
`
`7 3 x CR
`Ix PR
`3 x SD
`
`CO ; Untreated animals; GEM ; gemcitabine-treated animals;
`PD ; progressive disease; SD ; stable disease; R ; objective
`response.
`
`Clinical toxicity in all courses was mild. As expected
`·nausea and vomiting were the most common adverse
`events, leaving only 38.5% of patients unaffected. Other
`frequently reported adverse events
`included fever
`(35.9%), flu-like syndrome (I 7.9%) and skin rash ( 17.9%).
`Grade Ill toxicity was observed in 2 patients, I with dys(cid:173)
`pnea and I with myocardial infarction.
`
`Discussion
`
`Due to encouraging preclinical data indicating that
`gemcitabine is a potent cytostatic drug in vitro as well as
`in vivo [6, 16- 18], clinical studies in patients with ad(cid:173)
`vanced colon cancer [ I 9], leukemic diseases [20], squa(cid:173)
`mous cell carcinoma of the head and neck [21], small cell
`[22] and non-small cell lung cancer [23, 24], breast carci(cid:173)
`noma [25], ovarian cancer [26], pancreatic cancer [27],
`bladder cancer [28), gastric cancer or in patients with
`advanced malignant melanoma [29, 30] have already
`been initiated with different success.
`The present study supplies comprehensive in vitro, in
`vivo and clinical data on human RCC. The data obtained
`in vitro present gemcitabine as a highly effective drug
`against RCC cell lines at concentrations that were much
`lower than peak concentrations ( dFdC: 50-150 µM =
`12.5-37.5 µg/ml; data from Lilly) or even steady state
`dFdC levels ( 15-43.8 µM) that could be achieved in
`human plasma [20, 31 ]. The relative resistance of SN I 2C
`
`Table 2. Characteristics of eligible pa(cid:173)
`tients (n; 37)
`
`Characteristics
`
`Patients
`
`Males
`Females
`Performance status
`0
`I
`2
`3
`Metastatic sites
`Lung
`Lymph node
`Bone
`Liver
`Kidney
`Other
`Number of sites (n ; 39)
`I x
`2 X
`3 X
`>3 X
`Prior therapy
`Surgery
`Radiotherapy
`Immunotherapy
`
`n
`
`29
`8
`
`15
`19
`2
`
`30
`15
`7
`4
`5
`15
`
`20
`10
`7
`2
`
`34
`5
`20
`
`%
`
`40.5
`51.4
`5.4
`2.7
`
`81.1
`40.5
`18.9
`10.8
`13.5
`40.5
`
`51.2
`25.6
`17.9
`5. 1
`
`91.9
`13.5
`54.1
`
`The mean age of the patients was 56.62
`± 9.31 years (range 38- 74).
`
`Table 3. Best tumor responses of eligible
`patients treated with gemcitabine
`
`Tumor response
`
`Eligible patients
`(n; 37)
`
`CR
`PR
`Stable disease
`Progressive disease
`Not applicable
`Objective response
`(CR+ PR)
`
`n
`
`I
`2
`18
`13
`3
`
`3
`
`%
`
`2.7
`5.4
`48.6
`35.1
`8.1
`
`8.1
`
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`Gemeitabine against Renal Cell Carcinoma
`
`Oncology 1996;53:476-481
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`479
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`cells to gemcitabine in vitro compa red to ACHN cells was
`confirmed in vivo by the fact that SN 12C xenografts did
`not respond to a treatment with 40 mg/kg i.p. gemcita(cid:173)
`bine. Nevertheless, other groups have shown that nude
`mice tolerate much higher dosages [ 17], thus the dose of
`gemcitabine used in our study might have been to low for
`SN I 2C xenografts.
`There have been two previous reports of the clin ical
`applications of gemcitabine in RCC before. In a phase I
`study, the only patient with RCC attained a PR after
`administration of low-dose gemcitabine (65 mg/m2) twice
`a week for 3 weeks [32]. In addition, 18 patients with his(cid:173)
`tologically proven metastatic or locally recurrent RCC
`were treated in a phase II trial with gemcitabine (800 mg/
`m2) on days I, 8 and 15 of a 28-day cycle. One PR was
`observed, resulting in an overall response rate of 6% [33].
`T he overall response rate of 8. 1 % found in our study fo r
`gemcitabine monotherapy indicates that this regimen
`cannot be considered more active than other chemothera(cid:173)
`py approaches in the treatment of metastatic RCC. Al(cid:173)
`though it is not clear whether a do:;e-re:;punse relationship
`exists for gemcitabine in any tumor entity, it is too early to
`
`consider gemcitabine as clinically ineffective, since a 50%
`higher dose can be tolerated [28].
`In conclusion, the present preclinical data confirm
`gemcitabine as an active chemotherapeutic drug against
`human RCC cells in vitro and in vivo. Moreover, dFdC
`does show some minor activity for patients with advanced
`or metastatic RCC. The hypothesis that higher doses of
`gemcitabine are more likely to induce an increased antitu(cid:173)
`mor response needs to be clarified. Therefore, future clini(cid:173)
`cal trials are still required. Moreover, besides an esti(cid:173)
`mated benefit by increased dosages, a schedule containing
`cytokines may lead to an improved antineoplastic re(cid:173)
`sponse by activated immunologic cascades for cytokines.
`This prompted fu rther gemcitabine experiments which
`indicated a n additive (or synergistic) effect of sequentially
`applied interferon-a. [34].
`
`Acknowledgements
`
`Experiments were supported by Lilly Deutschland.
`
`·····················································································································································
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`Rohde/De Muldcr/Weissbach/Osieka/
`Blatter/ Jakse
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