Cancer Chemother Pharmacol (1996) 37: 491-495
`
`dliiiiiii;ihiitli•ii.-
`
`© Springer-Verlag 1996_
`
`P.H.M. De Mulder· L. Weissbach · G. Jakse
`R. Osieka · J. Blatter
`Gemcitabine: a phase II study in patients with advanced renal cancer
`
`Received: 23 January 1995/Accepted: 11 July 1995
`
`Abstract Gemcitabine is a fluorine-substituted cytara(cid:173)
`bine analog with broad experimental antitumor activ(cid:173)
`ity. It's activity was explored in chemotherapy-naive
`patients with advanced progressive renal-cell carci(cid:173)
`noma. A total of 39 patients were included in the study,
`of whom 37 were fully evaluable. In five patients the
`primary tumor remained in situ. Gemcitabine at
`800 mg/m 2 was given as a weekly 30-min infusion for
`3 consecutive weeks followed by 1 week of rest. One
`complete response and two partial responses were ob(cid:173)
`served giving a response rate of 8.1 % [95% confidence
`interval (CI), 2-22%). The duration of the responses is
`currently 32, 15, and 19 months, respectively. The me(cid:173)
`dian survival for all patients was 12.3 months. Gem(cid:173)
`citabine was generally well tolerated, with nausea and
`vomiting (20.5% grade III) and neutropenia (5.3%
`grade III) being the most significant side effects. Gem(cid:173)
`citabine given at this dose level and on this schedule has
`only limited activity in advanced renal-cell carcinoma.
`
`Key words Gemcitabine • Renal-cell cancer •
`Metastatic disease
`
`P.H.M. De Mulder (181)
`Department of Medical Oncology, University Hospital NiJmegen,
`P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
`
`L. Weissbach
`Department of Urology, Krankenhaus am Urban, Dieffenbach(cid:173)
`strasse 1, D-10967 Berlin, Germany
`
`G. Jakse
`Department of Urology, Klinik der RWTH, Pauwelsstrasse, D-5100
`Aachen, Germany
`
`R. Osieka
`Department of Medicine IV, Klmik der RWTH, Pauwelsstrasse,
`D-5100 Aachen, Germany
`
`J. Blatter
`Lilly Deutschland GmbH, Postfach 1441, D-6380 Bad Homburg,
`Germany
`
`Introduction
`
`Patients with renal-cell carcinoma (RCC) currently
`have few therapeutic options once metastatic disease
`has developed. Approximately 25% of the patients
`have metastatic disease at the time of first presentation
`[1]. The median survival for these patients is 6-12
`months, independent of treatment [2]. Spontaneous
`regression of metastases after tumor nephrectomy oc(cid:173)
`curs' in less than 1 % of cases [3]. Treatment with
`hormones has no proven impact on survival [ 4, 5]. The
`r~sults of chemotherapy have been consistently disap(cid:173)
`pointing, with most studies revealing response rates
`below 10%. Agents with some activity are vinblastine
`and floxuridine. One of the explanations for this rela(cid:173)
`tive chemotherapy insensitivity is the high level of
`expression of the multi drug resistance gene in the
`proximal tubular cell, known to be the origin of re(cid:173)
`nal-cell carcinoma. Several forms of immunotherapy
`with interferons and interleukin-2 have been applied,
`resulting in a limited number of sometimes durable
`responses [6, 7]. Further studies with new agents are
`therefore indicated.
`Gemcitabine (2'2-difluorodeoxcytidine), a pyrimid(cid:173)
`ine antimetabolite, has been developed as a new de(cid:173)
`oxycytidine analogue. In several murine solid-tumor
`and human xenograft models, gemcitabine has been
`identified as an active compound with a very broad
`therapeutic index. The dose-limiting side effects in
`phase I studies were myelosuppression and, for a more
`frequent, daily-times-5 regimen, a flu-like syndrome
`consisting of fever, malaise, headache, and rigors; in
`rare cases, hypotension was observed. The regimen
`chosen for further exploration in the phase II setting
`was weekly administration times 3 every 4 weeks. In
`this paper we report on the results we obtained in
`a multicenter phase II study in advanced progressive
`RCC.
`
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`492
`
`Patients and methods
`
`This was an open, nonrandomized study to determine the objective
`response rate to gemcitabine of patients with advanced RCC who
`had not had previous chemotherapy. The study was conducted from
`three centers in Germany and one in The Netherlands. The prin(cid:173)
`ciples of good clinical practice and the Declaration of Helsinki were
`adhered to and the protocol was approved by the local ethics
`committees. Informed consent was obtained from all patients before
`their inclusion in the study.
`
`Criteria for entry
`
`To be included in the study, patients (aged 18-75 years) had to have
`histologically or cytologically confirmed metastatic or inoperable
`advanced renal cell adenocarcinoma. They had to have a life expect(cid:173)
`ancy of at least 3 months and a performance status of 0-2 on the
`WHO scale. Nephrectomy was permitted, but lhis had to have been
`at least 3 weeks before the start of the study together with documen(cid:173)
`tation of disease progression. If an area had been irradiated, there
`had
`to be measurable disease outside
`this area. Palliative
`radiotherapy was allowed in areas outside the axial skeleton. There
`had to be adequate bone marrow reserve (leukocytes, 2: 4 x 109 /I;
`hemoglobin, 10 g/dl [6.7 mmol/1], platelets, 2: 100 x 109 /1). The fol(cid:173)
`lowing laboratory criteria had to be fulfilled: plasma creatinine levels
`of~ 160 mmol/1, plasma bilirubin concentrations lower than twice
`the normal value, and aspartate transaminase/alanine transferase
`(AST/ ALT) levels lower than 3 times the normal value. AST and
`ALT could be elevated to 5 times the normal value in patients with
`known metastatic disease in the liver. The prothrombin time (PT)
`and partial thromboplastin time (PTT) had to be ~ 1.5 times the
`normal value.
`Patients were excluded from the study if they had any of the
`following: bilateral renal cancer, bony lesions as the only measurable
`disease, life-threatening metastases, or a second malignancy (except
`for in situ carcinoma of the cervix or adequately treated basal-cell
`carcinoma of the skin). Further exclusion criteria were central ner(cid:173)
`vous system involvement, hypercalcemia ( > 10.5 mg/di), active un(cid:173)
`controlled infection, or any serious concomitant systemic disorder
`deemed by the investigator to be incompatible with the study.
`Patients could not have received previous chemotherapy, although
`prior treatment with a biological response modifier was allowed.
`Concomitant hormonal and corticosteroid treatments were not al(cid:173)
`lowed. Men and women had to take medically approved contracept(cid:173)
`ive precautions (if necessary) during the trial and for 3 months after
`receiving the final dose of study drug. Finally, patients who could
`not be adequately followed for the duration of the study were
`excluded.
`
`either range, the injection was omitted. Patients with a grade 3 non(cid:173)
`hematological toxicity could either have their dose reduced by 50%
`or have therapy withheld, depending on the judgement of the investi(cid:173)
`gator. Patients with a life-threatening grade 4 non-hematological
`toxicity were removed from the study unless they were responding,
`in which case a 50% dose reduction could be instituted when the
`toxicity resolved.
`
`Evaluation of response and toxicity
`
`All patients who completed one cycle of therapy (including those
`withdrawn within this period for toxicity) qualified to be analyzed
`for efficacy, and all patients who were enrolled in the study were
`analyzed for safety. Efficacy was examined in each patient before
`each therapy cycle, i.e., every 4 weeks (medical history and physical
`examination, performance status evaluation, analgesics use), and
`before every other therapy cycle, i.e., every 8 weeks [chest X-ray,
`computerized tomography (CT) scan if appropriate, radiological
`tests]. Patients were then reviewed at 1 month after the last dose of
`study drug for assessment of efficacy and every 3 months for evalu(cid:173)
`ation of survival and disease-free survival.
`All responders were evaluated by a panel of independent experts,
`the Oncology Review Board (ORB). The evaluations were conduc(cid:173)
`ted using standard WHO criteria for measurable disease, duration of
`response, and survival. Efficacy data-analysis methods included de(cid:173)
`termination of the tumor response rate and calculation of the 95%
`confidence intervals (Cis). Data for supportive response parameters
`such as performance status, weight, and analgesics consumption and
`for other disease-related symptoms reflecting either patients benefit
`or their clinical condition were also collected prospectively for all
`patients. Improvement had to be maintained for at least 4 weeks to
`be considered clinically relevant.
`
`Results
`
`Between February 1990 and July 1991, 39 patients (29
`men and 10 women) were enrolled in the study. All
`received at least 1 dose of gemcitabine, and 37 were
`eligible for evaluation of efficacy. The disease charac(cid:173)
`teristics at baseline are shown in Table 1. The median
`interval from diagnosis of the tumor to entry into the
`study was 12.6 months (range, 0-92.5 months). Of the
`37 qualified patients, 43.2% had undergone previous
`surgery in an attempt at curative resection and 13.5%
`were receiving analgesics.
`
`Treatment
`
`Efficacy
`
`Gemcitabine at 800 mg/m 2 was given intravenously (infusion period,
`30 min) once a week for a consecutive 3-week period, which was
`followed by 1 week of rest, this constituting a cycle of 28 days.
`Patients who completed one cycle of therapy at 800 mg/m 2 could
`have the subsequent dose increased by up to 20%, provided that
`they had shown no significant change from baseline in hematologi(cid:173)
`cal parameters and that nonhematological toxicity had not been
`more severe than WHO grade 1. If the patient tolerated this escala(cid:173)
`tion for the whole cycle, subsequent cycles could be given in dose
`• Dose
`escalations of up to 20% to a maximum of 1200 mg/m 2
`adjustments were made on the basis of assessments of hematological
`and non-hematological toxicities. Only 50% of a dose was given if
`the WBC was 2: 2.0 but < 3.0 x 109 /1 or the platelet count was
`50-99 x 109 /1. If the cell counts dropped below the lower level of
`
`Of the 39 patients enrolled, 18 withdrew from the study
`due to lack of efficacy. Three patients were confirmed by
`the ORB as being responders to treatment with gem(cid:173)
`citabine, giving a response rate of 8.1 % (95% CI,
`1.7-21.9%). One patient experienced a complete re(cid:173)
`sponse (CR). This was a 51-year-old man with a local
`recurrence after previous nephrectomy, who experienced
`a partial response (PR) after two cycles and a CR after
`four cycles. Disease progression has not been reported to
`date (32 months after the start of treatment).
`Two patients achieved a PR. One was a 47-year-old
`man who entered the study at 36.5 months following
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`Table 1 Summary of patients and disease characteristics at base-
`line
`
`Eligible Patients
`M/F
`
`Age (years):
`Mean± SD
`Range
`
`Site of disease:
`Lung
`Lymph node
`Bone
`Liver
`Kidney
`Other
`
`Prior therapy:
`Any surgery
`Radiotherapy
`Immunotherapy
`
`Performance status:
`0
`1
`2
`3
`
`Level of analgesia:
`0
`1
`2
`"3
`
`Number of sites (n = 39):
`1
`2
`3
`>3
`
`37
`29/8
`
`56.62 ± 9.31
`38-74
`
`30(81.1%)
`15 (40.5%)
`7 (18.9%)
`4 (10.8%)
`5 (13.5%)
`15 (40.5%)
`
`34 (91.9%)
`5 (13.5%)
`20 (54.1 %)
`
`15 (40.5%)
`19 (51.4%)
`2(5.4%)
`1 (2.7%)
`
`32 (86.5%)
`3 (8.1 %)
`1 (2.7%)
`1 (2.7%)
`
`20 (51.2%)
`10 (25.6%)
`7 (17.9%)
`2 (5.1%)
`
`a nephrectomy for the primary tumor, when a CT scan
`revealed recurrent disease in a retrocrural lymph node.
`A PR was seen after two cycles, and the patient was
`withdrawn from the study after three cycles at his own
`request. At disease progression (after 12 months), he
`was treated further with gemcitabine (five cycles) and
`again achieved a PR after two cycles, but his disease
`progressed in the retrocrural nodes thereafter and
`treatment was discontinued .• The second patient who
`showed a PR was a 57-year-old man. He was pre(cid:173)
`treated with alpha- and gamma-interferon. On entering
`the study, he showed 13 measurable lung metastases.
`After ten cycles a PR was noted with concomitant
`improvement of his performance status. He received
`a total of 16 cycles. At 9 months after discontinuation,
`clear progression was documented. Gemcitabine treat(cid:173)
`ment was restarted and continued for a total of 16
`months, resulting in disease stabilization. In all, this
`patient has received up to 100 gemcitabine infusions.
`His survival from the start of treatment is currently 48
`months.
`A third case reported by the investigator as a PR was
`not confirmed by the ORB. The radiology was difficult
`
`493
`
`to interpret, but it was thought that the patient had
`a mixed response, with some lesions responding while
`others progressed. The patient clearly progressed both
`locally and in his lung after five cycles, and this resulted
`in study termination.
`The median time to disease progression after the
`study was 3. 7 months; the minimum was 0. 7 months
`and the maximum was 33.9 months at the data cutoff
`date. Six patients had not declared disease progression.
`The median overall survival was 12.3 months; the min(cid:173)
`imum was 0.7 months and the maximum was 33.9
`months at the data cutoff date. In all, 13 patients were
`not reported to have died.
`Disease progression data were available for 31 quali(cid:173)
`fied patients and, as at baseline, were typical for
`patients with renal carcinoma. The major site of meta(cid:173)
`static failure was the lung in 23 patients, the lymph
`nodes in 4 patients, and the brain in 3 patients, with
`a wide distribution of disease progression occurring at
`other anatomical sites. There was no meaningful im(cid:173)
`provement in any of the secondary efficacy parameters
`assessed.
`
`Safety
`
`Dose, administration
`
`During this study, a total of 39 patients received at least
`1 dose of gemcitabine. A mean of 3. 7 (range Q-16) cycles
`were completed. Gemcitabine was generally well toler(cid:173)
`ated, with only 1.6% of all injections being omitted and
`only 12.8% being reduced in dose. Hematological
`toxicity accounted for four dose omissions; diarrhea,
`for three omissions; and edema, for one omission. One
`further omission occurred when the patient failed to
`attend the clinic. Most dose reductions (70%) occurred
`during the first three cycles, usually as a result of
`leukopenia (83% of all dose reductions). In addition,
`4.6% of injections were escalated above the protocol(cid:173)
`defined starting dose.
`
`WHO laboratory toxicity
`
`WHO laboratory toxicities are reported in Table 2
`as the maximal toxicity experienced by the patient.
`tolerance of gemcitabine was good.
`The overall
`There was no WHO grade 4 toxicity, and grade 3
`toxicity for anemia, leukopenia, and thrombocytopenia
`were reported in only 13.2%, 5.3%, and 7.9% of
`patients, respectively. Although disturbances in hep(cid:173)
`atic enzymes were commonly found, these were mostly
`mild (only one patient had grade 3 toxicity) and of
`little clinical significance. When the data were analyzed
`according to therapy cycle, there appeared to be no
`trend toward increased toxicity as multiple cycles were
`given.
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`494
`
`Table 2 WHO grades for
`laboratory and clinical toxicity
`(% of patients, all 39 patients)"
`
`Toxicity parameter
`(laboratory)
`
`Number of
`patients with
`data
`
`Alkaline phosphatase
`Alkaline transaminase
`Aspartate Transammase
`Bilirubm
`Blood urea nitrogen
`Creatinine
`Hemoglobin
`Hematuria
`White blood cells
`Segmented neutrophilsb
`Platelets
`Proteinuna
`
`38
`38
`38
`36
`38
`38
`38
`37
`38
`38
`38
`38
`
`Toxicity parameter clinical)
`
`0
`
`Allergic
`Cutaneous
`Fever
`Cardiac function
`Hair
`Infect10n
`Nausea/vomitmg
`Pam
`Peripheral neurotoxicity
`Pulmonary
`
`92.3
`71.8
`64.1
`92.3
`89.7
`89.7
`38.5
`87.2
`92.3
`92.3
`
`0
`
`71.1
`36.8
`63.2
`97.1
`73.7
`57.9
`28.9
`54.1
`26.3
`31.6
`76.3
`44.7
`
`7.7
`20.5
`17.9
`2.6
`5.1
`7.7
`28.2
`7.7
`7.7
`5.1
`
`2
`
`7.9
`5.3
`2.6
`0
`5.3
`0
`26.3
`16.2
`34.2
`28.9
`7.9
`7.9
`
`3
`
`2.6
`7.9
`5.3
`0
`0
`0
`13.2
`2.7
`5.3
`15.8
`7.9
`0
`
`4
`
`0
`0
`0
`0
`0
`0
`0
`0
`0
`2.6
`0
`0
`
`18.4
`50.0
`28.9
`8.3
`21.1
`42.1
`31.6
`27.0
`34.2
`21.1
`7.9
`47.4
`
`2
`
`3
`
`4
`
`7.7
`17.9
`
`5.1
`
`12.8
`5.1
`
`2.6
`
`2.6
`
`2.6
`20.5
`
`2.6
`
`"Maximal recorded WHO grade
`bSegmented neutrophil counts have been coverted to WHO scores using granulocyte count criteria
`
`WHO clinical toxicity
`
`The clinical toxicity is summarized in Tabie 2. There
`was one grade 4 toxicity: cardiac function. This patient
`had a history of cardiac disease, including a myocardial
`infarction, and died of heart failure and arrhythmia,
`which was not thought to be drug-related. A second
`patient developed pneumonia after two injections of
`gemcitabine and rapidly deteriorated and died. The
`pneumonia was thought to be both disease- and drug(cid:173)
`related by the investigator, but there was no concomi(cid:173)
`tant leukopenia.
`As expected, nausea and vomiting were the most
`common adverse events encountered, with only 38.5%
`of patients remaining unaffected. Grade 1 toxicity
`(nausea) was reported by 28.2% of patients: grade
`2 toxicity (transient vomiting), by 12.8%; and grade
`3 toxicity (vomiting requiring therapy), by 20.5%.
`However, no grade 4 toxicity (intractable vomiting) was
`reported. Other frequently reported adverse events in(cid:173)
`cluded fever (35.9%), asthenia (35.9%), flu-like syn-
`
`drome (17.9%), and skin rash (17.9%). Grade 3 toxicity
`was reported by two patients, one with dyspnea and
`one with a myocardial infarction.
`The occurrence of alopecia was minimal. There was
`no grade 3 or 4 toxicity, and 89. 7% of patients reported
`no hair loss at all. The majority of patients reported no
`pain during the study (87.2%).
`Seven patients were withdrawn due to the following
`adverse events experienced during the study irrespect(cid:173)
`ive of drug causality: persistent pretibial edema (one
`patient); worsening exanthema (one patient); severe
`nausea and vomiting ( one patient); asthenia, pain,
`nausea, and vomiting (one patient); myocardial infarc(cid:173)
`tion (one patient); and thrombocytopenia (one patient).
`
`Discussion
`
`In view of the overall response rate of 8.1 %, gem(cid:173)
`citabine monotherapy delivered at a dose of 800 mg/m 2
`weekly for 3 weeks followed by 1 week of rest should
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`not be considered active in advanced renal-cell carci(cid:173)
`noma when used at the tested dose and regimen. The
`population studied had a WHO performance status of
`0 or 1 in 91.9% of cases, and the majority had pulmon(cid:173)
`ary and nodal disease. Therefore, the present cohort is
`a reflection of the type of patient entered in study
`protocols with biological response modifiers, the excep(cid:173)
`tion being that five patients had their primary tumor in
`situ.
`The responses observed were of good quality, and
`the appearance of a response in our third patient after
`ten cycles was remarkable. This patient never pro(cid:173)
`gressed during treatment, and after the restart of gem(cid:173)
`citabine, disease stabilization occurred but no regres(cid:173)
`sion was observed, suggesting more of a cytostatic than
`a cytotoxic effect in this particular patient. The median
`survival of 12.3 months compares favorably with that
`obtained in many other studies but is probably more
`a reflection of the patient population than a result of
`therapy.
`The toxicity of gemcitabine was fairly acceptable,
`with nausea and vomiting being the most prominent
`feature. It is unclear whether the newly available 5-
`hydroxytryptamine3 antagonist might prevent this side
`effect, as it was not routinely applied in the present
`study. Bone marrow toxicity was generally mild, and
`there was no incidence of neutropenic fever. In one
`patient, grade IV granulocytopenia was seen. A more
`recently completed phase I study revealed a maximal
`tolerated dose (MTD) of 1250 mg/m 2 per week given
`for 3 weeks followed by 1 week of rest in non pretreated
`patients [8]. A review of 201 chemotherapy-naive pa(cid:173)
`tients treated at the same dose showed the occurrence
`of grade III neutropenia in 23% of the patients and of
`grade IV neutropenia in 6% [9]. In our study, only in
`4.6% of the injections was the dose escalated, on the
`other hand, only 12.8% involved dose reductions due
`
`to bone marrow toxicity. It is unclear whether a dose(cid:173)
`response relationship exists for gemcitabine in renal(cid:173)
`cell cancer. In view of the phase I data presented thus
`far, a further dose escalation might be possible. The
`results of our study are in agreement with those ob(cid:173)
`tained in an earlier reported, smaller phase II study
`applying the same dose and regimen, where only one
`PR was noted [10].
`
`References
`
`1. Ritchie A WS, Chisholm GD (1983) The natural history of renal
`cell carcinoma. Semin Oncol 10: 390-400
`2. De Forges A, Rey A, Klink M, et al (1988) Prognostic factors in
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`3. Montie JE, Stewart BH, Straffon RA, et al (1977) The role of
`adjunctive nephrectomy in patients with metastatic renal cell
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`4. Harris DT (1983) Hormonal therapy and chemotherapy of renal
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`5. Yagoda A, Bander NH (1989) Failure of cytotoxic chemother(cid:173)
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`6. McCune CS (1983) Immunologic therapies in kidney carcinoma.
`Semin Oncol 10: 431-436
`7. Rosenberg SA, Yang JC, Topalian SL, et al (1994) Treatment of
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`Gell cancer using high-dose bolus
`interleukin-2. JAMA
`271: 907-913
`8. Pollera CF, Ceribelli A, Grecco M, et al (1992) Weekly gem(cid:173)
`citabine: a phase I study with short and prolonged infus10n
`schedules (abstract). Proc Am Soc Clin Oncol fl: 329
`9. Tonato M (1993). Gemcitabine safety overview. In: Gemcitabine
`novel combination of efficacy and tolerability. Proceedings
`European Conference Clinical Oncology 7 Satellite Symposium,
`Jerusalem, Israel. pp 14-16
`10. Mertens WC, Eisenhauer EA, Moore M, et al (1993) Gem(cid:173)
`citabine m advanced renal cell carcinoma. A phase II study of
`the National Cancer Institute of Canada Clinical Trials Group.
`Ann Oncol 4:331-332
`
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