Cytokines and Cytotoxic Agents in Renal Cell Carcinoma:
`A Review
`
`Michael Stahl, Hans-J. Wilke, Siegfried Seeber, and Hans-J. Schmoll
`
`W ITH increasing incidence, approxi~lately
`
`20,000 new cases of renal cell carcmoma
`(RCC) are diagnosed in the United States per
`year. Up to 80% of these patients will develop
`metastases, and prognosis of metastatic disease
`is poor. The clinical course of metastatic RCC is
`very heterogeneous. Long-lasting stable periods
`as well as rapid tumor growth are well known
`and rather unique for adult malignancies. Even
`spontaneous tumor regressions may occur. Based
`on cumulated data, the incidence of this phe(cid:173)
`nomenon is less than 1 %, I although it was re(cid:173)
`ported in up to 7% of patients in selected series. 2
`Spontaneous regression is believed to be immune
`mediated and a result of a host's antitumor re(cid:173)
`sponse. 3
`,4 This was one of the rationales behind
`the fact that, besides conventional chemotherapy
`and hormonal approaches, an increasing number
`of studies with biologic response modifiers have
`been conducted in RCC during the last 10 years.
`Comparable to other tumor entities, several
`prognostic factors have been determined; these
`have proved to be important predictors for re(cid:173)
`sponse and survival of systemically treated pa(cid:173)
`tients with metastatic RCC. Prognostic favorable
`factors are good performance status, resection of
`prirryary tumor, long interval between nephrec(cid:173)
`tomy and development of metastases, lung me-
`.
`I
`t 3 5-7 F
`tastases only, and no one mvo vemen .' . or
`b
`example, Sarna et al6 retrospectively analyzed
`their data from three consecutive interferon (IFN)
`trials. Thirty-seven percent of the 84 patients
`showed tumor response, whereas in patients with
`only lung metastases, the response rate was 53%.
`Overall median survival had been 49 weeks, but
`patients with a good performance status and only
`
`From the Departmelll of Intemal A1edicine (Cancer Re(cid:173)
`search), Essen University Medical School, West German
`Cancer Center, Essen, Germany; and the Department He(cid:173)
`matology/Oncology, Hannover University A1edical School,
`Hannover, Germany.
`Address repril1l requests to Michael Stahl, MD, IImere Klinik
`und Poliklinik (TlIInOi/orschung), WestdelIIsches TlIIl1orzen(cid:173)
`(/'lim, HI1{elandstr. 55, D-4300 Essen 1, Gerinany.
`Copyright © 1992 by H/'B. Saunders Company
`0093-7754/92/1902-0416$05.00/0
`
`lung metastases had a median survival of 102
`weeks. Patient selection has therefore taken into
`consideration when comparing treatment results.
`
`HORMONAL THERAPY
`
`Autochthonous kidney tumors can be induced
`in syrian hamsters by prolonged administration
`of diethylstilbestrol. 8 In this animal model, tumor
`growth can be influenced by progesterones, an(cid:173)
`drogens, and anti-estrogens,9 supporting the ra(cid:173)
`tionale for numerous phase II studies with hor(cid:173)
`monal agents, as did the detection of hormone
`receptors on RCCs. 'O
`However, in clinical trials, hormonal treatment
`failed to show significant activity in RCC. Pro(cid:173)
`gesterones, androgens, or anti-estrogens, alone or
`in combination, induced less than 10% objective
`remissions in more than 700 treated patients (cu(cid:173)
`mulative data from phase II/III trials9). This may
`be pmily due to the fact that the role of hormone
`receptors in renal cancer had been overestimated.
`In more recent investigations, the number of re(cid:173)
`ceptor-positive tumors and their receptor con(cid:173)
`tents were markedly lower than previously re(cid:173)
`ported. '1
`An estrogen receptor-independent, cytotoxic
`effect of the anti-estrogen tamoxifen was de(cid:173)
`scribed in vitro with doses above 1 X 10-6 mol!
`L. Il
`,13 These findings prompted two clinical trials
`with high-dose tamoxifen (100 to 150 mg/m2/d)
`in patients with progressive RCC (documented
`prior to treatment). In a study of 34 patients, Stahl
`et al reported four patients with objective re(cid:173)
`sponses (12%) lasting a median of 20 months,
`and 17 patients with no change (50%).14 These
`results were confirmed by a German multicenter
`trial 15 in which 12% of patients had objective re(cid:173)
`sponses, 63% of patients had no change, and there
`was a median overall survival of 15 months. Only
`cine third of the patients had good prognostic fac(cid:173)
`tors.
`
`CHEMOTHERAPY
`
`In the past 15 years, more than 50 single-agent
`phase II trials of RCC using different cytotoxic
`drugs have been reported.9,16 However, only vin-
`
`70
`
`Seminars in, Oncology, Vol 19, No 2, Suppl 4 (April), 1992: pp 70-79
`
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`
`SYSTEMIC TREATMENT OF RENAL CELL CARCINOMA
`
`71
`
`Table 1. Recombinant Interleron-a in Metastatic Renal Cell Carcinoma
`
`Study
`
`Quesada et al26
`
`• (1985)
`
`Quesada et al 26 (1985)
`Umeda and Niijima27 (1986)
`Umeda and Niijima 27 (1986)
`Figlin et al 28 (1988)
`Muss et al29 • (1987)
`
`Fossa et al30 (1988)
`Marshall et al 31 (1989)
`Levens et al 32 (1989)
`Fossa et al 33 t (1990)
`
`Summarized
`
`IFN
`
`2a
`2a
`2a
`2a
`2b
`2a
`2b
`2b
`
`2a
`2b
`2a
`2a
`
`Dace/Schedule 110' Unitsl
`
`21m2 qd
`201m2 qd
`201m2 qd
`3-36/m2 qd
`3-10/m2 3-5 d/wk
`3-36/m2 qd
`2-10/m 2 tiw
`30-50/m 2 d 1-5 every
`3 wk
`18 tiw
`1 qd
`10 qd
`18 tiw
`
`No. of
`Evaluable
`Patients
`
`CR + PR 1%)
`
`Median
`Remission
`Duration Imo)
`
`Median
`Survival 1m 0)
`
`15
`15
`26
`108
`45
`19
`51
`46
`
`86
`16
`15
`23
`
`465
`
`0
`27
`31
`14
`18
`26
`10
`7
`
`7
`25
`27
`23
`
`14% (95% CI.
`11%-17.5%)
`
`3
`NA
`
`2.5
`9.5
`
`16
`
`NA
`NA
`9
`9
`
`13
`NA
`
`NA
`18.5
`
`NA
`
`9
`NA
`NA
`11
`
`Abbreviations: qd. daily; tiw. three times per week; NA. not available; 95% CI. 95% confidence interval.
`• Randomized trial.
`t Plus prednisone orally daily.
`
`blastine and floxuridin (FUDR) have shown re(cid:173)
`producible moderate activity. In 1977, Hrushesky
`and Murphy repOlied 33 responses in a series of
`135 patients (25%) being treated with vinblastine
`in different trials.17 In most of these trials, re(cid:173)
`sponse criteria were not clearly defined or did
`not fulfill modern standard criteria for response
`estimation. Analyzing vinblastine studies being
`published since 1979, an overall remission rate
`of 16% (45 of 277 patients) was achieved, with
`feW. complete remissions (CRs), short-lasting re(cid:173)
`mi~sion duration (5 to 6 months), and a median
`survival time of approximately 8 months.I,ls
`Of interest are the results being achieved with
`the fluoropyrimidine FUDR, given by circadian(cid:173)
`shaped 14-day infusion, as described by Hru(cid:173)
`shesky et al. I9 These investigators observed 11
`objective remissions (four CRs and seven partial
`remissions [PRs]) in 56 patients (19.6%) with
`metastatic RCC. The remission duration was 11
`months and overall survival was 14 months. All
`patients were previously nephrectomized and one
`third had a good performance status and/or only
`lung metastases. These data are in concordance
`with the results of Wilkinson et al20 and Geoffrois
`et al,21 who reported three PRs of 10 patients and
`four PRs of 25 patients, respectively. A com-
`I pletely negative result was published by Richards
`et al,22 who used a 5-day continuous-infusion
`schedule of FUDR. No objective remission was
`
`observed in 29 evaluable patients, whose char(cid:173)
`acteristics were comparable to those of the Hru(cid:173)
`shesky et al trial.
`Combination chemotherapy, mostly based on
`vinca alkaloids, did not result in higher remission
`rates or longer survival times compared with vin(cid:173)
`blastine monotherapy, but frequently increased
`toxicity.9
`
`IMMUNOTHERAPY
`
`InteJ.feron-O'
`Since the first report of IFN-O' (human leu(cid:173)
`kocyte derived) by Quesada et al in 1983,23 nu(cid:173)
`merous phase II and III studies using IFN-O' de(cid:173)
`rived from human leukocytes, lymphocytes, or
`recombinant interferon (rIFN) have been pub(cid:173)
`lished. From these trials it can be concluded that
`neither the source of IFN-O' nor the route of ad(cid:173)
`ministration significantly influenced its efficacy.24
`Because of the better availability ofrIFNs, most
`trials of the last years were conducted with rIFN-
`0'. Summarizing study results with rIFN, an
`pverall remission rate of 14% (95% confidence
`interval, 11 % to 17.5%), median remission du(cid:173)
`rations of2.5 to 16 months, and median survival
`times of9 to 18.5 months were achieved in 465
`patients (Table 1). Two thirds of these trials ac(cid:173)
`crued less than 30 patients. This fact and patient
`selection may be an explanation for the partly
`marked differences of published treatment results.
`
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`
`72
`
`STAHL ET AL
`
`Table 2. Recombinant Interferon-a and Vinblastine in Metastatic Renal Cell Carcinoma
`
`Study
`
`Fossa et al42 (1986)
`
`Fossa43 (1988)
`Fossa et al 30 (1988)
`Bergerat et al44 (1988)
`
`Bergerat et al44 (1988)
`
`Cetto et al45 (1988)
`Schornagel et al46
`(1989)
`Sertoli et al 47 (1989)
`Schuster et al4B (1990)
`Palmeri et al49 (1 990)
`Kriegmair et alSO (1990)
`
`IFN (10' Units)fVinblastine Dose
`(mg/kg)
`
`2a 36 tiw + 0.1-0.15 qd for
`2-3 wk
`2a 18 tiw + 0.1 qd for 3 wk
`2a 18 tiw + 0.1 qd for 3 wk
`2a 10-20/m 2 tiw + 0.075-
`0.15 qd for 3 wk
`2a 181m 2 tiw + 0.1 qd for 3
`wk
`2b 31m2 tiw + 0.1 qd for 3 wk
`2a 18 tiw + 0.1 qd for 3 wk
`
`2a 18 tiw + 0.1 qd for 3 wk
`2a 18tiw+0.l qdfor3wk
`2a 18 tiw + 0.1 qd for 3 wk
`NA
`NA
`
`No. of
`Evaluable
`Patients
`
`CR + PR (%)
`
`No Change
`(%)
`
`Median
`Response
`Duration (mo)
`
`Median
`Survival (mo)
`
`16
`
`12
`91
`20
`
`20
`
`lB
`56
`
`20
`34
`11
`16
`
`31
`
`17
`22
`40
`
`45
`
`44
`16
`
`10
`18
`18
`31
`
`31
`
`33
`35
`25
`
`15
`
`17
`57
`
`55
`47
`46
`NA
`
`8
`
`7.5
`NA
`8
`
`8
`
`5
`6
`
`9+
`10
`7
`NA
`
`NA
`
`NA
`9
`NA
`
`NA
`
`16
`9
`
`NA
`NA
`NA
`NA
`
`Summarized
`
`324
`
`23.5%
`
`38% (95% CI. 18.5%-28%)
`
`Abbreviations: tiw. three times per week; qd. daily; NA. not available; 95% CI. 95% confidence interval.
`
`Two randomized trials have addressed the issue
`of whether the rIFN activity in RCC is dose de(cid:173)
`pendent, as suggested by several investigators.25
`Quesada et al26 randomized 30 patients between
`low-dose (2 X 106 V/m2 intramuscularly) and
`high-dose (20 X 106 V/m2 intramuscularly) rIFN(cid:173)
`a A daily. In the low-dose arm, no objective re(cid:173)
`mission was observed, compared with 27% in the
`high-dose arm. However, toxicity significantly
`increased with high-dose rIFN and survival times
`were tpe same in both arms (13 months).
`Muss et al randomized two different doses and
`schedules of rIFN-a 2b29 (2 to 10 X 106 V/m2
`three times per week v 30 to 50 X 106 V/m2 days
`1 to 5 every 3 weeks). Activity was equal in both
`arms, and patients with tumor progression in the
`low-dose arm did not benefit from cross-over to
`the high-dose schedule.
`It cannot be concluded from these trials
`whether IFN dose influences treatment results.
`The patient numbers per treatment arm were too
`small to detect differences of significant power
`and to avoid the bias of patient selection (prog(cid:173)
`nostic factors).
`Other Intelferons and Combinations
`of Intetferons
`Few phase 1111 trials of RCC using IFN-{J, or
`IF;N-')' have been published, and they were with(cid:173)
`out evidence of superior activity compared with
`studies using interferon-a. 34-36
`
`In vitro, IFN-a and IFN-')' show synergistic
`activity,37 partly explained by the different cell
`surface receptor for both compounds, giving the
`basis for combining them in clinical trials. Two
`randomized studies that compared IFN-a and
`IFN-')' alone with IFN-a plus IFN-')' failed to
`show a clinical relevant synergism of the com(cid:173)
`bination in advanced RCc.38,39
`A more recent approach is the application of
`so called biologically active doses of IFN_,),.40
`Aulitzky et al treated 20 patients with very low
`doses ofIFN-,), (10 to 500 f.lg once per week).40
`Two CRs lasting more than 20 months and four
`PRs lasting 6 to 24+ months were achieved (re(cid:173)
`sponse rate, 30%). Because of the moderate side
`effects, a long median treatment period of 10
`months was possible. Besides the selection ofpa(cid:173)
`tients with good prognosis (only one patient had
`primary tumor and half of the patients had nor(cid:173)
`mal performance status and only lung metas(cid:173)
`tases), this may be one reason for the good treat(cid:173)
`ment results, which warrant further evaluation.
`
`Intetferons Combined With Cytotoxic Agents
`
`In vitro studies with different cell lines showed
`synergism of interferons, mainly IFN-a, with a
`number of cytotoxic agents. 41 Because of their
`single-agent activity against RCC, most investi(cid:173)
`gators combined vinblastine and IFN-a in clinical
`trials., The results of 11 phase II and III studies
`
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`
`SYSTEMIC TREATMENT OF RENAL CELL CARCINOMA
`
`73
`
`are summarized in Table 2. With this combina(cid:173)
`tion, a remission rate of 23.5% (range, 10% to
`45%; 95% confidence interval, 18.5% to 28%) and
`a tumor stabilization rate of approximately 30%
`were achieved in 324 evaluable patients. Median
`remission duration was 5 to 10 months. Median
`survival times were available from only three
`trials (9, 9, and 16 months, respectively). Com(cid:173)
`pared with treatment results obtained using
`IFN-tX alone (Table 1), the combination with
`vinblastine seems to induce slightly higher ob(cid:173)
`jective remission rates, but without any impact
`on remission duration or survival.
`A direct comparison between IFN-tX alone or
`in combination with vinblastine was done in two
`randomized studies with contradictory results.
`Fossa et al stated in a European multicenter trial
`that the combination of IFN and vinblastine re(cid:173)
`sulted in higher response rates (22% v 7%) and
`longer median survival times (8.7 v 9.2 months)
`without increased toxicity.30 Although the differ(cid:173)
`ence in response rates and the corresponding 95%
`confidence intervals (1.5 to 12.5% v 13.5 to
`30.5%) are impressive, a survival advantage of 13
`days is not clinically relevant. In a recently pub(cid:173)
`lished randomized multicenter trial with IFN-tX(cid:173)
`nl with or without vinblastine,5! the combination
`failed to improve treatment results. It is of note
`that a small subset of 16 patients with lung me(cid:173)
`tastases only had a response rate of 44% in this
`study. This again emphasizes the role of patient
`selecti~n in the treatment of RCC.
`COlhbinations of IFNs and other cytotoxic
`agents are currently under investigation. First re(cid:173)
`sults with rIFN-tX 2a, 5-fluorouracil, and mito(cid:173)
`mycin C with or without embolization of primary
`tumor are promising, but preliminary. 52
`Polychemotherapy did not increase efficacy of
`IFN in metastatic RCC. Despite some promising
`results with combination chemotherapy (5-flu(cid:173)
`orouracil, doxorubicin, mitomycin, and cisplatin)
`following IFN in a phase II trial, 53 a randomized
`trial revealed only marginal efficacy of this che(cid:173)
`motherapy alone or alternated with IFN_tX.54
`
`Recombinant Interleukin-2
`Interleukin-2 (IL-2), a product of activated T
`lymphocytes, is able to induce regression of me(cid:173)
`tastases in animal models.55 Since 1985, clinical
`sttidies with high-dose intravenous IL-2 have
`demonstrated antitumor activity in patients pre-
`
`senting with metastatic RCC. Rosenberg et al re(cid:173)
`ported one complete remission in 21 evaluable
`patients, 56 but IL-2 treatment was associated with
`severe side effects. In the recent past, a lot oftrials
`have been conducted with IL-2 using different
`doses, schedules, and routes of administration to
`improve efficacy and to reduce toxicity (Table 3).
`It could be demonstrated that lower doses ofIL-
`2 «3 X 106 U /m2) are sufficient to produce im(cid:173)
`mune enhancement comparable to that of high(cid:173)
`dose IL_267 and that dose reduction can avoid
`the most severe side effects of IL-2, such as cap(cid:173)
`illary leak syndrome and hypotension. Summa(cid:173)
`rizing the results of 15 phase 1/11, phase II, and
`phase III studies, recombinant IL-2 (rIL-2)
`achieved a remission rate of 18% (range, 0% to
`33%; 95% confidence interval, 14% to 22%) and
`median remission durations of 5 to 19 months
`for CRs and 2 to 6.5 months for PRs. Median
`survival times available from three of these stud(cid:173)
`ies were 8.5, 11, and 11 + months, respectively.
`
`Interleukin-2 Combined With Interferon-tX
`Interleukin-2 or IFN-tX alone are only margin(cid:173)
`ally active in RCC. Their different modes of ac(cid:173)
`tion and their synergistic effects when used in
`experimental murine models72 prompted the in(cid:173)
`vestigation of combinated IL-2/IFN-tX therapy in
`advanced RCC. The differences in dose and ap(cid:173)
`plication duration of IL-2 (bolus injection or
`continuous infusion), dose and route of admin(cid:173)
`istration of IFN (intravenous, intramuscularly,
`subcutaneous), as well as the different timing of
`the two cytokines make the comparison of pub(cid:173)
`lished data difficult. Remission rates ranged from
`0% to 50%, with infrequent but mostly long-last(cid:173)
`ing complete remissions (Table 4). The majority
`of the patients entered into these trials had a good
`performance status, prior nephrectomy, and low
`tumor burden. The influence of treatment with
`IL-2 and IFN-tX on patient survival cannot be
`estimated because overall survival data are not
`available from the literature (Table 4). Compa(cid:173)
`rable to the trials with IL-2 alone, the more recent
`trials reported obtaining substantially less toxicity
`by using continuous infusions of lower doses of
`IL-2 (2 X 106 U/m2)80 or by giving only a 2-day
`pulse with high doses followed by a low-dose
`maintenance subcutaneously.79 This enabled pa(cid:173)
`tients to be treated in an outpatient fashion, and
`efficacy of the treatment seems to be comparable.
`
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`
`74
`
`Table 3. Recombinant Interleukin-2 in Advanced Renal Cell Carcinoma
`
`Study
`Whitehead et al67
`(1987)
`Rosenberg et al68
`(1988)
`Sosman et al69 (1988)
`Paciucci et al60 (1988)
`Perez et al61 (1989)
`Klasa and Silver62
`(1989)
`Stater et alB3 (1989)
`Aso et al64 (1989)
`Negrier et al66 (1989)
`Bukowski et al66 (1990)
`A tzpodient et alB7
`(1990)
`Galligioni et alB8 (1990)
`Bajorin et al69 (1990)
`Poo et al70 (1991)
`Atkins et a(11 (1991)
`
`Dose
`
`LD/HD SO
`
`HD-BI
`
`LD-BI/CI
`HD-CI
`HD-CI
`HD-BI*
`
`HD-CI
`LD-CI qd
`HD-CI
`HD-BI tiw
`LD SO tiw
`
`HD-CI
`LD-CI
`HD-BI
`HD-BI
`
`.No. of
`Patients
`
`No. of
`CRs
`
`14
`
`38
`
`17
`5
`12
`.13
`
`18
`60
`32
`41
`5
`
`18
`24
`15
`30
`
`0
`
`4
`
`0
`0
`0
`0
`
`3
`2
`
`0
`
`3
`1
`0
`
`CR + PR (%)
`
`0
`
`18.5
`
`18
`20
`8
`8
`
`18
`15
`19
`12
`20
`
`33
`12
`27
`27
`
`Median
`Response
`Duration (mo)
`(CRjPR)
`-/-
`
`6/NA
`
`-/2
`-/NA
`-/NA
`-/NA
`
`5/6.5
`5+
`6+
`19/3.5
`-/5
`
`4+/4+
`16+/NA
`-/NA
`7+/4+
`
`STAHL ET AL
`
`Median
`Survival (mo)
`
`NA
`
`NA
`
`NA
`NA
`NA
`NA
`
`NA
`NA
`8.5
`11
`11+
`
`NA
`NA
`NA
`NA
`
`18 (95% CI, 14%-22%)
`16
`342
`Summarized
`Abbreviations: LD, low dose «3 X 1OB/m2); HD, high dose; BI, bolus injection; CI, continuous infusion; qd, every day; tiw, three times
`per week; SO, subcutaneous; NA, not available; 95% CI, 95% confidence interval.
`* Splenic artery perfusion.
`
`However, there is still no clear evidence of su(cid:173)
`periority of the combination compared with IL-
`2 alone. Preliminary results of a randomized
`phase II trial conducted by the NCI Extramural
`IL-2 Working Group7l showed a lower response
`rate in the IL-2/IFN-a arm compared with IL-2
`alone (three of 28 patients [11 %] v eight of 30
`patients [27%]).
`
`Adoptive Immunotherapy
`In 1987, the treatment with lymphokine-acti(cid:173)
`vated killer (LAK) cells and high-dose IL-2 prom(cid:173)
`ised to become a breakthrough in the management
`of metastatic RCC. Rosenberg et al achieved 12
`objective and seven minor responses in 36 patients
`(53%) with RCC.59 This so-called adoptive im(cid:173)
`munotherapy used IL-2 and the patients' autol(cid:173)
`ogous lymphocytes, which were stimulated by
`.IL-2 ex vivo and were then reinfused. Adoptive
`immunotherapy was complicated by severe and
`partially life-threatening side effects, which make
`it necessary to treat many of the patients within
`intensive care units. The modification of this ap(cid:173)
`proach by using continuous-infusion IL-287 de(cid:173)
`creased toxicity, but selection of patients with
`
`normal performance status and without comor(cid:173)
`bidities was still necessary. Despite this careful pa(cid:173)
`tient selection, further phase II trials with IL-2 and
`LAK cells could not confirm the good results ob(cid:173)
`tained by Rosenberg et al (Table 5). In two larger
`studies, one a study from the National Cancer
`Institute98 and the other a European multicenter
`study,65 remission rates of only 9% and 21 % were
`achieved, respectively. Preliminary data of a ran(cid:173)
`domized trial with 45 evaluable patients69 showed
`no increase in efficacy by administration of LAK
`cells to IL-2 (objective response rate, 9.5% v 11 %
`with IL-2 alone). Survival of responding patients
`often exceeded 15 months, but overall survival
`data have not been reported.
`Treatment with tumor-infiltrating lympho(cid:173)
`cytes (TILs) is a second form of adoptive im(cid:173)
`mtmotherapy. For this approach, TILs were iso(cid:173)
`lated from resected renal tumors or biopsy
`samples of tumors, then expanded in vitro with
`IL-2; they were then reinfused over several days.
`Despite their specific cytolytic activities against
`autologous tumor cells in vitro,100 clinical results
`with TIL in metastatic RCC were not superior
`to any other immunotherapy.lOl,102
`
`\
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`Table 4. Recombinant Interferon-a and Interleukin-2 in Metastatic Renal Cell Carcinoma
`
`Study
`
`IL-2 Dose
`
`IFN
`
`No. of
`Patients
`
`Median
`Response
`Duration (rna)
`(CR/PR)
`
`CR+ PR
`1%)
`
`Median
`Survival (rna)
`
`No. of
`CRs
`o
`
`Lee et al 73 (1989)
`5
`2a SO
`LD-CI
`NA
`0
`NA
`LD-CI
`Lindeman et al 74 (1990)
`24
`2a SO
`NA
`4
`7+/NA
`Figlin et al76 (1990)
`22
`LD-CI
`NA
`32
`2a IM/sq
`NA
`Mittelman et aV6 (1 990)
`LD-CI
`7
`2b 1M
`NA
`43
`NA
`Lipton et al77 (1990)
`12
`LD-BI
`3
`50
`2a 1M
`NA
`12+/7+
`o
`Pichert et al78 (1991)
`ND
`6
`2a SO
`LD-CI
`0
`NA
`Atzpodien et al79 (1991)
`4
`34
`2bSO
`HD/LD SO
`29
`NA
`19+/NA
`Demchak et al80 (1991)
`o
`LD-CI
`17
`29
`2a SO
`NA
`-/5+
`Rosenberg et al81 (1989)
`4
`35
`2b IV
`31
`LD/HD IV
`NA
`12+/8+
`Budd et al82 (1990)
`NA
`21
`NA
`47
`2a IV
`LD/HD-CI
`NA
`o
`West et al88 (1990)
`HD-CI
`NA
`12
`41
`2b SO
`NA
`Bartsch et al84 (1990)
`o
`19
`2b SO
`HD-CI
`NA
`16
`NA
`o
`Morant et al85 (1990)
`HD-CI
`NA
`25
`8
`2a IV
`NA
`o
`Negrier et al86 (1990)
`HD-CI
`37
`22
`2b IV
`NA
`NA
`Atkins et al71 (1991)
`o
`28
`2a SO
`HD-BI
`11
`NA
`-/5+
`Abbreviations: LD, low dose «3 X 106 U/m2); CI, continuous infusion; BI, bolus injection; HD, high dose; SO, subcutaneously; IV,
`intravenously; 1M, intramuscularly; NA. not available.
`
`Other Cytokines and Combinations
`Antitumor effects were seen with recombinant
`tumor necrosis factor (rTNF) in RCC in vitro
`and in vivo. Synergism between rTNF and rIFN
`in human RCC, heterotransplanted on nude
`mice, was described by Otto et aI, who subse(cid:173)
`quently initiated a clinical trial with this com(cid:173)
`bination.103 Two CRs and four PRs were ob(cid:173)
`served among 14 evaluable patients. Although
`these data are very preliminary, further investi(cid:173)
`gation pf rTNF /rIFN seems to be meaningful.
`I
`
`SUMMARY AND CONCLUSIONS
`In spite of the numerous efforts to develop an
`effective systemic treatment for advanced RCC,
`the prognosis of this tumor has not essentially
`changed during the past 20 years. With respect
`to remission rates and survival, neither chemo(cid:173)
`therapy nor hormonal treatment were able to
`demonstrate clinical relevant activity. Objective
`remission rates were usually less than 10% to 15%,
`and no clear improvement of survival was shown.
`The same is true in general for the newer im-
`
`Table 5. Interleukin-2 and Lymphokine-Activated Killer Cells in Metastatic Renal Cell Carcinoma
`
`Study
`Rosenberg et al68 (1988)
`Fisher et al88 (1988)
`Stahel et al89 (1988)
`Dillman et al90 (1989)
`Mittelman et al91 (1989)
`Paciucci et al92 (1989)
`Weiss et al93 (1989)
`Eberlein et al94 (1989)
`Smith et al96 (1989)
`Negrier et al65 (1989)
`Thompson et al96 (1990)
`Bajorin et al69 (1990)
`Parkinson et al97 (1990)
`Tho~pson et al9B (1991)
`Bernstein et al99 (1991)
`
`Dose (HO/LO)
`
`HD-BI
`HD-BI
`HD-CI
`HD-CI
`LD-BI
`LD + HD-CI
`HD-CI/BI
`LD-CI
`HD-CI/BI
`HD-CI
`HD-CI
`HD-CI
`HD-BI/CI
`HD/LD-CI
`HD-CI
`
`No. of
`Patients
`
`No. of
`CRs
`
`CR+ PR
`(%)
`
`54
`32
`9
`31
`12
`9
`61
`12
`13
`51
`20
`21
`47
`9
`17
`
`7
`2
`
`2
`0
`
`NA
`
`5
`2
`2
`2
`
`2
`
`31.5
`16
`44
`13
`8
`11
`21
`42
`15
`27
`25
`14
`9
`44
`35
`
`Median
`Response
`Duration (rna)
`(CR/PR)
`
`10/6
`11+/15+
`-/2+
`6+
`NA
`-/1
`NA
`NA
`-/4
`7+
`13+/9
`21+/NA
`23+/8
`2+/3+
`14+/4+
`
`Median
`Survival (rna)
`
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`NA
`13
`NA
`NA
`NA
`NA
`NA
`
`Abbreviations: HD, high. dose (>3 X 10· U/m2); BI, bolus injection; CI, continu~us infusion; LD, low dose; NA, not available.
`
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`76
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`STAHL ET AL
`
`munomodulatory approaches with IFNs, IL-2,
`or adoptive immunotherapy, although they seem
`to be slightly more active than chemotherapy or
`conventional hormone therapy:
`It is obvious that the simple summary of treat(cid:173)
`ment results, achieved with a single agent or with
`drug combinations, may lead to negotiation of
`positive single-trial results. This experience is well
`known in the history of systemic treatment of
`malignancies, and these considerations are also
`of importance when analyzing study results of
`systemic treatment in RCC.
`With all treatment modalities, a wide range of
`remission rates were seen in different trials in RCC.
`The retrospective comparison of these trials, es- ,
`pecially in chemotherapy and hormonal therapy,
`strongly suggests that selection of patients with good
`prognostic factors, such as normal performance
`status, prior nephrectomy, lung metastases only,
`and no bone involvement, was the most important
`precondition for higher response rates.
`
`These prognostic factors surely have the same
`impOliance for immunotherapy results. 3,6,5 1 An
`additional relevant factor in immunotherapy may
`be dose and scheduling; however, this cannot be
`determined at this time because in most trials
`patient numbers were small and doses and/or
`routes of administration of the cytokines, alone
`or in combination with activated cells (LAK,
`TIL), were too heterogeneous.
`It is unquestionable that none of the available
`systemic approaches can be recommended as
`standar~ treatment for advanced RCC today and
`that treatment of metastatic RCC remains pal(cid:173)
`liative. Therefore, it is absolutely necessary to
`carefully weigh effects and side effects of each
`therapy. This situation should not result in ther(cid:173)
`apeutic nihilism, but should lead to a careful re(cid:173)
`evaluation of published positive results and to
`the conduction of clinically and experimentally
`well-designed trials with sufficient numbers of
`patients.
`
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