In this thesis both in vitro and in vivo properties of recombinant human hematopoietic growth factors are described. In chapter 1 the effects of five different recombinant human hematopoietic growth factors (GM-CSF, G-CSF, IL-3, IL-4 and IL-6) on the in vitro proliferation of a panel of eleven human SCLC cell lines is decribed. ...

Zie: Summary and conclusions

Biesma, Bonne,

Biesma, Bonne

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Impact of hematopoietic growth factors on cancer treatment

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 University of Groningen
Impact of hematopoietic growth factors on cancer treatment
Biesma, Bonne
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from
it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date:
1993
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Biesma, B. (1993). Impact of hematopoietic growth factors on cancer treatment Krips Repro B.V. Meppel
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Download date: 10-02-2018
ChaPter 7
STJMMARY AND CONCLUSIONS
In this thesis both in vitro and in vivo properties of recombinant human hematopoietic growth
factors are described.
In chapter I the effects of five different recombinant human hematopoietic growth
factors (GM-CSF, G-CSF, lL-3,1L-4, and IL-6) on the in vitro proliferation of a panel of
eleven human SCLC cell lines is described. The results demonstrate that the in vitro
proliferation of only one cell line (GLC-20) could be stimulated by one of the hematopoietic
growth factors tested (rhIL-3). RhGM-CSF, rhG-CSF, rhIL-4, rhIL-6 and the autocrine growth
factors insulin and bombesin, could not further augment the rhIL-3 supported proliferation.
RhIL-3 binding studies demonstrated the presence of high affinity and low afhnity rhIL-3
receptors on the GLC-20 cells. Finally, it was shown that the toxic effects of adriamycin and
cisplatin on the proliferation of the GLC-20 cell line could partially be abrogated in the
presence of rhIL-3. These data demonstrate that in some cases hematopoietic growth factors
can modulate the in vitro proliferation of non-hematopoietic tumor cells and counteract the
effects of chemotherapeutic drugs.
In chapter 2 the results of a double-blind placebo controlled trial, in which thirty
patients with chemotherapy related leukopenia and fever were treated with standard antibiotics
and seven days of intravenously administered rhGM-CSF or placebo (2.8 pglkg/day), are
reported. The aim of this study was to investigate whether rhGM-CSF treatment resulted in an
accelerated recovery of the hematopoiesis of this patient group. RhGM-CSF administration
resulted in a faster percentage increase of peripheral neutrophil count after two and three days
of treatment, except in patients treated with ablative chemotherapy followed by autologous bone
marrow transplantation. However, in this relatively small study, rhGM-CSF did not shorten
the period of fever or antibiotic administration. An increased in vivo release of tumor necrosis
factor-alpha and IL-6 was not observed. These data suggest that a subpopulation of patients
with chemotherapy related leukopenia and fever may benefit from rhGM-CSF treatment in view
of the observed effects on the neutrophil count. In order to further evaluate our observations
a multicentre trial has been initiated.
A different approach to chemotherapy-induced myelosuppression is attempting to prevent
or reduce the severity of this myelosuppression by treating the patients with a hematopoietic
growth factor. Chapter 3 contains the results of a placebo-controlled double-blind dose-finding
trial with rhGM-CSF (1.5,3, or 6 pglkg s.c.) administered on days 6-12 to patients treated
with chemotherapy (carboplatin-cyclophosphamide on day 1) for advanced ovarian cancer.
RhGM-CSF, given on an outpatient basis, demonstrated ability to raise the mean leukocyte and
121
neutrophil count at all dose levels as compared with the control group. Neutrophil counts of
less than O.5xld/l occurred less frequently at the 6 pglkglday rhGM-CSF dose level compared
to the placebo-treated group. At 3 and 6 pglkglday rhGM-CSF also increased the mean platelet
count in comparison with the placebo group. Chemotherapy dose reduction or postponement
due to myelotoxicity occurred in 9128 cycles in the placebo group versus 5/44 cycles in the
rhGM-CSF group, a difference which was not significant. RhGM-CSF related toxicity consisted
of local reactions at the injection site, with local skin inhltrates necessitating withdrawal from
the study of two patients. Capillary leakage of l3ll-albumin was increased in all patients after
the hrst chemotherapy course, but was not affected by rhGM-CSF treatment. Tumor necrosis
factor-alpha and C-reactive protein serum levels increased during rhGM-CSF administration
at the 6 prg dose level, but Interleukin-6 serum levels were not raised by rhGM-CSF
administration. We conclude that a dose of 3 and 6 p.glkglday rhGM-CSF reduces the severity
of neutropenia and thrombocytopenia after carboplatin-cyclophosphamide at the cost of in
general mild side effects.
Although our study with rhGM-CSF in ovarian cancer (chapter 3) demonstrated a
positive effect on the platelet counts, results from other studies demonstrate a variable effect
of rhGM-CSF on thrombopoiesis. RhIL-3 is a hematopoietic growth factor that affects the
myeloid, erythroid and megakaryocytic lineage both in vitro and in vivo. In chapter 4 the
results of a phase I/II trial with rhIL-3 in patients with advanced ovarian cancer eligible for
treatment with chemotherapy (carboplatin-cyclophosphamide) are reported. Patients received
1, 5, 10 or 15 p"glkglday rhIL-3 (days 5-ll) in cycles 1, 3 and 5 by continuous i.v. infusion
or once daily s.c. administration. In control cycles 2, 4 and 6 no rhIL-3 was administered.
RhIL-3 signifrcantly increased the recovery of leukocyte, neutrophil and platelet counts,
especially at 5, l0 and 15 pglkg rhIL-3. No difference in efficacy between s.c. and i.v. rhIL-3
treatment was found. The incidence of chemotherapy postponement for insufhcient bone
miurow recovery was significantly reduced in the rhIL-3 treated patients. RhIL-3 up to doses
of l0 p.glkg/day could be administered without severe side effects. At 15 ptglkglday rhIL-3
headache was doselimiting. RhIL-3 slightly raised tumor necrosis factor alpha, C-reactive
protein and serum amyloid A plasma levels, while no effect on Interleukin-6 plasma levels was
observed. We conclude that rhIL-3 administered to patients on chemotherapy treatment for
ovarian cancer reduces both neutropenia and thrombocytopenia and that up to lO pglkglday
rhIL-3 can be given safely on an outpatient basis.
Chapter 5 contains the results of a pharmacokinetic study of rhIL-3 administered s.c.
and by continuous i.v. infusion (1, 5, l0 or 15 pglkg/day) in patients treated with
chemotherapy for advanced ovarian cancer as described in chapter 4. During the seven day
course no plasma accumulation of s.c. administered rhIL-3 occurred. No significant difference
in elimination half life times between s.c. and i.v. administered rhIL-3 could be demonstrated.
In addition, the bioavailability of s.c. administered rhIL-3 was nearly 100%. Since there was
no difference in hematological efficacy between the two routes of rhIL-3 administration, as
r22
already demonstrated in
to have no disadvantages
Finally, in chapt
chemotherapy regimens
chemotherapy followed b
We conclude tha
oncology and hematolol
chemotherapy-induced m
thesis. and rhG-CSF thet
duration of neutropenia
chemotherapy and bone r
in a wide range of tun
application of rhGMCS.
complications, antibiotic
Results may be further ir
these cytokines, especiall
At this stage, rh
thrombocytopenia. In ad
side effects are more outr
earlier acting hematopoie
act on several cell linei
responsible for the side r
Other possible car
and IL-6) have reached tl
of growth factors are bl
proteins.
In view of the sti
proliferation of tumor ce
these growth factors in
hematopoietic growth fac
cells. Such an in vivo
hematopoietic growth far
chemotherapy. Until now
phenomenon. In contrast
thus creating more vulner
studies are needed to de
response or survival rat
hematopoietic growth fa<
Although hemat
already demonstrated in chapter 4, we conclude that the s.c. route of administration appears
to have no disadvantages over the i.v. route and may facilitate its clinical application.
Finally, in chapter 6 the role of hematopoietic growth factors in standard dose
chemotherapy regimens and in chemotherapy dose-intensification, including ablative
chemotherapy followed by bone miurow rescue is reviewed.
We conclude that the introduction of rh hematopoietic growth factors to clinical
oncology and hematology has created the opportunity to ameliorate to a certain extent
chemotherapy-induced myelosuppression. Forboth rhGM-CSF, as partially demonstrated in this
thesis, and rhG-CSF there is evidence that these hematopoietic growth factors can reduce the
duration of neutropenia following standard dose chemotherapy as well as after ablative
chemotherapy and bone marrow transplantation. Promising as the results may be, more studies
in a wide range of tumor types will have to be performed to clearly demonstrate that
application of ThGMCSF or rhG-CSF will lead to a decrease in the rate of infectious
complications, antibiotic use and hospitalization, and hnally in an enhanced patient survival.
Results may be further improved by defining the optimal dose and administration schedule of
these cytokines, especially during multiple cycles of standard dose chemotherapy.
At this stage, rhIL-3 seems the first candidate for reducing chemotherapy-induced
thrombocytopenia. In addition, it also stimulates neutropoiesis. However, the rhIL-3 related
side effects are more outspoken compared to rhGM-CSF and rhG-CSF. It may well be that the
earlier acting hematopoietic growth factors have a less favorable toxicity profile as these factors
act on several cell lineages and may enhance the release of multiple cytokines, partially
responsible for the side effects.
Other possible candidates for stimulation of thrombopoiesis and myelopoiesis (e.g. IL-1
and IL-6) have reached the early stages of clinical investigation. Studies in which combinations
of growth factors are being used have been initiated recently, as have studies with fusion
proteins.
In view of the stimulatory effect of some hematopoietic growth factors on the in vitro
proliferation of tumor cell lines, certain hazards may be attached to the clinical application of
these growth factors in oncology and hematology. In hematology there is evidence that
hematopoietic growth factors can induce in vivo proliferation of acute myeloid leukemia tumor
cells. Such an in vivo proliferation of tumor cells, induced by the administration of
hematopoietic growth factors, may affect response and survival rates in patients treated with
chemotherapy. Until now, there are no clinical data that demonstrate this growth factor-induced
phenomenon. In contrast, growth factors may be used to stimulate proliferation of tumor cells,
thus creating more vulnerable targets for chemotherapeutic drugs. However, very large clinical
studies are needed to demonstrate such a possible effect of hematopoietic growth factors on
response or survival rates. The same holds true for a possible anti-tumor effect of some
hematopoietic growth factors.
Although hematopoietic growth factors have demonstrated ability to reduce
t23
chemotherapy-induced myelosuppression it remains to be determined whether this will, in the
long run, lead to enhanced patient survival rates by allowing chemotherapy dose-intensification.
Certainly, at this stage the degree of chemotherapy dose intensification achieved by applying
a single growth factor has been limited. Therefore, it seems unrealistic to expect great
improvements in survival rates. A combination of hematopoietic growth factors, in which the
sequence of administration reflects the in vivo mechanism of hematopoiesis may allow a more
pronounced dose-intensifi cation.
In addition, reinfusion of peripheral harvested stem cells after ablative chemotherapy
may in many cases replace bone marrow reinfusion. The number of peripheral circulating stem
cells, and subsequently the number of harvested cells, can be increased by administering
hematopoietic growth factors. At this stage it appears that a combination of growth factors may
be superior to a single growth factor. Since in the near future stem cell collecting may be
mainly performed on an outpatient basis, this may facilitate chemotherapy dose-intensification
in a large number of patients, as hopefully the duration of hospitalization will be shortened
considerably.
The outcome of such studies will determine whether the use of hematopoietic growth
factors in clinical oncology and hematology should be considered as supportive care, or as a
vital tool in increasing both response and survival rates in cancer patients by allowing
chemotherapy dose-intensihcation.
ftn der belangrijks
beenmergdePressie. Dl
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trombocytenaantal me
beenmergdePressie bes
te intensiferen, teneinc
Bij het merendt
van bloedcellen zich il
bloedaanmaak zijn de
eiwitten kan meestal
beenmergdePressie onr
is het mogelijk geworr
duur en ernst van che
Het doel van t
groeifaktoren, zoals t
(rhGM-CSF) en rh inl
en tromboPenie kon r
gerelateerde, bijwerkl
In hoofdstuk
effekt van vijf versch
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op mogelijk stimuler'
Stimulatie van de in
cellijn, de GLC-20
rereptoren voor IL-3
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effekt van adriamYcir
in de aanwezigheid
hematoPoetische gr(
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kan verzwakken'
Hoofdstuk 2
waarin gedurende 7
t24


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   University of GroningenImpact of hematopoietic growth factors on cancer treatmentBiesma, BonneIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:1993Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Biesma, B. (1993). Impact of hematopoietic growth factors on cancer treatment. [S.n.].CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 12-11-2019Stellingen behorende bij het proefschrift van Bonne Biesma 1. Het positieve effect van rhGM-CSF op het trombocytenaantal in vivo dient niet als een toevalsbevinding te word en afgedaan. 2. Koorts dient als een belangrijke en ongewenste bijwerking van sommige hematopoetische groeifaktoren beschouwd te worden. 3. Bij patienten met een solide tumor moeten chemotherapie en een hematopoetische groeifaktor niet gelijktijdig toegediend worden. 4. Subcutane toediening van een hematopoetische groeifaktor verdient de voorkeur boven intraveneuze toediening. 5. Om een additioneel anti-tumor effekt van hematopoetische groeifaktoren naast een effekt van chemotherapie te demonstreren is een meta-analyse noodzakelijk. 6. lndien chirurgische behandeling van het gemetastaseerde carcinoi'.d onmogelijk is dient, bij afwezigheid van symptomen, geen therapie gestart te worden. 7. Bij het inschatten van de kans op het optreden van ernstige bijwerkingen van "ecstasy", is het bepalen van de plasmaspiegel van beperkte waarde. 8. Voor een kaatsende spits moet je in Friesland zijn. 9. Of een fies wijn goed za1 ouderen hangt niet zozeer af van het feit of de wijn voldoende tannine en fruit bevat, alswel van het geduld van de bezitter. 10. . .. , a particular problem being Risenshein, a LOL in NAD whose bone marrow had been wiped out by our cytotoxic agents and had failed to regenerate blood cells, which meant that she was bound to die. (In: The House of God, Samuel Shem) Groningen, 15 september 1993 

Impact of hematopoietic growth factors on cancer treatment

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