Granulocyte growth factors: Achieving a consensus*

Annals of Oncology 6: 237-244, 1995. O 1995 Kluwer Academic Publishers. Printed in the Netherlands.

Commentary Granulocyte growth factors: Achieving a consensus*

1

University Hospital, Leuven, Belgium; 2Ospedale San Giovanni, Bellinzona, Switzerland; 3Hospital Universitario '12 de Octubre', Madrid; Hospital Clinic I Provincial, Barcelona, Spain; iIstituto Nazionale Tumori, Milano, Italy; 6H6pital Pitie Salpetriere, Paris; 1H6pital Henri Mondor, Creteil Cedex, France; sMedizinische Hochschule, Hannover, Germany f**See pages 241-242 for list of participants)

4

Summary

A consensus meeting held under the auspices of the European School of Oncology concluded that the use of granulocyte growth factors is definitely indicated, or acceptable given existing evidence, in the following circumstances: to alleviate congenital neutropenia; in the mobilisation of peripheral blood progenitor cells for autotransfusion; to encourage engraftment following bone marrow transplantation and in cases of failed engraftment; to support continuation of ganciclovir anti-CMV therapy in certain patients with AIDS, where the switch to foscarnet is contraindicated or where

Introduction

In order to maximise patient benefit while minimising costs, the development of guidelines for the use of expensive drugs is essential. The granulocyte growth factors have entered an era of consolidation. Initial enthusiasm for their widespread use in the prophylaxis of chemotherapy-induced neutropenia and as a support for bone marrow transplantation has been tempered by the lack of data to demonstrate clear survival benefit. However, the extensive replacement of autologous bone marrow transplantation by the autotransfusion of progenitor cells derived from peripheral blood - for which growth factors are an essential aid to cell mobilisation - has opened up a major new area of use. Moreover, the therapeutic application of colony stimulating factors in congenital and acquired chronic neutropenias has become almost standard practice. The 1994 Munich meeting of the European School of Oncology set itself the not inconsiderable task of achieving a consensus on the use of granulocyte growth factors in haematological and solid tumours and infectious disease. Discussion was divided into four parallel workshops: on stem cell transplantation (bone marrow transplantation and the use of progenitor cells derived

toxicity to foscarnet develops. It was also agreed that there is an overwhelming need for carefully controlled clinical trials in a wide range of indications in which growth factor use may improve outcome. In the majority of tumours, the possible benefit of dose optimisation and intensification, and therefore the role of growth factors in support of such measures has still to be defined. Extramedullary toxicities may in these instances become dose limiting. Key words: growth factors, neutropenia, peripheral blood progenitor cells, bone marrow transplantation, AIDS

from peripheral blood); standard chemotherapy; intensive chemotherapy; and infection/AIDS. There was some overlap in subject matter between the workshop on intensive chemotherapy and that on stem cell transplantation, and these two sections of the following report may usefully be considered together. To establish uniformity, all workshops were asked to assign potential indications for growth factors to one of the following groups: I Definite indication II Acceptable indication, supported by data in Possibly useful but not sufficiently documented IV Requires investigation V No indication They were also asked to distinguish carefully between a range of possible uses: primary prophylaxis, in which growth factor is administered to all patients with the first cycle of chemotherapy; secondary prophylaxis, in which it is given on subsequent cycles to patients with previous episodes of severe neutropenia and/or sepsis; and interventional, when the factor is given to treat already acquired acute or chronic neutropenias. It was generally felt by the participants that for the administration of granulocyte growth factors there is no advantage of the intravenous versus the subcutane-

• Position Paper of a European School of Oncology Consensus Conference 'Use of Granulocyte Growth Factors' held September 10,1994. Chairman: M. Boogaerts. Workshop Chairmen/Moderators: F. Cavalli, H. Cortes-Funes, J. M. Gatell, A. M. Gianni, D. Khayat, Y. Levy, H. Link.

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M. Boogaerts,1 F. Cavalli,2 H. Cortes-Funes,3 J. M. Gatell,4 A. M. Gianni,5 D. Khayat,6 Y. Levy7 & H. Link8

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ous route; that side effects are more commonly reported with GM-CSF than with G-CSF. Whether the use of glycosylated versus unglycosylated products accounts for differences in in vivo activities (bio-availability) is unclear, but glycosylation may permit usage of lower dosages and increased cost benefit.

is again no perceived difference between the effectiveness of G-CSF and GM-CSF. Growth factors may also be useful in cases of graft failure. Peripheral blood progenitor cells

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In the autologous use of peripherally derived progenitor cells, mobilisation by growth factors is essential in Stem cell transplantation: Bone marrow and peripher- all patients (category I). There is no evidence that G-CSF and GM-CSF differ in their capacity to mobilally derived progenitor cells ise progenitor cells, and there are as yet no published Chairman: Professor Alessandro Gianni, Istituto Na- data on their combination. zionale Tumori, Milan, Italy. The ideal is to combine disease oriented chemotherapy with progenitor cell mobilisation using growth facThe workshop was conscious that its consensus was tors. This allows more predictable and massive mobilibased as much on the wisdom of experience as on data sation. As an example, when G-CSF is given following derived from controlled studies. It also confined its high-dose cyclophosphamide, the peak concentration deliberations to solid tumours and lymphoma. Never- of committed progenitors in the peripheral blood is approximately 10-fold higher as compared to when theless, it made several general recommendations. The most important is that autologous bone marrow G-CSF is given alone. Not all chemotherapy regimens transplantation be considered an outdated procedure. are equally effective, but it is relatively easy to identify, When compared with the use of peripherally derived for each disease, a regimen ideal for both antitumour progenitor cells, ABMT is associated with far greater activity and mobilisation. morbidity and mortality, it results in slower engraftGrowth factors should be administered from the day ment and is more expensive. It should therefore no following chemotherapy until the target number of longer be considered 'state-of-the-arf. There may be a peripheral progenitors is harvested. The precise numfew occasions on which ABMT is still justified. How- ber of progenitor cells needed is still open to debate, ever, in the great majority of cases, and wherever pos- although controversy mainly reflects a lack of clearly sible, progenitor cells should be derived from periph- defined end-points. If the aim of the circulating proeral blood rather than bone marrow. genitor cell autotransfusion is to supply a safe dose for stable hematopoietic reconstitution (threshold dose), the amount is low, most likely in the range of 1-2 x 106 Autologous bone marrow transplantation CD34+ cells/kg body weight. If, on the other hand, we want to use a dose fostering a very rapid and complete Nevertheless, when ABMT is undertaken (as it may haematopoietic recovery in nearly all autotransfused still be in heavily pre-treated patients, in AML, ALL patients (optimal dose), the amount is considerably and CML) growth factor support post-transfusion is higher, in the 5-8 x 106 CD34+ cells/kg body weight appropriate. Opinion was equally divided as to whether the indication is definite (I) or simply acceptable (n). range. The cost/benefit implications of CSF use in this conThe importance of growth factors use following protext have yet to be established. genitor cell infusion is not so clear and requires further There are insufficient data to be categorical about investigation. GM-CSF appears to make little differthe optimal point for starting growth factor administra- ence. With G-CSF, there may be faster engraftment, but tion, and this may depend on the conditioning schedule only by 1-2 days. used. However, growth factors should be given until In the transplantation of allogeneic peripheral blood there is stable engraftment, defined as three consecu- progenitor cells, it is too early to determine the possible tive days on which the neutrophil count exceeds 0.1 x role of growth factors. But early results with allogeneic 109/l. The type of growth factor used is not thought to progenitor cell transplantation look extraordinarily make a difference. However with GM-CSF, side effects promising. may be considerable and obscure the clinical picture. In the case of engraftment failure with peripherally derived progenitor cells, whether autologous or allogeneic, the cost/benefit of growth factor use is uncerAllogeneic bone marrow transplantation tain. In this instance, use of growth factors post-transplantaOn a point of terminology, the workshop took the tion is considered potentially useful in accelerating re- view that the term 'autologous transplantation' should covery (class EH indication). No increase in graft versus be replaced by 'autologous transfusion', since transplantation implies the transfer of cells foreign to the host disease has been reported. There is no clear objection in starting growth factors recipient. on day seven rather than day one. As with ABMT, CSFs should be given until engraftment is stable. There

239 Standard chemotherapy for solid tumours and haematological malignancies

Chairman: Professor Franco Cavalli, Ospedale San Giovanni, Bellinzona, Switzerland. Moderator: Dr. Hernan Cortes-Funes, Hospital Universitario '12 de Octubre', Madrid, Spain.

It must be remembered that for most chemotherapy regimens myelosuppression is the dose limiting toxicity. In order to achieve the maximum possible antitumour activity, a degree of myelosuppression is unavoidable. This is particularly true for curative treatments. The degree of myelosuppression may vary from one regimen to another, however, in general, an ANC nadir in the order of 0.5-1.5 x 109/l should be reached with most regimens. The definition of standard regimens may vary according to countries and to institutions. However, this panel considers the following regimens to be standard treatment: • for breast cancer, anthracycline-containing regimens or CMF (cyclophosphamide, methotrexate, 5-fluorouracil) including variants; • for NSCLC, chemotherapy is not a standard treatment. However, if there is an indication for cytotoxic treatment, cisplatin-containing regimens should be used; • for SCLC, chemotherapy should encompass ifosfamide or cyclophosphamide, etoposide and cisplatin: depending on the regimens, adriamycin may be added; • in ovarian cancer, the standard regimen is cisplatin-cytoxan. Today, a cisplatin-taxoids regimen may be appropriate; • for AML, the standard regimen includes the '7 and 3' combination of ara C/daunorubicin, while for ALL the combination vincristine/adriamycin/ prednisone is the standard induction regimen; • for aggressive lymphoma, the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combination and its variants are considered to be the standard, while for indolent lymphomas there is no established standard treatment. Growth factors in non-myeloid malignancies Except in Switzerland, there is regulatory approval for use of growth factors when neutropenia reaches the level of less than 0.5 x 109/l. In Switzerland, complications of neutropenia must be present. However, in practice, the restrictions on the use of growth factors are imposed more by the institutions concerned than by governmental authorities. As a general point, it was accepted that there is a need to tailor therapy to the individual patient. With standard chemotherapy, it is not usually appropriate to

Myeloid malignancies and MDS The potential relevance of growth factors in conjunction with standard chemotherapy in these conditions is still under investigation. No recommendations can be made. Intensified chemotherapy for solid tumours and haematological malignancies

Chairman: Professor Dr. Hartmut Link, Medizinische Hochschule, Hannover, Germany. Moderator Professor David Khayat, Hopital Pitie Salpetriere, Paris, France. The definition of intensive chemotherapy is not without difficulty. It is relatively common for higher than standard doses to be used, but the range of doses employed is great. The increasing employment of peripheral stem cell transplantation is likely to alter the pattern of use of intensified regimens. The two areas therefore cannot be considered in isolation. For the purposes of this discussion, intensive chemotherapy does not necessarily imply myeloablation, but use of higher than standard doses or dose intensity. The goal of growth factor use in this context is to reduce bone marrow toxicity and morbidity in the context of chemotherapy regimens designed to increase disease-free and ultimate survival. In Austria, The Netherlands, Germany, Belgium, Switzerland and Denmark, growth factors are used in support of intensified chemotherapy only as part of

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Chemotherapy

use granulocyte growth factors for primary prophylaxis, i.e., to give them with the first course of chemotherapy in all patients (class HI). However, in individual patients, there may be a justification for growth factors with the first chemotherapy cycle if life-threatening complications are anticipated or if a reduction in the scheduled dose might endanger long-term success. When the aim of treatment is curative, as in germ cell cancers and lymphoma, the aim should be to deliver more than 75% of the scheduled dose. For secondary prophylaxis, it was also thought appropriate to give growth factors if the patient's prospects were likely to be endangered either by infection or by the need for dose reduction. In addition, growth factors may be acceptable in patients with chemoresistant tumours who have shown an initial clear-cut response and in whom maintenance of remission is a goal (category HI). Therapeutic use of growth factors is appropriate when infection is likely to be life-threatening or when neutropenia of more than 5-7 days (with or without fever) is predicted. In these circumstances, use of growth factors may reduce the need for antibiotics and shorten hospital stay. Nevertheless, the cost-benefit ratio for the use of growth factors in these indications has still not been established.

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controlled clinical trials. In Sweden, Finland and Great Britain, there is some usage outside trials. According to the classification given, the indications for growth factor use in conduction with intensified therapy were judged to be as follows:

Infection/AIDS

Solid tumours

In all aspects of HTV and other infections, there is an urgent need for clinical trials to determine the value of treatment with growth factors. Such support may have a role to play in HTV infection and AIDS in particular, since both antiretroviral therapy and drugs used to treat opportunistic infections are myelotoxic. In the case of patients being treated with ganciclovir for cytomegalovirus (CMV) disease, there is early evidence that growth factors may be of benefit. In other areas, there is reason to believe that their use may be beneficial, but at present data are lacking. There are certain considerations specific to the HTV context. GM-CSF has been shown in vitro and in vivo to promote the proliferation of HTV itself and so should be used only in conjuction with zidovudine or other antiretrovirals. Also, the doses of growth factor relevant to HTV disease are likely to be lower than those currently used in haematology and oncology-

n m m in

m m m m rv rv V IV

rv

V V

Non-solid tumours

Strength of indication

ALL AML Hodgkin's disease First line Second line CLL Multiple myeloma Non-Hodgkin's lymphoma Low grade Very high grade Large cell CML

n m IV

n rv rv V

n m V

The issue of how dose intensification might best be achieved must be addressed separately for each disease and disease stage. At present, the data on which such discussion might be based are not available. One exception is a study in SCLC showing that reducing the dose interval from three weeks to one week does not improve outcome. The effects of GM-CSF and G-CSF appear to be equivalent. In terms of side effects, there is the possibility that GM-CSF might cause a greater incidence of fever. In summary, there were no conditions in which intensified chemotherapy with growth factor support was thought to be definitely indicated. The second-line treatment of testicular cancer and Hodgkin's disease were thought to be acceptable indications, justified by available data. So too was the treatment of ALL, very high grade NHL and soft tissue sarcoma. However, further good randomised clinical trials are needed.

Chronic neutropenia related directly to HIV infection Moderate neutropenia, with 1-1.5 x 109 neutrophils/1, is almost universal in patients with HTV but does not lead to infection. The chronic neutropenia associated with HTV infection is therefore not a valid indication for treatment with G-CSF or GM-CSF (class in-TV). The more severe neutropenic episodes that occur are generally associated with identifiable causes such as opportunistic infection, antiretroviral therapy, or neoplasms. Opportunistic infections There have been no clinical trials to establish whether the administration of granulocyte growth factors can prevent the occurrence of opportunistic infections. The possible effects of growth factors in the treatment of chronic neutropenia caused by opportunistic infections such as CMV and disseminated mycobacteriosis have not yet been investigated. In some cases of profound neutropenia and related complications, growth factors may be helpful, but the indication should be considered class Ht-TV. Most important clinically is the early diagnosis and adequate treatment of the infection. Neutropenia induced by antiretroviral therapy Despite recent controversy, zidovudine remains the key antiretroviral drug in HTV disease and, as mono therapy in previously untreated patients, is superior to both ddl

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Testicular cancer Post-relapse Soft tissue sarcoma Neoadjuvant therapy Ovarian cancer SCLC Metastatic breast cancer Nasopharyngeal cancer Non-metastatic breast cancer High risk Standard risk NSCLC Limited disease Extensive disease Bladder cancer Gastric cancer Colorectal Other

Strength of indication

Chairman: Dr. Jose Gatell, Hospital Clinic I Provincial, Barcelona, Spain. Moderator: Dr. Yves Levy, Hopital Henri Mondor, Creteil, France.

241 therapy to be better maintained, and lowers the risk that CMV disease will progress. If neutropenia occurs in the context of ganciclovir therapy, the patient should be switched to foscarnet. If foscarnet intolerance (such as renal insufficiency) develops, ganciclovir can be resumed with the addition of GM-CSF (class n) or G-CSF (class m). From published data, growth factors given during ganciclovir therapy with the aim of maintaining a neutrophil count of greater than 1.0 x 109/l should be administered at the following doses: GM-CSF 5 ng/kg/ daily; G-CSF 300 ugAtay to three times a week. HIV-associated tumours

In countries such as Spain, in which only around a third of people with AIDS are homosexual, 5%-10% of patients develop Kaposi's sarcoma. In other countries the incidence of this tumour can be as high as 30%. Neutropenia induced by the treatment of opportunistic Worldwide, at least 10% of AIDS patients develop lymphoma infections The indications for growth factor use in this context The pattern of opportunistic infections seen in patients should follow those appropriate to chemotherapy in with AIDS is not the same as that in patients with solid patients with non-HTV associated malignancies. G-CSF or haematological tumours who have profound neutro- may be used in lymphoma (indication n). GM-CSF penia. In recent experience in Barcelona, for example, should only be used in conjunction with zidovudine around a third of patients develop tuberculosis at some because of its proven capacity to stimulate proliferation stage in their disease. Growth factor support in the of HIV. treatment of this disease is not generally relevant. Twenty-five percent develop Pneumocystis carinii Other infections pneumonia, treated by cotrimoxazole. With this agent, drug-related neutropenia may be experienced. The Potential indications include sepsis in neonates, in paposition is similar with the treatment of toxoplasmosis, tients with severe burns/trauma, in severe infection seen in up to 20% of patients. post surgery, and in pre-surgical prophylaxis. However, the clearest potential for growth factor Clinical trials are needed to investigate the possible support is probably in the context of CMV disease, use of growth factors for the prophylaxis and treatment which affects roughly 10%-20% of AIDS cases. Ganci- of acute and chronic infections. From animal models, it clovir remains the drug most frequently used in first- is evident that an increased risk of infection may occur line treatment and maintenance therapy, particularly even in the absence of neutropenia. However the rapid for CMV retinitis. This drug is highly myelotoxic at the stimulation of peripheral neutrophil numbers may also concentrations required to inhibit CMV replication. lead to toxicity. Neutropenia develops at doses of 5-10 mg/kg/day, is related to cumulative exposure, and occurs after a median treatment duration of twelve days. AIDS patients ** List of participants are frequently treated with both ganciclovir and zidovudine, which potentiates bone marrow toxicity. The M. Abecassis, C. Alexopoulos, R. Andreesen, K. Arasneutrophil count falls below 0.75 x 109/l in as many as teh, X. Bellmunt, C. Blomqvist, I. Bodrogi, J. Bonne90% of patients. terre, S. Britton, P. Brown, P. Ciesler, P. H. M. de The newer drug foscarnet is less myelotoxic than Mulder, A. Efremidis, J. Ellegaard, C. Faucher, E. ganciclovir, with the result that zidovudine therapy can Fitzsimmons, J. Forjaz Lacerda, P. Fuchsberger, S. be more readily continued; and its use has shown a Gharakhanian, G. Giaccone, J. L. Gonzalez Larriba, V. small survival advantage when compared with ganci- Gorbunova, J. Gouveia, G. Groenewegen, P. Gute, A. clovir. However, foscarnet is more expensive. Hanauske, N. Hansen, R. Herrmann, W.-D. HirschThe AIDS Clinical Trial Group (ACTG study 073) mann, D.-K. Hofffeld, W. Jedrzejczak, E. Kanfer, P. is comparing the use of ganciclovir alone with ganci- Kier, H. Kiihnle, B. Lamersdorf, B. Lebeau, K. Lechclovir plus a growth factor (in this case GM-CSF) in ner, D. Linch (Presenter), J. Lopez Lopez, C. Manepatients also receiving zidovudine. Its preliminary find- gold, D. Metcalf (Guest Speaker), J. Mezger, D. Milliings suggest that use of the growth factor reduces the gan, G. Panagos, A. Parker, L. Perey, K.-H. Pfliiger, M. incidence of neutropenic episodes, allows anti-CMV Pfreundschuh, G. Rigatos, T. Ruutu, M. Sanz Alonso,

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(dideoxyinosine) and ddC (dideoxycytidine). Zidovudine remains the only anti-HTV drug for which a survival benefit has been demonstrated. Zidovudine monotherapy is undoubtedly myelotoxic. Controlled trials show that neutropenia developed in 10%-50% of treated patients, compared with 2%-10% of those on placebo, and is often dose-limiting. We have no longterm data on the use of G-CSF or GM-CSF is neutropenia secondary to zidovudine therapy (class m-IV). If such neutropenia occurs, the main option is to switch to an alternative antiretroviral drug. If this option fails or is not considered adequate, then the continuation of zidovudine with the addition of a growth factor may be appropriate. It is increasingly likely that zidovudine will be used in combination with other antiretrovirals, which are also myelotoxic. Growth factors may become more important in this context.

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H. Scarffe, S. Schey, S. Seeber, G. Sheehan, B. Simonsson, N. Viriolas, C. von Schilling, N. Wilking. -

Acknowledgements -

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Further reading

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The European School of Oncology gratefully acknowledges an educational grant from Chugai RhonePoulenc which made the meeting possible. The authors would like to thank the participants of the meeting, also Ms. Pat Russell and Dr. Rob Stepney for the organisation of the conference and assistance in preparation of the manuscript

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