Second international symposium on ‘Hormonal manipulation of cancer: Peptides, growth factors and new (anti)steroidal agents’

Annals of Oncology 2: 183-189, 1991. O 1991 Kluwer Academic Publishers. Printed in the Netherlands.

Commentary Second international symposium on 'Hormonal manipulation of cancer: Peptides, growth factors and new (anti)steroidal agents' Meeting report, April 9-11, 1990, Rotterdam, the Netherlands J. G. M. Klijn Division of Endocrine Oncology, Department of Medical Oncology, Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands

rate of clones in the absence of steroids, changes in response to growth factors or in growth factor (receptor) In view of the great success of the first symposium 4 response to steroids, downregulation or disappearance years ago (June 1986) [1, 2], a Second International of steroid receptors, mutations of steroid-binding EORTC Symposium on 'Hormonal Manipulation of domain yielding a truncated receptor that has full bioCancer Peptides, Growth Factors and New (Anti)Ste- logical activity, mechanisms adaptive to steroid withroidal Agents' was held in Rotterdam, 9-11 April, drawal, and other possible reasons. Rennie et al. con1990. The 3-day programme focused on new biological cluded that progression of stem cells of the androgenfindings and endocrine therapeutic approaches in a dependent Shionogi mouse mammary carcinoma to an broad spectrum of malignant tumours. The over 200 androgen-independent state, in which they are resistant abstracts have been published in the European Journal to the killing effects of cell death genes, might be preof Cancer [3], while the proceedings of the meeting will vented by the inhibition of androgen-repressed adapbe published in the Journal of Steroid Biochemistry [4]. tive mechanisms which come into play when androgens This second symposium was attended by 500 special- are withdrawn. Pure anti-oestrogens, such as ICI ists of various disciplines such as medical oncology, 164,384, may be expected to completely suppress exendocrinology, internal medicine, urology, gynaecolo- pression of oestrogen-responsive genes and therefore gy, surgery, radiotherapy, biochemistry, cell biology and to be of greater efficacy in controlling breast cancer pharmacology. As chairman of the symposium, in this growth than a partial agonist such as tamoxifen. Indeed, report I will try to summarize the data presented at our Gibson and Jordan demonstrated in athymic mice with meeting according to several topics, tumour types and MCF-7 tumours that tamoxifen as well as oestradiol treatment modalities. The readers, however, have to can stimulate tumour growth after the failure of longrealize that it will be impossible to review all data of the term endocrine therapy with tamoxifen. Growth of 205 presentations. In view of the limited space I will these tumours (MCF-7 TAM) can be inhibited with the restrict myself mainly to prognostic factors and endo- pure antioestrogen ICI 164,384 or withdrawal of tamoxifen. These findings, together with the observation crine therapy. that tamoxifen can also stimulate the growth of human endometrial tumours in athymic animals and perhaps in patients, are important with respect to long-term Growth regulation of tumours adjuvant therapy with tamoxifen. For more detailed information on these subjects I would like to refer to the There were several reports on oncogenes and the proceedings [4]. growth regulation of various tumour types such as breast cancer, prostate cancer, gynaecologic and gastroenteropancreatic tumours, hepatomas, lung tumours, etc. Dickson, Osborne, Vignon, Harris, Prognostic factors and significance of peptide horCoombes, Waxman, Johnson and Havemann stressed mones the importance of different growth factors and peptide hormones. In addition, several authors (Green, Darbre, Chromosomal abnormalities in breast cancer have been Gibson and Jordan, Vignon, Trapman, Rennie, Satyas- demonstrated on chromosomes lp, lq, 3p, 8q, lip, waroop) presented data on the transition from a llq, 13q, 17p, 17q and 18q. Aneuploidy occurs in steroid-responsive to a steroid-unresponsive state. Such more than half of all breast cancers and is related to transition might be caused by incomplete suppression poor prognosis. There were several reports, orally or by of steroid-responsive genes, increased basal growth poster, on the prognostic value of amplification or Introduction

184 54% in ERVPR+/pS2~ patients. In node-positive patients, pS2 status discriminates strongly between a good- and a bad-prognosis group with a 54% difference (88% vs 34%) in overall survival between pS2+ and pS2" subgroups. In node-negative patients, pS2 appeared in our hands to be the most powerful prognosticator, with a 31% difference in 5-year disease-free survival between low- and high-risk patients (89% vs 58%). The lactotrophic hormones prolactin (PRL) and growth hormone (GH) play a role in the growth of certain experimental and human cancers such as breast and prostatic cancer. Furthermore, GH regulates the synthesis and secretion of somatomedin C (i.e. IGF-1) in the liver and probably locally in multiple tissues. Patients with relatively high plasma concentrations of these hormones or IGF-1 have poor prognoses compared to patients with lower concentrations. Receptors for these lactotrophic hormones have been demonstrated in experimental and human mammary tumours. Bonneterre et al. found that 43% of human breast cancers had free PRL-R and that 72% had total PRL-R. Total PRL-R appeared to have prognostic value by univariate analysis but mainly in node-positive patients. Also Berrutti, Dogliotti et al. showed a positive relationship between PRL-R and overall survival, even using the Cox analysis. So at present, two studies have showed a positive association between PRL-R and survival (Bonneterre, Berrutti and Dogliotti) and one study (Waseda) a negative one. The role of the pineal gland hormone melatonin in cancer was described by Dogliotti et al. A number of Receptors for IGF-1 were demonstrated in 90% of experimental studies support the view that melatonin primary breast cancers with a positive relationship affects neoplastic growth but data in human studies are between IGF-l-R and steroid receptor (ER, PR) levels. controversial. In a series of 132 patients with several Foekens et al. found no correlation between IGF-l-R types of cancer Dogliotti found a higher mean melalevels and survival, but Peyrat et al. observed a signifi- tonin level than in healthy controls without any correlacant prognostic benefit for breast cancer patients tion with PRL or GH concentrations. Two posters dealt with melatonin as a treatment modality of experimental whose tumours were IGF-R-positive. Rochefort et al. reviewed some studies on the prog- and human advanced malignancies by stimulation of nostic value of cathepsin D, the precursor of a lysoso- several immune reactions. mal protease secreted in excess by breast cancer cells De Jong et al. investigated inhibin immunoreactivity as compared with normal mammary cells. There ap- in a number of gonadal and non-gonadal tumours. Dog peared a significant correlation between high cathepsin Sertoli cell tumours and human granulosa cell and D concentrations in the cytosol of primary breast can- Leydig cell tumours appeared to contain high concencer patients and development of metastasis. The prog- trations of inhibin-like material. Levels comparable nostic value was the best in node-negative breast can- with those in normal testes and ovaries were detected cer, but in contrast Namer et al. found that total cathep- in human testicular non-seminomas and in ovarian cyssin D was an independent prognostic factor mainly in tadenomas, thecomas and adenofibromas. The authors node-positive patients. Jager et al. found no prognostic concluded that the positive effects of inhibin and value of cathepsin D but their follow-up of a relatively related proteins such as growth and differentiation facsmall series of patients was short-term. tors should be envisaged when dealing with patients with inhibin-producing tumours. An interesting new prognostic marker is pS2, which is an 84 aminoacid long protein with unknown function LHRH-like material and LHRH receptors have and mainly expressed in ER + tumours. In a col- been demonstrated in several experimental and human laborative study Foekens et al. found a very strong tumours. Emons demonstrated LHRH receptors in prognostic value in both node-negative and node-posi- human uterine and ovarian cancer and Waxman et al. tive patients and in ER + patients. The five-year overall in human prostate cancers. Fekete and Schally found survival was 97% in ERVPRVpS2 + patients and only LHRH receptors in 52% of primary breast cancer with (over) expression of various oncogenes (neu, c-erb B-2, int-2, myc, bcl-1, hst-1). Amplification and overexpression of these oncogenes have been detected in a minority of patients (10-30%) and are frequently related to more aggressive breast tumours and to poor prognosis, but, in general, the prognostic value is weak and mainly present in node-positive patients. Also a high proliferative activity of tumours, measured by the thymidine labelling index, s-phase fraction or Ki67-index, indicates poor prognosis. There is no agreement in the literature regarding the relationship between EGF-R and tumour size, lymph node status, differentiation grade, ploidy, proliferation indices and age of the patient. On the basis of 20 studies, EGF-R positivity was observed in 41-90% of ER-negative and in 6-47% of ER-positive tumours. Harris reported that EGF-R was second only to axillary node status as a prognostic marker for all patients. The best prognostic value was found in node-negative or ER-negative patients, in contrast to the findings of Foekens et al. which indicated the best prognostic value for EGF-R in node-positive and ER-positive patients. Coombes et al. studied the prognostic significance of transcripts of EGF-R and found some level of EGF-R expression in 51% of tumours. Statistically, there was no difference in survival between groups which were negative or positive for EGF-R transcripts. With respect to metastatic breast cancer, Harris et al. reported a negative relationship between EGF-R and response to first-line endocrine therapy with tamoxifen and the absence of a correlation between EGF-R status and response to chemotherapy with Mitoxantrone.

185 no association with steroid or EGF receptors. Thus far the prognostic value of LHRH receptors is unknown. Also somatostatin-like material has been shown in several tumours. Somatostatin receptors (SS-R) have been detected by Schally et al. and Reubi et al. in a broad range of experimental and human tumours such as: prostate and breast cancers, pituitary tumours, endocrine gastroenteropancreatic tumours, solid pancreatic and colorectal cancers, small cell lung carcinomas, ovarian cancers, medullary thyroid carcinomas and brain tumours such as meningiomas. The incidence, density and distribution of somatostatin receptors is different among tumour types. The response to treatment with somatostatin analogues seems related to SS-R levels. The prognostic value of SS-R is investigated only in breast cancer and indicates that patients with SS-R-positive tumours have a better prognosis than patients with SS-R-negative tumours. For our extensive review on prognostic factors in breast cancer I would like to refer to reference 5. Several studies have investigated the prognostic value of oncogenes and growth factors in gynaecologic carcinomas. Bauknegt et al. found a correlation between progressive disease of ovarian carcinomas after chemotherapy and high amounts of c-myc RNA. Berns et al. demonstrated an amplification of the int-2 gene in 2 of 20 cases and ras polymorfisms in 2 of 6 cases of ovarian cancer. Bauknegt et al. found that EGF-R+ ovarian carcinomas responded significantly better to chemotherapy. However, similar survival times existed between the EGF-R+ and EGF-R" groups and the survival times of patients who had responded to the treatment was reduced in the EGF-R+ group. These authors found a positive correlation between the EGF-R ligand binding assay, immunohistochemistry and the relative amounts of mRNA by Northern blotting. However, Foekens and HenzenLogmans et al. found no significant correlation between EGF-R measured by immunohistochemistry and by Scatchard analysis in ovarian cancer. Their collaborators, Rodenburg et al., found that patients with immunohistochemically EGF-R+ cancer showed a worse prognosis. Berns and Foekens et al. demonstrated also IGF-l-R in all ovarian cancers investigated using both autoradiography and Scatchard analysis. These levels were higher than those found in benign tumours and normal ovarian tissues. The prognostic significance of IGF-l-R in ovarian carcinoma awaits further study. With respect to endometrial and cervical carcinoma Bauknegt et al. reported a high incidence of EGF-R+ tumours. Previously they reported for endometrial cancer that high EGF-R levels were related to poor prognosis.

Endocrine therapy Prostate cancer

The reports on the treatment of prostate cancer dealt especially with LHRH agonist depot formulations, LHRH antagonists, new anti-androgens, complete androgen blockade by orchidectomy or LHRH agonists in combination with anti-androgens, and aromatase inhibitors. Schally, Sandow and Habenicht presented data on new potent LHRH antagonists. The antagonists have the advantage over agonists that its castrating effect is induced on the first treatment day, while it takes 2-3 weeks for the agonists. With respect to the LHRH agonists, Sandow et al. and Debruyne et al. showed that a single dose of the new slow-release depot preparations of buserelin and goserelin (Zoladex) are effective for at least 3 months. Debruyne et al. reported a clinical flare-up of disease in 10% of the patients before tumour remission. Therefore, the addition of an antiandrogen is recommended. With respect to anti-androgens, data on cyproterone acetate (CPA), flutamide and the new anti-androgens, anandron and casodex, were presented. Steroidal antiandrogens such as CPA suppress, while pure antiandrogens stimulate, pituitary-gonadal function apart from direct antitumour effects via the androgen receptor, which is the main mechanism of action. Rasmussen indicated that the increase of plasma testosterone levels by the pure anti-androgens such as flutamide seem to revert to normal levels within a year and might preserve libido and sexual potency. Mahler and Denis presented data of a phase II study with casodex indicating that this drug in humans is not only peripherally selectively active in view of a rise of LH and testosterone by blockade of central androgen receptors. They demonstrated a 50% reduction of PSA levels in nearly all patients and partial responses in a few. Gynaecomastia was the most frequent side effect, but on the other hand, libido and potency were maintained in some patients. There were 7 presentations on the results of the major studies concerning the value of first-line complete androgen blockade by antiandrogens in combination with surgical or medical castration with LHRH analogues, a very hot topic in the treatment of prostate cancer. Labrie et al. presented data concerning their 7-year clinical experience which showed a strong advantage for the combination therapy in comparison with single-treatment results in historical controls. Using response rate, progression-free and overall survival as parameters, 4 of 6 large randomized studies concerning nearly 2500 patients showed significant improvement of one or more of these 3 parameters by combination treatment compared with surgical or medical castration alone, but the results were not so impressive as those of Labrie. Crawford observed an increase of overall survival from 27.9 to 35.0 months.

186 The improvement was most pronounced in patients with minimal metastatic disease and good performance status. With respect to second-line treatment of prostate cancer-progressing under endocrine treatment, Newling et al. found no difference in efficacy between oral estramustine phosphate and Mitomycin C, which showed a median progression-free and overall survival of 5 and 10 months, respectively. Brodie et al. studied the effect of aromatase and 5-a-reductase inhibitors in human prostatic cancers. Using both the 3 H 2 O assay and measurement of aromatase mRNA amplification with the polymerase chain reaction, they were not able to confirm the presence of aromatase in human prostate cancer. However, they demonstrated that the aromatase inhibitor 4-hydroxy-androstenedione (4-OHA) can inhibit 5-a-reductase in cancer tissue, although to a lesser extent than a more specifically-acting 5-a-reductase inhibitor (4-MA). Other aromatase inhibitors were without effect. Dowsett et al. demonstrated that 4-OHA is only poorly efficacious in advanced prostatic cancer. Breast cancer There were several reports on the effects of new pure antioestrogens. Of great interest is the observation that pure antioestrogens can inhibit the growth of tumours resistant to tamoxifen. In experimental models pure antioestrogens such as ICI 164,384 also showed a greater antitumour efficacy than tamoxifen and no (partial) oestrogen agonistic actions. El Etreby et al. and Bakker et al. showed antitumour activity of the antiprogestins Onapristone and Mifepristone in rat mammary tumours and in vitro. The drugs are mainly active via the progesterone receptor but interestingly, oestrogen-stimulated tumour growth can be blocked by antiprogestins, both in vitro and in vivo. Bakker et al. found additive antitumour effects of tamoxifen and antiprogestin treatment in rat mammary tumours. El Etreby demonstrated accumulation of tumour cells in G 0 G| phase of the cell cycle and the appearance of apoptosis. In two clinical studies Mifepristone appeared effective as second- or third-line treatment of tamoxifen or progestin-resistant tumours. At present newer antiprogestins with less antiglucocorticoid side effects are in development. Results of new aromatase inhibitors were also presented. Santen et al. and Dowsett et al. reported that CGS 16949A has a nearly 1000-fold greater potency than aminoglutethimide and showed evident antitumour effects without significant side effects in postmenopausal breast cancer. Bhatnagar presented striking antitumour effects of an even newer aromatase inhibitor, CGS 20267, which appeared as effective as castration in DMBA-induced rat mammary tumours. In a first phase I study Trunet et al. showed that even very low single dosages of 0.002-O.250 mg caused 5090% suppression of plasma oestradiol levels, which

was maintained for 2-3 days. De Coster presented data of another potent selective non-steroidal aromatase inhibitor (R76713) tested in experimental models in vitro and in vivo. Santen, Brodie and Dowsett gave an overview on the results with 4-OHA, while Bruning et al. reported data on the effects of low- and medium-dose aminoglutethimide with or without hydrocortisone alone. Preliminary data show a similar reduction of serum oestrogens at 8 weeks in all treatment groups, but at 6 months this suppressive effect disappeared in the group treated with hydrocortisone alone, suggesting increased aromatase activity with prolonged glucocorticoid treatment. Miller et al. demonstrated aromatase actvity in 72% of 247 primary breast cancers. Aromatase activity was unrelated to age, menopausal status, tumour size, lymph node status or histology, but was positively related to ER content. A significant positive relationship was found between tumour aromatase and response to aminoglutethimide but not to tamoxifen (although a trend was evident). On the other hand tumours without aromatase activity were associated with increased survival at 36 months in patients with primary breast cancer, suggesting that local oestrogen biosynthesis promotes tumour growth in certain patients. Based on at least 10 phase II studies, in unselected premenopausal women with metastatic breast cancer, single treatment with LHRH analogues causes 40% objective response. Nicholson showed that addition of tamoxifen to Zoladex caused no adverse endocrinological interaction. The use of the combination of drugs appears to be associated with an increased incidence of static disease, which occurs at the expense of partial responses, but progression-free survival was longer in responsive women treated with the combination of drugs. At present, large randomized trials on treatment with LHRH analogues and tamoxifen are ongoing, also within the EORTC. Objective responses are rare in ER-negative tumours, especially when EGF-R is positive. Schally et al. and Klijn et al. demonstrated clear antitumour effects of several somatostatin analogues in experimental models in vitro and in vivo, which are related to the presence of somatostatin receptors. Somatostatin receptors have been demonstrated in 2045% of human breast cancers, but so far there are only a few data on the clinical efficacy of somatostatin analogues showing limited efficacy in heavily pretreated patients. The potential clinical benefit of suppressing GH, PRL and 1GF-1 secretion as presented by Manni et al. has to be established in larger clinical trials involving less heavily pretreated patients. Agents such as suramin, interferons, retinoids and vit D also appeared to be able to inhibit the growth of mammary tumour cells. Ovarian cancer Emons et al. demonstrated LHRH receptors in 80% of

187 40 ovarian epithelial carcinomata, indicating possible direct growth inhibitory effects of LHRH analogues in addition to suppression of gonadotropin secretion. Emons reviewed the results of some clinical studies. Cantwell et al. also reported objective responses of LHRH analogue treatment in pretreated patients with advanced ovarian cancer. In general, after pretreatment with chemotherapy, LHRH analogues cause 10% objective remissions, as is known for other forms of second-line endocrine therapies such as anti-oestrogens and progestins. In addition, Slotman and Rao described clear antitumour effects of antiandrogens on human ovarian cancer cells in vitro. Finally, a low percentage of human ovarian tumours contain somatostatin receptors, but the clinical significance is unclear. Endometrial cancer Satyaswaroop reviewed the results of studies concerning treatment with progestins in advanced endometrial cancer. Overall progestins cause an objective response in 30% of cases with a mean duration of 1012 months. In an experimental model for human endometrial carcinomas in nude mice he investigated the role of steroid receptors in eliciting hormonal responses, the effect of combination treatment with tamoxifen and progestin, and the mechanism of resistance to this treatment after an initial response. Emons reported the presence of LHRH receptors in human endometrial cancers, but the efficacy of LHRH agonist treatment in advanced endometrial cancer is unknown.

ease in 6 of 33 patients by LHRH analogue treatment. Lamers reported that cholecystokinin (CCK) stimulates the growth of the pancreas and pancreatic tumours. These effects can be counteracted by CCK receptor antagonists. Some human pancreatic tumours contain receptors for CCK, but clinical studies on CCK antagonist treatment in patients with advanced pancreatic cancer are needed. Gastric cancer Seitz et al. demonstrated modified expression of the oestrogen regulated pS2 protein in 17 gastric cancers. The clinical value is as yet unclear. Miller found specific binding sites for somatostatin in 12 of 13 human gastric tumours, but Klijn et al. reported only stable disease in 1 of 4 patients with metastatic gastric cancer treated with Sandostatin. Colorectal adenocarcinoma It has been reported that SS-R can occur in human colorectal adenocarcinomas. Miller even reported specific binding sites for somatostatin in 90% of 20 tumours. However, Klijn et al. found no antitumour effect of Sandostatin treatment in a rat colorectal tumour model and only stable disease in 4 of 16 patients with metastatic colorectal cancer. The efficacy of antisteroidal treatment in this tumour type is very low. Melatonin might have some effect on colorectal cancer growth.

Hepatocellular carcinoma Endocrine gastroenteropancreatic tumours and carcinoids There is no doubt about the relationship between hepatocellular carcinoma and hormones. Johnson deA high incidence of SS-R in these endocrine tumours scribed the influence of sex hormones, whose plasma was described by Reubi et al. In 66 patients with meta- concentrations in cirrhotic patients frequently change, static carcinoid tumours Kvols reported an objective of peptide hormones and growth factors on the growth partial tumour response by Sandostatin treatment in of these tumours. He reviewed results of endocrine 17% and a subjective and biochemical (5HIAA) re- treatment in clinical trials showing that objective remissponse of about 80%. The occurrence of response sions can be reached by progestins, antioestrogens and appeared related to tumoural SS-R levels. antiandrogens. He observed an associated fall in free 5a-dihydrotestosterone in 5 patients (20%) with an Pancreatic adenocarcinomas objective response to cyproterone acetate in a series of 25 patients. Schally et al. and Meijers et al. reported a decrease of carcinogen-induced neoplastic pancreatic lesions in Meningioma hamsters by somatostatin analogue treatment. Schally et al. and Klijn et al. found about 50-70% tumour The majority of meningiomas contain high-affinity growth inhibition by somatostatin analogue treatment progesterone receptors. Lamberts et al. reported that in transplantable rat pancreatic tumours. In a clinical progresterone stimulates and that the antiprogestin study Klijn et al. observed only stable disease in 3 of 14 Mifepristone (RU 486) inhibits the growth of cultured patients with metastatic pancreatic cancer by chronic meningioma cells. In a clinical study concerning 10 Sandostatin treatment. This was explained by a lack of patients with inoperable meningiomas treated for 12 SS-receptors in human pancreatic cancers. months with 200 mg Mifepristone daily he found an LHRH analogues and antisteroidal agents can also objective response in 3 and stable disease in another 3 inhibit the growth of experimental pancreatic cancers, patients measured by CT scans. Subjective improvebut in a clinical study Sperti et al. found only stable dis- ment was observed in 6 patients. Grunberg et al. and

188 Haak et al. also observed antitumour effects of Mifepristone in 5 of 14 and in 2 of 2 patients, respectively. The combined results of these 3 studies show that antiprogestin treatment with Mifepristone caused clear tumour growth inhibition in 10 (40%) of 25 patients. Reubi et al. also reported the presence of somatostatin receptors in meningiomas, but clinical trials with somatostatin analogues have still to be carried out. Pituitary tumours In the last decade medical treatment has appeared highly effective in patients with pituitary tumours, and more and more it is replacing the surgical and radiotherapeutical approach. Dopamine agonists are especially effective for PRL secreting and somatostatin analogues for GH secreting pituitary tumours showing inhibitory effects in more than 80% of the patients. Sarcomas Receptors or transcripts for IGFs have been demonstrated in sarcomas. Growth inhibitory effects of somatostatin analogues have been reported in experimental chondrosarcoma (Schally et al), but not in experimental rhabdomyosarcomas in rats (Klijn et al). Steroid receptors have also been demonstrated in sarcomas. Harraga et al. demonstrated stimulatory effects of testosterone on a transplantable fibrosarcoma in the rat mediated by androgen receptors, while antiandrogens and surgical castration caused growth inhibitory effects. However, clinical results of endocrine treatment modalities for sarcomas are lacking. Hormonal recruitment of tumour cells prior to chemotherapy A current hypothesis suggests that short-term hormonal stimulation of tumour cell growth increases the cytotoxicity of chemotherapy. Bontenbal et al. and San ten et al. confirmed the efficacy of oestrogen and androgen priming in experimental systems concerning breast and prostate cancer, respectively. Bontenbal et al. reported a 3- to 5-fold increase in the percentage of MCF-7 cells in the S-phase of the cell cycle after stimulation with oestradiol or insulin. Subsequent incubation with doxorubicin resulted in an augmented inhibition of cell growth compared to unstimulated controls. Santen showed that androgen priming before but not after chemotherapy enhanced the degree of tumour suppression by chemotherapy in the Dunning rat prostatic tumour model. However, the results of clinical studies are so far less successful. Although Conte et al. were able to demonstrate tumour proliferative activity of short-term priming with diethylsnlbestrol in patients with breast cancers, they found only limited advantages of oestrogen priming in 3 randomized trials. Preliminary results of a double-blind randomized trial reported by Paridaens et al. comparing the efficacy of

chemotherapy (FAC) with or without oestrogen recruitment showed no significant difference in response rate, progression-free or overall survival between the two treatment groups. It can be concluded that the validity of the hormonal recruitment concept has not yet been established in clinical practice, so that this approach remains experimental. Better treatment schemes have to be developed. Conte investigated the efficacy of GH and found that this hormone can significantly increase tumour proliferative activity in advanced human breast cancer. Further studies are needed to prove a clear clinical advantage. Growth factor antagonist treatment with suramin Suramin, a polyanionic compound, blocks binding of some growth factors to their respective receptors, inhibits several enzyme systems and possesses adrenocorticolytic properties. There were 7 presentations on the effects of suramin in experimental models and in patients. Dose-dependent antitumour effects were described in mammary, prostatic and adrenal cancer cell lines. Berns et al. and La Rocca et al. have reported that suramin inhibits bFGF and androgen-induced growth of prostatic tumour cells. Di Salle found inhibition of 5a-reductase activity in vitro, while in vivo in rats, suramin did not influence the testosterone effects mediated by its 5a-reduced metabolite dehydrotestosterone. Setyono-Han and Klijn et al. reported growth inhibitory effects of suramin on a transplantable pancreatic tumour in rats. With respect to clinical studies, La Rocca et al. observed a partial response in 2 and minor responses in another 2 of 16 patients with metastatic adrenocortical cancer. Among 35 patients with hormone-resistant metastatic prostate cancer they observed complete responses in 3 (20%) of 15 patients with measurable soft tissue disease and improvement in bone scan abnormalities thus far in only 3 (9%) of the 35 patients with suramin therapy. Twenty-two percent of the patients showed normalization of their PSA levels. In addition 4 of 7 patients with heavily pretreated nodular lymphoma showed partial responses. Klijn et al. reported preliminary results of a broad phase II study in patients with several tumour types. They observed limited antitumour efficacy and many haematological, biochemical and endocrine side effects. The main clinical side effects are rash and fever. Van Rijswijk reported reduction of PSA of >90% in 3 and more than 50% reduction in size of a measurable lymph node in 1 of 9 patients with hormone-resistant metastatic prostate cancer. It can be concluded that suramin has antitumour effects, especially in heavily pretreated patients with lymphomas, prostate and adrenal cancer. Corticosteroids have to be added in view of the occurrence of adrenal insufficiency during long-term treatment. Plasma levels must be monitored in order to prevent serious side effects and to plan the succeeding courses of suramin on time. It can be expected that more spe-

189 cific growth factor antagonists will be developed in the 2. Proceedings First International Symposium on 'Hormonal Manipulation of Cancer Peptides, Growth Factors and New future. Conclusions This symposium underlined the important role of hormones and/or growth factors in the growth regulation of many types of cancer. The number of hormonal agents and endocrine treatment modalities is rapidly increasing, while the number of clinical indications for endocrine treatment is increasing more gradually. Significant improvement in treatment results has been reported for several subgroups of patients as well as promising results of certain new treatment modalities in experimental models. These findings, together with the relatively low toxicity of endocrine therapy, emphasize the importance of research in the field of endocrine oncology today and in the future.

References

(Anti)Steroidal Agents'. In: Klijn JGM, Paridaens R, Foekens JA, eds. EORTC Monograph Series, Vol 18, New York, Raven Press, 1987, pp 1-535. 3. Abstracts Second International Symposium on 'Hormonal Manipulation of Cancer Peptides, Growth Factors and New (Anti)Steroidal Agents'. Eur J Cancer 1990; 26: 142-97. 4. Proceedings Second International Symposium on 'Hormonal Manipulation of Cancer: Peptides, Growth Factors and New (Anti)Steroidal Agents'. In: Klijn JGM, Foekens JA, Schroder FH, eds. J Steroid Biochem Molec Biol 1990; december issue. 5. Klijn JGM, Foekens JA. Prognostic factors in breast cancer. In: Goldhirsch A, ed. Endocrine Therapy of Breast Cancer IV. Monograph Series of the European School of Oncology, 1990; december issue, pp 17-30.

Received 7 September 1990; accepted 12 October 1990. Correspondence to: Dr. Jan G.M. Klijn, M.D. Division of Endocrine Oncology Department of Medical Oncology Dr. Daniel den Hoed Cancer Center Groene Hilledijk 301 3075 EA Rotterdam The Netherlands

1. Abstracts First International Symposium on 'Hormonal Manipulation of Cancer Peptides, Growth Factors and New (Anti)Steroidal Agents'. Eur J Cancer Clin Oncol 1986; 22: 711-51.

Book review New concepts in cancer. Metastasis, oncogenes and growth factors. P. Fabre monograph series, Vol. 3. C. Etievant, J. Cross, Y. M. Rustum (eds). MacMillan Press, Basingstoke, UK., 1990, 246 pp., £40.00. The book comprises the presentations given at a recent meeting held at Castres, in France. Each chapter deals with a specific topic which reflects the research interests of the respective authors. No attempt has been made to integrate the information supplied in the different chapters, which are completely independent of one another, and which follow no particular sequence. Nevertheless, the majority of the chapters are well written and contain sufficient new details about the

Annals of Oncology 2: 189, 1991.

various topics to be potentially of interest to experimental oncologists. It would be difficult in any case to summarize in a single book the information available on all these topics. For specialists, there already exist many good reviews and books on these topics written by these and other distinguished scientists; for those who do not follow the scientific literature on these topics the book can be misleading because there are no general reviews covering the main recent discoveries; the emphasis is on selected aspects related to the individual author's current work. M. D'lncalci Milan