2 years after recruitment


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2 years after recruitment

  1. 1. BCO 2001; Vol 4 (July) GnRH analogues in the management of early breast cancer Michael Baum, Elizabeth Shah University College London (UCL) Medical School, London, UK Introduction The World overview of adjuvant systemic therapy in early breast cancer of 1985 turns out to be one of the seminal events in the whole history of the subject. For the first time unequivocal and statistically robust data were presented to the medical community which confirmed that the appropriate use of adjuvant systemic therapy was associated with a significant and prolonged improvement in survival.(1) The follow up overview analyses of 1990, 1995 and 2000 added to and strengthened the original observations. (2–6) Since 1985 mortality rates for breast cancer in the UK have fallen by approximately 30% from an all time high in the late 1970’s and this fall has been ascribed in the main to the widespread adoption of adjuvant systemic therapy.(7) There were two anticipated and one surprise observation emerging from the 1985 overview. Firstly the advantage of combination chemotherapy amongst pre-menopausal women with little or no detectable effect in the older women. Secondly the value of tamoxifen amongst post-menopausal women with no demonstrable effect amongst pre-menopausal women. However the joker in the pack was the meta-analyses of the mature data from a few relatively small trials of ovarian suppression (surgical castration or ovarian irradiation). The benefits of ovarian suppression were of the same order of magnitude as those achieved by cytotoxic chemotherapy. The observations of 1985 effectively established a research agenda for the next fifteen years, maturing at the time of the overview in Oxford of September 2000. This agenda included further trials on the role of cytotoxic chemotherapy in post-menopausal women, trials of tamoxifen in pre- menopausal women. The selection of tamoxifen on the basis of oestrogen receptor status and the benefits of combining chemotherapy and endocrine therapy. The purpose of this publication is not really to discuss the results of the latest world overview which are by now extremely well known but to explore and interpret another group of trials that followed on from the observations of the effect of ovarian suppression on the natural history of early breast cancer amongst pre-menopausal women. Does adjuvant chemotherapy mediate its effect indirectly via chemical ovarian suppression?
  2. 2. The original observation that ovarian suppression and chemotherapy each produced an improvement in disease free survival for pre-menopausal women poses the question as to whether this effect was mediated indirectly by the same biochemical pathways? There are four sets of observations that support this hypothesis. 1. Firstly it is recognised that cytotoxic chemotherapy will induce amenorrhoea in a proportion of pre-menopausal women ranging from about 60% to close on 100% depending on age. The younger the woman, the more resistance to the castrating effect of cytotoxic drugs.(8) 2. Next the endocrinological profile of a woman exposed to cytotoxic chemotherapy similar to that of a castrate woman. In other words oestradiol levels fall and gonadatrophin levels rise. (9,10) 3. There is now an extensive literature illustrating the fact that the induction of amenorrhoea by adjuvant cytotoxic chemotherapy is in itself a prognostic factor. Those women developing a permanent amenorrhoea fare better than those whose menstrual periods return during or after the completion of the course of treatment. This association is seen most clearly amongst women whose tumours express the oestrogenprogesterone receptors. (11–13) 4. Finally there are the trials which attempt to make a head on comparison of endocrine therapy and chemotherapy for pre-menopausal women stratified according to their oestrogen receptor status. These trials will now be discussed in greater detail. The Scottish trial The Scottish breast cancer trial organisation were the first to attempt a head on comparison of ovarian suppression vs cytotoxic chemotherapy in early breast cancer. (14) In this study ovarian suppression was achieved either by surgical castration or X-ray menopause. Patients of all pathological stage and oestrogen receptor status were recruited and randomised to ovarian suppression or six cycles of classical CMF. The trial was a long time recruiting and the eventual numbers were modest incontemporary terms. Nevertheless these results provided additional ammunition to support the next generation of studies. The results of the trial were more or less as anticipated in that there was an apparent equivalence amongst the unselected patients. However when stratified according to oestrogen receptor status those who were ER positive fared better with ovarian suppression whereas those who were ER negative faired better with cytotoxic chemotherapy (Table). Trials involving the GNRH analogues A more recent portfolio of clinical trials for pre-menopausal women commenced recruiting in the mid 1980’s following the availability of the GNRH agonist (primarily goserelin) This class of drug acting on the hypothalamus
  3. 3. produces a reversible ovarian suppression down regulating gonadotrophin release via the process of tachyphylaxis acting on the LHRH receptors of a pituitary gland (15) (Figure 1). Goserelin had already been demonstrated to be a safe and effective treatment for advanced or metastatic breast cancer in pre-menopausal women providing an alternative to surgical castration or an X-ray menopause. (16,17). This drug therefore appeared to be an ideal candidate for use in the adjuvant treatment of early breast cancer particularly for the younger woman who wished to preserve fertility and also where there were long term concerns about osteoporosis for a prematurely castrated woman. The trials to be described can be looked upon in three broad categories. Firstly equivalence trials of goserelin vs standard chemotherapy. Secondly trials comparing combination endocrine therapy with goserelin and tamoxifen vs standard chemotherapy and thirdly trials exploring the additive effect of endocrine therapy for women undergoing standard cytotoxic therapy as first choice. The ZEBRA trial The ZEBRA trial is an international collaborative group designed and powered to demonstrate equivalence between goserelin and adjuvant chemotherapy (18) (Figure 2). Following surgery patients were randomised to two years of goserelin or six cycles of CMF. Close on 2,000 patients were recruited, both ER positive, ER-ve and ER unknown and the results have recently been presented at a number of scientific meetings. Where the women were known to be oestrogen receptor positive the results demonstrated an ‘equivalence’ within a pre-determined and statistically acceptable narrow confidence interval. This ‘equivalence’ is not an intuitively obvious outcome if one assumes that cytotoxic chemotherapy can achieve its effect directly by cell kill and indirectly by ovarian suppression. However this could be explained by a significant proportion of the patients receiving CMF failing to achieve permanent amenorrhoea The IBCSG VIII trial which has yet to be reported (Figure 3) has two arms identical to the ZEBRA analyses which will help confirm whether these two approaches are equivalent for oestrogen receptor positive patients. (19) Trials of combination endocrine therapy vs chemotherapy There are two trials which have recently reported comparing ovarian suppression and tamoxifen with conventional CMF, namely GROCTA02 (20) (Figure 4) and the Austrian breast cancer study group (ABCSG) trial (21) (Figure 5). The Italian breast cancer adjuvant group (GROCTA) compared ovarian ablation (which included oophorectomy and ovarian irradiation although 70% of the patients had goserelin) plus five years of tamoxifen vs CMF. They included 244 pre-menopausal women who were ER positive and node positive or negative with a median follow up of close on five years. The Austrian study compared goserelin for three years and tamoxifen for five years vs six cycles of CMF. They recruited just over 1000 pre-menopausal patients all of whom were hormone receptor-positive but either node positive
  4. 4. or node negative with a median follow up of close on four years. Both studies demonstrated the benefit of combining ovarian suppression and tamoxifen vs CMF alone . In the Austrian study, patients treated with combination endocrine treatment had a significantly improved recurrence-free survival compared with CMF (p<0.02) while in the Italian study there was no difference between tamoxifen plus ovarian suppression and CMF with respect to either disease-free or overall survival. Again these results are not surprising if one bears in mind CMF fails to achieve complete amenorrhoea in 100% of cases and the more recent evidence that the addition of tamoxifen to cytotoxic chemotherapy improves outcome over chemotherapy alone. This particular issue has been addressed directly by the inter-group study to be described next. INT 0101E5188 (Inter Group Study ECOGSWOGCALGB Trial) (22) The design of this trial is illustrated in Figure 6. After local therapy patients are randomised between six cycles of CAF, six cycles of CAF followed by five years of goserelin and six cycles of CAF followed by goserelin and tamoxifen each for five years. Just over 1500 pre-menopausal patients were recruited all of whom were ER and or PR positive with involved axillary lymph nodes and the median follow up is now six years. The latest results show a significant improvement in five year disease free survival for the addition of goserelin and tamoxifen to chemotherapy compared with the addition of goserelin alone and there was a small numerical but non-significant benefit for adding goserelin alone to chemotherapy. There was also anecdotal evidence that thebenefit of adding goserelin alone to chemotherapy was more apparent in the very young women who failed to achieve amenorrhoea on CAF. ZIPP combined analysis (23) Shortly after the 1985 world overview four collaborative groups met in order to design a prospective multi-centre clinical trial to explore the options of adjuvant systemic therapy for pre-menopausal women. The groups concerned were the British Cancer Research Campaign Breast Cancer Trials Group, the Stockholm Breast Cancer Trials Group, a group of South East Sweden and an Italian collaborative group GIVIO. The intention was that each group would run a trial of similar design with the idea of a meta-analysis as the data matured. The design of the trial is complex and it is illustrated in Figure 7. Following adequate local therapy a decision was made whether or not the patient should receive adjuvant chemotherapy. In the majority of cases this was determined by the lymph node status. The patients were then randomised four ways in order to develop a two x two factorial design. The randomisation options were goserelin for two years, tamoxifen for two years, goserelin and tamoxifen both for two years or no adjuvant endocrine therapy. 2,631 patients were recruited for the combined analyses. All were less than 50 years old and were both oestrogen receptor positive and negative or node positive and node negative. 43% of the patients had adjuvant chemotherapy
  5. 5. as an elective option prior to randomisation to the endocrine treatment. The median follow up for the latest analyses is approximately five years. Halfway through the recruitment, maturation of data from other trials (in particular the CRC adjuvant tamoxifen trials) demonstrated that tamoxifen did indeed have a role for pre-menopausal women and participants in the trial were given the option of elective tamoxifen for patients judged to be suitable for this treatment. The ‘elective’ tamoxifen group therefore were predominantly oestrogen receptor positive. In a 2 x 2 factorial analyses the intention is to analyse the data for ‘main effect’ which would be tamoxifen either in the presence of absence of goserelin or goserelin either in the presence or absence of tamoxifen. Because close on, 50% of the patients were in the end given elective tamoxifen the statistical power of that component of the analyses is very weak and contributed little to the overview analyses of September 2000 which reinforced the advice of prescribing tamoxifen for oestrogen receptor positive pre-menopausal women. The complexity of the ZIPP trial analyses demonstrates the hazard of attempting to answer all the questions whilst running the hazard of answering none. However taking these results and adding them to the sum of experience to the trials reported above, the message that appears is clear with the "signal detectable above the background noise" In unselected patients there is a significant advantage in prescribing goserelin for disease free survival which reaches borderline significance for overall survival . Both the CRC and the Stockholm components of the overview reached significance on their own, whereas the other two groups failed to show a significant advantage although with wide confidence intervals and no statistical evidence of heterogeneity. (it is worth noting that the GIVIO group of patients had the highest exposure of chemotherapy than any of the other groups). Pre-determined sub-set analyses demonstrate a significant advantage in DFS for oestrogen receptor positive patients. There are also numerical advantages, which failed to reach conventional levels of significance for patients who were node positive or receiving chemotherapy as part of their treatment plan (essentially these are the same group of patients). However those patients who were node negative ie predominantly chemotherapy naïve, showed a significant advantage in DFS Even though this is the largest of all the trials, when one gets down to sub /sub set analyses, in particular the advantage of adding tamoxifen to goserelin in the presence of chemotherapy one simply runs out of statistical power. However it is worth noting that in the clinically relevant scenario where tamoxifen is prescribed electively, we witness a highly significant advantage in disease free survival, with over a 40% relative risk reduction compared with those patients who are chemotherapy naïve and not receiving goserelin (this particular analysis is supported by the observations of the GROCTA and ABCSG trials). Clinical guidelines From this mass of emerging new data it is possible to distil some rational clinical guidelines for everyday practice. Firstly the GNRH analogues have no
  6. 6. role to play in oestrogen receptor negative patients ( with one exception-vide infra ) but must be considered to have a role where the tumours are oestrogen receptor positive. At the very least, patients receiving adjuvant chemotherapy who fail to achieve amenorrhoea should be offered ovarian suppression either with GNRH analogues or perhaps if close to the natural menopause, with endoscopic ovarian ablation. Furthermore an element of choice now emerges and it is therefore important to involve the patient in the decision making process Many patients are terrified by the short term toxicity of chemotherapy and also need to be informed of the long term consequences of a permanent chemical castration and other side effects such as cognitive impairment.(24) It is evident that for ER positive patients, two years of goserelin is equivalent to CMF but offers a woman the potential of return of normal ovarian function, fertility and protection from the long term consequences of osteoporosis. In the same way that tamoxifen has an added advantage over chemotherapy alone we can argue that tamoxifen added to goserelin would be an advantage over goserelin alone and equivalent to chemotherapy plus tamoxifen. However much of the difficulty in deciding on these therapeutic options are more culturalsociological than scientific. In Europe the choice is relatively easy where the endocrine option has always been considered realistic. However in the USA where chemotherapy was adopted as the gold standard (prematurely in our opinion) together with fear of litigation, these recommendations might be considered too radical or even dare we say it, heretical. The potential for GNRH analogues to preserve fertility in the presence of chemotherapy. One final issue that needs to be considered and that is the potential role of GNRH analogues in the preservation of fertility in women at risk of ovarian damage from cytotoxic chemotherapy. There may be a simple way of managing these women by deliberately producing a state of temporary, reversible medical castration during chemotherapy. Following on from the observation that prepubertal children receiving chemotherapy are less likely to develop gonadal dysfunction, it was hypothesised that inhibition of the hypothalamic-pituitary axis by GnRH agonists would result in quiescent gonads, simulating the pre-pubertal milieu, and thus rendering the gonads less susceptible to cytotoxic effects. This hypothesis was tested in an animal model and it was found that the GnRH agonist, leuprolide, prevented loss of ovarian follicles in adult female rats (25). The proposed mechanism was deprivation of the follicles of gonadotrophins and interference with the process of recruitment of follicles from the quiescent pool into the chemotherapy-sensitive pool of maturing follicles. Promising results were also achieved by administering a GnRH agonist to young women with lymphoma during combination chemotherapy regimes where 93.7% of the women experienced resumption of ovarian function after termination of treatment (26).
  7. 7. Our hypothesis is that temporary interruption of the hypothalamic-pituitary- gonadal axis by concurrent administration of goserelin, a GnRH analogue, during cytotoxic chemotherapy may protect the ovary from irreversible damage and thus diminish the incidence of premature ovarian failure in premenopausal women. Goserelin down-regulates the human pituitary receptors and thus decreases the levels of the gonadotrophins, Follicle- stimulating Hormone (FSH) and Luteinising Hormone. A prospective multi- centre randomized controlled trial has been set up to test this hypothesis in premenopausal women undergoing treatment for breast cancer and lymphomas. Patients suitable for entry into this trial are female patients 40 years of age or below, with oestrogen receptor negative primary breast cancer or Hodgkin's / non- Hodgkin's lymphoma, requiring adjuvant chemotherapy. They are randomised to receive either chemotherapy alone or goserelin and chemotherapy together; goserelin given for the duration of chemotherapy. The main endpoint is ovarian function after treatment, which is assessed by clinical, biochemical and radiological parameters in combination. Furthermore, long-term ovarian reserve may be predicted by correlating serum inhibin-B and FSH levels. Conclusion It is essential that both practicing clinicians at the front line and their well informed patients realise that we are passing through a time of uncertainty and revolution concerning the role of ovarian suppression in the management of early breast cancer. However we all feel confident with the maturation of the trials already described together with the long awaited publication of the IBCSG VIII trial, these will be clarified. Adopting an entrenched position at this stage, is no service to science or humanity. Figure 1: Mode of action of goserelin. (a) Hypersecretion of luteinizing hormone (LH) following acute administration of goserelin; (b) hyposecretion of LH after chronic administration of goserelin. (a) (b) Figure 2: Protocol for the ZEBRA trial of goserelin vs CMF (cyclophosphamide, methotrexate, 5-flurouracil) treatment.
  8. 8. Figure 3: IBCSG VIII protocol of goserelin vs CMF (cyclophosphamide, methotrexate, 5-flurouracil) vs the combination. A fourth arm of no treatment was discontinued 2 years after recruitment. Figure 4: Protocol for the GROCTA trial of ovarian suppression plus tamoxifen (5 years) vs CMF (cyclophosphamide, methotrexate, 5- flurouracil) treatment. Ovarian suppression was achieved either by oophorectomy (n=6), ovarian irradiation (n=31) or 2 years goserelin treatment (n=87). Figure 5: Protocol for the ABCSG trial of goserelin (3 years) plus tamoxifen (5 years) vs CMF (cyclophosphamide, methotrexate, 5-flurouracil) treatment. Figure 6: ECOG/SWOG protocol of CAF (cyclophosphamide, adriamycin, 5- flurouracil) vs CAF plus goserelin vs CAF plus goserelin plus tamoxifen. Figure 7: Protocol for the ZIPP analysis of goserelin (2 years) vs tamoxifen (2 years) vs goserelin + tamoxifen (2 years) vs no further treatment. Table. Relation between ER concentration and first event. (Adapted with permission from Scottish Cancer Trials Breast Group. Lancet 1993;341:1293-8, © The Lancet Ltd.) (14)
  9. 9. ER (fmol/mg HR Ovarian ablation/CMF (95% Total pr) CI) 1.79 0-4 60 (0.82-3.89) } 1.74 (0.95-3.19) 1.59 5-19 40 (0.59-4.27) 0.70 20-99 116 (0.38-1.27) } 0.65 (0.37-1.15) 0.45 =100 22 (0.008-2.7) References: 1. Early Breast Cancer Trialists’ Collaborative Group. Effects of adjuvant tamoxifen and of cytotoxic therapy on mortality in early breast cancer: an overview of 61 randomised trials among 28,896 women. New England Journal of Medicine 1988; 319: 1681-92. 2. Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy. Lancet 1992; 339: 1-15, 71-85 3. Early Breast Cancer Trialists’ Collaborative Group. Ovarian ablation in early breast cancer: overview of the randomised trials. Lancet 1996; 348: 1189-96 4. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998; 351: 1451-67 5. Early Breast Cancer Trialists’ Collaborative Group. Polychemotherapy for early breast cancer: an overview of the randomised trials. Lancet 1998; 352: 930-42 6. Please note that the 2000 overview had not been published at the time of writing. 7. Quinn, M and Allen, E. Changes in incidence of and mortality from breast cancer in England and Wales since introduction of screening. British Medical Journal 1995; 311: 1391-5 8. Bines, J, Oleske DM and Cobleigh, MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. Journal of Clinical Oncology 1996; 14: 1718-29 9. Koyama, H, Wada T, Nishizawa, Y et al. Cyclophosphamide-induced ovarian failure and its therapeutic significance in patients with breast cancer. Cancer 1977; 39: 1403-9. 10. Mehta RR, Beattie CW, Das Gupta TK. Endocrine profile in breast cancer patients receiving chemotherapy. Breast Cancer Research and Treatment 1992; 20: 125-132
  10. 10. 11. Poikonen P, Saarto T, Elomaa I et al. Prognostic effect of amenorrhoea and elevated serum gonadotropin levels induced by adjuvant chemotherapy in premenopausal node-positive breast cancer patients. European Journal of Cancer 2000; 36: 43-8 12. Del Mastro L, Venturini M, Sertoli MR et al. Amenorrhea induced by adjuvant chemotherapy in early breast cancer patients: prognostic role and clinical implications. Breast Cancer Research and Treatment 1997; 43: 183-90 13. Pagani O, O’Neill A, Castiglione M et al. Prognostic impact of amenorrhoea after adjuvant chemotherapy in premenopausal breast cancer patients with axillary node involvement: results of the International Breast Cancer Study Group (IBCSG) trial VI. European Journal of Cancer 1998; 34: 632-40 14. Scottish Cancer Trials Breast Group and ICRF Breast Unit, Guy’s Hospital, London. Adjuvant ovarian ablation versus CMF chemotherapy in premenopausal women with pathological stage II breast carcinoma: the Scottish trial. Lancet 1993; 341: 1293-8 15. Jonat W. Luteinizing hormone-releasing hormone analogues - the rationale for adjuvant use in premenopausal women with early breast cancer. British Journal of Cancer 1998; 78 (Supplement 4): 5-8 16. Taylor CW, Green S, Dalton WS et al. Multicenter randomized clinical trial of goserelin versus surgical ovariectomy in premenopausal patients with receptor-positive metastatic breast cancer: an Intergroup study. Journal of Clinical Oncology 1998; 16: 994-9 17. Boccardo F, Rubagotti A, Perrotta A et al. Ovarian ablation versus goserelin with or without tamoxifen in pre-perimenopausal patients with advanced breast cancer: Results of a multicentric Italian study. Annals of Oncology 1994; 5: 337-42 18. Kaufmann M. ‘Zoladex’ (goserelin) vs CMF as adjuvant therapy in pre/perimenopausal, node-positive, early breast cancer: preliminary efficacy results from the ZEBRA study. Breast 2001; 10 (Supplement 1): S30, abstr P53 19. Castiglione-Gertsch M, Gelber RD, O’Neill A et al. Systemic adjuvant treatment for premenopausal node-negative breast cancer. European Journal of Cancer 2000; 36: 549-550 20. Boccardo F, Rubagotti A, Amoroso D et al. Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian supression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. Journal of Clinical Oncology 2000; 18: 2718-27 21. Jakesz R, Hausmaninger H, Samonigg H et al. Complete endocrine blockade with tamoxifen and goserelin is superior to CMF in the adjuvant treatment of premenopausal, lymph node-positive and -negative patients with hormone- responsive breast cancer. Breast 2001; 10 (Supplement 1): S10, abstr S26
  11. 11. 22. Davidson NE, O’Neill A, Vukov A. Effect of chemohormonal therapy in premenopausal, node-positive, receptor-positive breast cancer: an Eastern Cooperative Oncology Group Phase III Intergroup Trial (E5188, INT-0101). Breast 1999; 8: 232-233, abstr 069 23. Baum M, Houghton J, Odling-Smee W et al. Adjuvant ‘Zoladex’ in premenopausal patients with early breast cancer: results from the ZIPP trial. Breast 2001; 10 (Supplement 1): S32-3, abstr P64 24. Brezden CB, Phillips KA, Abdolell M et al. Cognitive function in breast cancer patients receiving adjuvant chemotherapy. Journal of Clinical Oncology 2000: 18; 2695-701 Ataya, K. M., McKanna, J. A., Weintraub, A. M., Clark, M. R. and LeMaire, W. J. A luteinising hormone-releasing hormone agonist 25. for the prevention of chemotherapy-induced ovarian follicular loss in rats. Cancer Res 1985; 45: 3651-56. Blumenfeld, Z., Avivi, I., Linn, S., Epelbaum, R., Ben-Shahar, M. and Haim, N. Prevention of irreversible chemotherapy-induced ovarian damage in young women with lymphoma by a gonadotrophin-releasing hormone agonist in parallel to chemotherapy. Hum Reprod 1996; 11: 1620-26