Annuls of Oncology 3: 801-807, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands.

Adljy vaunt therapy of primary breast camcer * 4th International Conference on Adjuvant Therapy of Primary Breast Cancer St. Gallen, Switzerland

1 University of Pennsylvania Cancer Center, Philadelphia, PA; 2Dana Farber Cancer Institute, Boston, MA, U.S.A.; 3Ospedale Civico, Lugano; "Kantonsspital Oncology Center, St. Gallen, Switzerland

statistically significant reductions in the annual rates of both recurrence and of death produced by tamoxifen in Adjuvant therapy for stage I and II breast cancer re- both node-negative and node-positive patients, by mains in evolution as new data emerge from controlled ovarian ablation below age 50, and by combination randomized trials and from the overview analysis by chemotherapy for patients below age 50 and for those the Early Breast Cancer Trialists' Collaborative Group. between 50-69 years of age [4]. For tamoxifen and The Fourth International Conference on Adjuvant combination chemotherapy, the avoidance of recurTherapy of Primary Breast Cancer, held in St. Gallen, rence is chiefly during the first 5 years, but the avoidSwitzerland in February, 1992, brought together breast ance of mortality is highly significant during both the cancer experts from all over the world to present their first and second 5 years, so the cumulative differences most recent data and to discuss the remaining chal- in survival are large both at five and then at 10 years. lenges that confront both clinicians and basic scientists. Indirect comparisons show that long-term tamoxifen The data presented at the 1992 St. Gallen confer- (e.g., two years or even five years) is significantly more ence allow us to revisit the treatment recommendations effective than shorter duration tamoxifen treatment made at the 1985 and 1990 NIH Consensus Develop- programs. Between ages 50 and 69, direct comparisons ment Conferences, as well as at the 1988 St. Gallen show that chemotherapy plus tamoxifen is superior to meeting [1-3]. The timing of the 1992 St. Gallen Con- chemotherapy alone for both recurrence and mortality, ference was fortunate in that the ten-year data from the and better than tamoxifen alone for recurrence. In Early Breast Cancer Trialists' Collaborative Group women aged under 50, chemotherapy and ovarian (hereafter referred to as the Overview) had recently ablation appear, by indirect comparison across two been published [4]. Four distinct overviews were con- separate overviews, to be of comparable efficacy. The ducted to evaluate whether adjuvant therapy with 30%-40% proportional risk reductions that can be produced by combined chemo-endocrine therapy in tamoxifen, chemotherapy, ovarian ablation or immunomiddle age are similar for node-positive and for nodetherapy, either alone or as part of combined modality negative patients, while the absolute improvement in treatment, reduced the risk of recurrence and death. ten-year survival is about twice as great for the nodeEligible randomized trials included those started bepositive patients [4]. Thus, the conclusions from the fore January, 1985, in which the modality under study ten-year Overview analysis clearly influenced the treatwas the only difference between treatments received by ment recommendations made at the 1992 St. Gallen two randomized groups of patients. Data were available Conference, which will be discussed in a later section. for 75,000 women randomized in 133 clinical trials. The timeliness of this Conference is illustrated by the The specific positive findings that attracted attention remarkable lack of conflict from different investigators, were based on 30,000 women in tamoxifen trials, 1800 who, using their own data and that from the ten-year women below age 50 in ovarian ablation trials, and Overview, came to similar conclusions regarding the 11,000 women in combination chemotherapy trials. 1992 St. Gallen treatment recommendations. It was clear that the ten-year Overview data presented by Peto and colleagues, greatly influenced the participants at the 1992 St. Gallen Conference. The Overview conclusions included demonstration of highly Conference highlights Introduction

* Published previously as Meeting Highlights: Adjuvant Therapy for Primary Breast Cancer in Journal of the National Cancer Institute 84: 1479-85, 1992.

The role of currently accepted and new prognostic factors was a subject of active debate. There was broad

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J. H. Glick,1 R. D. Gelber,2 A. Goldhirsch3 & H. J. Senn4

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Data presented at the Conference continue to demonstrate that breast conservation therapy (lumpectomy and radiation therapy) achieves equal ten-year overall survival as compared with modified radical mastectomy. Thus, lumpectomy and radiotherapy offer equal efficacy with less morbidity and are the preferred local treatment for most patients with early stage breast cancer. Margolese [10], reporting the data from NSABP, noted a 40% rate of local breast recurrence at nine years in patients who were treated with lumpectomy alone. However, there was no difference in overall survival between the lumpectomy alone as compared to lumpectomy and radiotherapy patients. A very low incidence of breast recurrence has been observed in recent NSABP trials in which chemotherapy was used in addition to radiotherapy to the conserved breast (2.6% breast recurrences in the chemotherapy group compared to 7.4% in the no treatment group) [11]. For patients with tumor size 3 cm. In this series of 227 patients, 82% had tumors measuring between 3.0-5.0 cm at the time of entry on study, while only 18% of tumors initially measured greater than 5.0 cm. Bonadonna administered 3-4 cycles of chemotherapy prior to surgery. The surgical technique included either lumpectomy or quadrantectomy for tumor sizes measuring less than 3 cm and mastectomy for tumors greater than 3 cm. Definitive radiotherapy was then administered. Although 91% of patients on this trial subsequently underwent breast conservation surgery, and only 9% required mastectomy, Fisher observed that 75%-80% of Bonadonna's patients would have been eligible for initial lumpectomy in the NSABP B-06 trial. Thus, the use of neoadjuvant chemotherapy for patients whose tumors measure 3.0 to 5.0 cm is not routinely recommended, since these patients are generally candidates for lumpectomy without initial chemotherapy. Harris [13] discussed the integration of primary radiotherapy and adjuvant chemotherapy. In a small retrospective series, they observed that significant delays in the initiation of radiotherapy, in order to allow the delivery of chemotherapy before radiation, may increase the rate of local recurrence in the treated breast. However, the small number of patients in this retrospective analysis make this conclusion tenuous at this time. Thus, the optimal sequencing of definitive radiation and chemotherapy remains an open question. Kurtz [14] also reviewed factors influencing the risk of breast recurrence following lumpectomy and radiation. He noted that patients age less than 35 incurred a significant increased risk of local recurrence as compared to older patients (p < 0.05). There was no influence of menopausal status, location of the primary in the breast, tumor size, axillary node status or hormone receptors in predicting for an increased local breast recurrence. Patients with an extensive intraductal component did have a significantly increased rate of local failure. Extensive intraductal component has been defined by Harris [13] as infiltrating ductal carcinoma in which intraductal carcinoma is predominantly present in the tumor (>25%) and intraductal carcinoma is present in sections of grossly normal adjacent breast tissue. Peto reviewed the data from the Early Breast Cancer Trialists' Collaborative Group [4[ and commented on the importance of these data as follows: the definitive effect of adjuvant therapy on ten year survival is clearly demonstrated; the extra mortality benefit was seen between years five and nine with the addition of tamoxifen; ovarian ablation in patients age less than 50 produced similar effects in the reduction of recurrence and mortality to those seen with combination chemotherapy; tamoxifen was effective in women greater than age 50 in significantly improving both relapse-free survival and overall survival for all women, even those who are estrogen receptor poor; there was a

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acceptance that rumor size, axillary lymph node status, hormone receptors and histopathology are important prognostic factors. Both Clark et al. [5], and Dressier et al. [6], stressed the importance of determining S-phase by flow cytometry as an important prognostic factor for node-negative patients. While S-phase determination by flow cytometry is broadly accepted in the United States as a routinely used prognostic variable for node-negative patients, Silvestrini from the NCI in Milan [7], did not confirm the value of S-phase as determined by flow cytometry for these patients. Instead, Silvestrini argued that the 3H-thymidine labelling index was the most important indicator of relapse. Clark et al. [5] discussed the prognostic significance of over-expression of the tumor suppressor gene p53 in node-negative patients. The incidence of p53 mutations, as determined by immunohistochemistry, was observed in 50% of patients and independently predicted for early recurrence in node-negative patients. Klijn et al. [8] discussed the prognostic value of the epidermal growth factor receptor (EGF-R), and concluded that EGF-R negative patients have improved disease-free and overall survival. However, they observed that the prognostic value and best cut-off value of EGF-R remain open to question. Despite the proliferation of new prognostic factors each year, the St. Gallen Conference participants concluded that only the number of axillarly lymph nodes involved, tumor size, age or menopausal status, histopathology, and hormone receptor status should be routinely used at this time. Baum [9] agreed with the routine use of these well-accepted prognostic factors.

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mained investigational and should not be used outside the context of the randomized controlled clinical trial. Tormey [18] reviewed the data from several randomized trials conducted by the Eastern Cooperative Oncology Group. These trials particularly addressed the role of long-term tamoxifen for at least five years versus shorter durations of tamoxifen (i.e., one year). The studies demonstrated that long-term tamoxifen (5 years) was associated with a significantly longer time to recurrence than the shorter term tamoxifen (one year) regimens (p < 0.02). However, there are no survival differences noted as yet in these trials. Fisher [11, 19] reviewed the NSABP data on nodepositive patients who were defined as 'non-responsive to tamoxifen', based on definitions in older NSABP studies which included selection criteria using age and progesterone receptor status. Doxorubicin and cyclophosphamide administered every 21 days for four cycles achieved equivalent disease-free and overall survival to conventional CMF adjuvant chemotherapy. In 'tamoxifen-responsive', estrogen receptor positive patients doxorubicin and cyclophosphamide were administered concurrently with tamoxifen (ACT) and were compared to tamoxifen alone. The ACT regimen achieved significantly improved five-year disease-free survival (70%) as compared to tamoxifen alone (60%) (p = 0.002), as well as significantly improved five-year overall survival (ACT 87% vs. 76% with tamoxifen alone, p = 0.002). The data from this NSABP trial, when viewed in the context of the ten-year Overview analysis, was influential in the proactive treatment recommendations for chemotherapy in postmenopausal patients made at the St. Gallen Conference. Although the Conference participants recognized that the majority of individual trials have not shown a survival benefit for adjuvant chemotherapy in the postmenopausal, node-positive group, the Overview analysis was important in the decision to recommend chemotherapy in this subgroup. The NSABP trials in node-negative patients were also reviewed by Fisher [11, 19] who presented the seven-year data from their B-13, which randomized patients with ER-negative tumors to methotrexate and 5-fluorouracil versus a no treatment control arm. At seven years, there remains a highly significant improved disease-free survival on the chemotherapy arm for both pre- and postmenopausal patients. Although no difference in overall survival for all patients entered on this trial was observed, in the subgroup of patients >50 years old, there is a significant improvement in overall survival (p = 0.004). An additional important observation was made by Fisher concerning tumors measuring ten positive axillary nodes was discussed by Abeloff [17]. Using a dose-intensive 16-week regimen developed at Johns Hopkins, Abeloff reported a 53% disease-free survival with a median follow-up of 40 months in this subgroup of patients. The data from Peters at Duke was also reviewed by Abeloff. With a median follow-up of two years in 85 eligible patients treated with standard adjuvant chemotherapy, followed by high-dose chemotherapy and bone marrow transplantation, the Duke group observed 72% five-year event-free survival. Although these data are provocative, there was general agreement at the St. Gallen meeting that the role of adjuvant high-dose chemotherapy and bone marrow transplantation re-

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Jordan et al. [21] used a laboratory model to describe the survival advantage observed by patients taking adjuvant tamoxifen. In their model, tamoxifen initially inhibits estrogen-stimulated growth of MCF-7 breast cancer cells transplanted into athymic mice. However, treatment of animals transplanted with MCF-7 tumors with tamoxifen for up to one year results in tamoxifen-stimulated tumor growth. At four years, these tamoxifen-stimulated tumors still maintained estrogen receptors, but the replacement of tamoxifen with physiological circulating levels of estradiol causes the immediate and total regression of established tumors. Jordan suggested that during adjuvant treatment with tamoxifen, tumor cells are initially prevented from growing during the first year but then clones of tamoxifen-stimulated tumor cells eventually emerge. The benefit from tamoxifen comes when treatment is stopped, and the circulating estradiol kills tamoxifen-dependent disease. This provocative laboratory observation has not yet been tested in clinical trials, but remains a new avenue of investigation. However, it should be noted that when tamoxifen treatment is stopped in the metastatic disease setting, tumor growth occurs, and this may be due to the large tumor volume seen in this situation. The long-term toxicities of adjuvant chemotherapy (CMF plus or minus doxorubicin) in 677 women with stage II breast cancer were reviewed by Valagussa et al. [22]. Doxorubicin was given to 455 patients, while breast radiotherapy after conservative surgery was given concurrently with chemotherapy in 291 patients. With a median follow-up of 52 months, virtually no long-term leukopenia was noted, while 2% of patients had a hemoglobin less than 12 grams. Venous thrombosis was observed in only 0.6% of patients undergoing chemotherapy. However, drug-related amenorrhea was a common finding and was observed in 69% of patients. There was no significant increase in the incidence of second neoplasms, which were observed in

0.9% of chemotherapy-treated patients. In addition, the incidence of doxorubicin-related cardiotoxicity was only 0.8%, while radiotherapy-related lung fibrosis was noted in 3.4% of patients (primarily diagnosed by chest x-ray). Gelber et al. [23], discussed how to compare the quality of life of breast cancer patients in clinical trials. They recommended that this is best done within randomized trials using the Q-TWiST technique based on time with and without specific types of toxic effects of therapy or with and without symptoms of recurrent disease as end points. They discussed methods to define the emotional adjustment which concerns almost every patient who has to be faced with the diagnosis of breast cancer. Their methodology facilities the comparison of treatment benefits and subjective side-effects from the patient's point of view. This methodology could be adopted in current and future trials of adjuvant therapy, particularly where the differences in treatment outcome are expected to be of small biological value. Hillner [24] discussed the financial costs, benefits and the role of patient risk preferences. He described a model that used the results of available randomized controlled trials in node-negative patients to assess the potential clinical and financial effects of the universal use of adjuvant chemotherapy. Using baseline assumptions, Hillner found that chemotherapy increases quality adjusted life expectancy and survival at a cost comparable to most medical interventions. The model highlighted the need for greater study of patient preferences and the need for accurate cost-accounting for oncologic therapies and the role of patient preferences.

Conclusions: The 1992 St. Gallen treatment recommendations

The 1985 and 1990 NIH Consensus Conferences, as well as the recent 10-year Overview from the Early Breast Cancer Trialists' Collaborative Group, present a wealth of data indicating that adjuvant chemotherapy and hormonal therapy are effective treatments for breast cancer patients with both positive and negative axillary lymph nodes [1, 2, 4]. However, there remains considerable debate regarding the use of adjuvant therapy in many common situations in clinical practice. Although optimal therapy has not been defined for any subset of patients, it is unfortunate that less than 5% of all such patients in the United States actually are entered into a clinical trial of adjuvant therapy. This is also true for most of Europe. Thus, practicing oncologists and their patients are continually faced with a therapeutic dilemma as to which node-negative patients should be observed and which should be treated with adjuvant therapy outside the setting of a clinical trial. In addition, much controversy remains regarding which subsets of node-positive patients should receive chemotherapy, hormonal manipulation, or both modalities. Outside the context of a clinical trial, and based

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tors for those entering this NSABP trial may explain this apparent discrepancy. Fisher also presented updated data on the tamoxifen versus placebo trial in node-negative, estrogen receptor positive patients [11, 19]. Significant improvement in both disease-free and overall survival at seven years was noted for patients on the tamoxifen arm. The benefit for tamoxifen was also seen for patients with smaller tumors

Adjuvant therapy of primary breast cancer. 4th International Conference on Adjuvant Therapy of Primary Breast Cancer St. Gallen, Switzerland.

Annuls of Oncology 3: 801-807, 1992. © 1992 Kluwer Academic Publishers. Printed in the Netherlands. Adljy vaunt therapy of primary breast camcer * 4t...
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