COMMENTARY Meeting Highlights: Adjuvant Therapy for Primary Breast Cancer John H. Glick,* Richard D. Gelber, Aron Goldhirsch, Hans-Jorg Senn
'The proceedings of this meeting will be published in Recent Results in Cancer Research.
Vol. 84, No. 19, October 7, 1992
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
For stage I and II breast cancer, therapies adjuvant to surgery remain in evolution as new data emerge from controlled randomized trials and from the overview analysis by the Early Breast Cancer Trialists' Collaborative Group. The Fourth International Conference on Adjuvant Therapy of Primary Breast Cancer1 held in St. Gallen, Switzerland, in February 1992, brought together breast cancer experts from all over the world to present their most recent data and to discuss the remaining challenges that confront both clinicians and basic scientists. The data presented at the 1992 St. Gallen Conference allow us to revisit the treatment recommendations made at the 1985 and 1990 NIH Consensus Development Conferences, as well as those made at the 1988 St. Gallen meeting (7-5). The timing of the 1992 St. Gallen Conference was fortunate in that the 10-year data from the Early Breast Cancer Trialists' Collaborative Group (the 10-year overview) recently had been published (4). In that study, four distinct overviews were conducted to evaluate whether adjuvant therapy with tamoxifen, chemotherapy, ovarian ablation, or immunotherapy, either alone or as part of combined modality treatment, reduced the risk of recurrence and death. Eligible randomized trials included those started before January 1985 in which the only difference between treatments received by two randomly assigned groups of patients was the modality under study. Data were available for 75 000 women randomly assigned in 133 clinical trials. The specific positive findings that attracted attention were based on 30000 women in tamoxifen trials, 1800 women below age 50 in ovarian ablation trials, and 11000 women in combination chemotherapy trials. It was clear that the 10-year overview data presented by Richard Peto (University of Oxford, Oxford, England) at the 1992 St. Gallen Conference greatly influenced the participants. The overview demonstrated statistically significant reductions in annual rates of both recurrence and death— reductions produced by tamoxifen in both lymph node-
negative and lymph node-positive patients, by ovarian ablation below age 50, and by combination chemotherapy for patients below age 50 and those between 50-69 years of age (4). For tamoxifen and combination chemotherapy, the reduction in recurrence is chiefly during the first 5 years, but the reduction in mortality is highly significant during both the first and second 5 years. Consequently, the cumulative differences in survival are large at 5 and then at 10 years. Indirect comparisons show that long-term tamoxifen use (e.g., 2-5 years) is significantly more effective than tamoxifen treatment programs of shorter duration. Between ages 50 and 69 years, direct comparisons show that chemotherapy plus tamoxifen is superior to chemotherapy alone for both recurrence and mortality and better than tamoxifen alone for recurrence. In women under 50, chemotherapy and ovarian ablation appear, by indirect comparison across two separate overviews, to be of comparable efficacy. The 30%-40% proportional risk reductions that-can be produced by combined chemoendocrine therapy in middle age are similar for node-positive and for node-negative patients, while the absolute improvement in 10year survival is about twice as great for the node-positive patients (4). The timeliness of this conference is illustrated by the remarkable accord among the investigators, who, using their own data and the 10-year overview results, came to similar conclusions regarding the 1992 St. Gallen treatment recommendations.
Conference Highlights Prognostic Factors The role of currently accepted and new prognostic factors was a subject of active debate. There was broad acceptance Received May 8, 1992; revised July 30, 1992; accepted August 6, 1992. J. H. Glick, University of Pennsylvania Cancer Center, Philadelphia, Pa. R. D. Gelber, Dana Farber Cancer Institute, Boston, Mass. A. Goldhirsch, Ospedale Civico, Lugano, Switzerland. H. J. Senn, Kantonsspital Oncology Center, St. Gallen, Switzerland. 'Correspondence to: John H. Glick, M.D., University of Pennsylvania Cancer Center, 6 Penn Tower, 3400 Spruce St., Philadelphia, PA 19104.
COMMENTARY
1479
Primary Therapy
controversy remains as to whether there is a subgroup of patients with small tumors ( « 1 cm) who can be treated with lumpectomy alone and spared the cost and possible morbidity of radiation therapy. Gianni Bonadonna (Istituto Nazionale Tumori, Milan) (12) discussed the Milan trial using primary systemic (neoadjuvant) chemotherapy for operable breast cancer. The principal aim of this trial was to increase the frequency of breast conservation treatment in patients with an initial tumor size greater than or equal to 3 cm. In this series of 227 patients, 82% had tumors measuring 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 three to four cycles of chemotherapy prior to surgery. The surgical technique included either lumpectomy or quadrantectomy for tumors 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, Bernard Fisher (NSABP Operations Office, Pittsburgh, Pa.) observed that 75%-80% of Bonadonna's patients would have been eligible for the NSABP B-06 trial. Thus, the use of neoadjuvant chemotherapy for patients with tumors of 3.0-5.0 cm is not routinely recommended, since these patients are generally candidates for lumpectomy without initial chemotherapy. Jay Harris (Harvard Medical School, Boston, Mass.) (73) discussed the integration of primary radiotherapy and adjuvant chemotherapy. In a small retrospective series of 295 patients, he observed that lengthy delays in the initiation of radiotherapy (to allow the delivery of chemotherapy before radiation) may increase the rate of local recurrence in the treated breast. The small number of patients in this retrospective analysis, however, makes this conclusion tenuous at this time. Thus, the optimal sequencing of definitive radiation and chemotherapy remains an open question. John Kurtz (University Hospital, Geneva, Switzerland) (14) also reviewed factors influencing the risk of breast tumor recurrence following lumpectomy and radiation. He noted that patients less than 35 years of age incurred a significantly increased risk of local recurrence compared with older patients (P25%) and is also detectable in sections of grossly normal adjacent breast tissue.
Data presented at the conference continue to demonstrate that both breast conservation therapy (lumpectomy and radiation therapy) and modified radical mastectomy achieve equivalent 10-year overall survival. Thus, lumpectomy and radiotherapy offer equal efficacy with less morbidity and are the preferred local treatment for most patients with earlystage breast cancer. Richard G. Margolese (Sir Mortimer Davis Jewish Hospital, Montreal) (10), reporting the data from the National Surgical Adjuvant Breast and Bowel Project (NSABP), noted a 40% rate of local recurrence 9 years after treatment with lumpectomy alone. There was no difference in overall survival, however, between patients receiving lumpectomy alone versus those receiving lumpectomy and radiotherapy. A very low incidence of breast tumor recurrence has been observed in recent NSABP trials in which chemotherapy was used in addition to radiotherapy to the conserved Adjuvant Systemic Therapy Overview breast (2.6% recurrences in the chemotherapy group compared with 7.4% in the no-treatment group) (77). For patients Peto reviewed the data from the Early Breast Cancer Trialwith tumor size less than or equal to 1.0 cm, the NSABP trial ists' Collaborative Group (4) and presented the following did not demonstrate a significant difference in local breast conclusions: tumor recurrence rate between patients receiving lumpectomy 1) The definitive effect of adjuvant therapy on 10-year surversus those receiving lumpectomy plus radiotherapy. Thus, vival is clearly demonstrated. 1480
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
that tumor size, axillary lymph node status, age or menopausal status, hormone receptors, and histopathology are important prognostic factors. Both Gary Clark (University of Texas Health Science Center, San Antonio, Tex.) (5) and Lynn Dressier (University of New Mexico Cancer Center, Albuquerque, N.M.) (6) stressed the importance of determining S-phase fraction 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 nodenegative patients, Rosella Silvestrini (Istituto Nazionale Tumori, Milan, Italy) (7) did not confirm the prognostic value of S-phase fraction as determined by flow cytometry for these patients. Instead, Silvestrini argued that the [3H]thymidine labeling index was the most important indicator of relapse. Clark discussed the prognostic significance of overexpression of the tumor suppressor gene p53 in node-negative patients. He reported studies showing a 50% incidence of p53 mutations (determined by immunohistochemistry) and suggesting that p53 is an independent predictor for early recurrence in node-negative patients (5). Jan Klijn (8) (Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands) 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. He observed, however, 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 axillary lymph nodes involved, tumor size, age or menopausal status, histopathology, and hormone receptor status should be routinely used at this time. Michael Baum (Royal Marsden Hospital, London, England) (9) agreed with the routine use of these well-accepted prognostic factors.
Vol. 84, No. 19, October 7, 1992
by high-dose chemotherapy and bone marrow transplantation, the Duke group observed 72% 5-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 remained investigational and that these techniques should not be used outside the context of the randomized controlled clinical trial. Adjuvant Systemic Therapy Trials Douglas Tormey (University of Wisconsin Clinical Cancer, Center, Madison, Wis.) (18) reviewed the data from several randomized trials conducted by the Eastern Cooperative Oncology Group. These trials addressed particularly the effect of duration of tamoxifen therapy. They demonstrated that longterm tamoxifen regimens (5 years) were associated with a significantly longer time to recurrence than shorter term tamoxifen (1 year) regimens (P70 years of age), node-positive, hormone receptor-positive patient, tamoxifen clearly remains the standard of care. For the elderly patient with node-positive, hormone receptor-negative breast cancer, the option of adjuvant chemotherapy must be considered if the patient's general medical condition warrants the administration of full-dose chemotherapy. Alternatively, tamoxifen could be administered to this subset.
Conclusion It now appears that almost all patients with clinical and pathologic stage I and II breast cancers, regardless of age or menopausal, nodal, or receptor status, will benefit from some Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
tor status. For estrogen receptor-positive patients, tamoxifen remains the mainstay of treatment. There is increasing evidence both from individual trials and from the overview data that tamoxifen combined with chemotherapy for this subgroup of patients may have additional benefit. Thus, the combination of tamoxifen plus chemotherapy is a reasonable alternative to tamoxifen alone for this subgroup. For postmenopausal patients in the high-risk, node-negative category who are estrogen receptor negative, adjuvant chemotherapy is indicated as standard treatment. The role of tamoxifen when added to chemotherapy in these receptor-negative patients remains controversial and is under investigation. 3) For the elderly patient (>70 years of age) in the highrisk, node-negative group, tamoxifen appears to be of benefit irrespective of estrogen receptor status. Full-dose chemotherapy might also be indicated for selected patients in good general medical condition with excellent performance status who are at high risk for recurrence. It is now apparent that all patients with node-negative breast cancer should have an oncologic consultation at the time of diagnosis to discuss their prognostic profile and the available therapeutic options, as well as to evaluate risks and benefits. Although the patient should be urged to participate in one of the many available clinical trials, it must be recognized that the vast majority of patients are treated outside that context. In this situation, a physician should recommend adjuvant chemotherapy with or without tamoxifen or tamoxifen with or without chemotherapy for all high-risk, node-negative patients, tamoxifen for the overwhelming majority of patients in the good-risk category, and observation versus tamoxifen for patients in the minimal/low-risk subgroup. Thus, the treatment recommendations made at St. Gallen in 1992 support the general recommendations made in the controversial 1988 NCI Clinical Alert (25).
form of adjuvant chemotherapy and/or hormonal therapy, both in terms of improved disease-free survival and overall survival. Thus, the 1992 St. Gallen treatment recommendations confirm and expand on the guidelines suggested at the time of the 1988 St. Gallen Conference (3). Although further clinical investigation is imperative, it is now incumbent upon physicians to apply the known adjuvant therapeutic regimens broadly, so as not to deny any patient the benefits of adjuvant therapy that already have been demonstrated.
(70) MARGOLESE RG: Selection and technique for lumpectomy. Recent Results Cancer Res. In press (77) FISHER B, WICKERHAM DL, REDMOND C: Recent developments in the
(12) (13) (14) (75) (16)
References
(8) KLUN JGM, BERNS PM, BONTENBAL M, ET AL: Critical review of
growth factors as clinical tools. Recent Results Cancer Res. In press (°) BAUM M: What did we learn from the international overview results about the effects of chemotherapy. Recent Results Cancer Res. In press
(18) (79)
(20) ROSEN PP, GROSHEN S, SAIOO PE, ET AL: Pathological prognostic fac-
tors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. A study of 644 patients with median follow-up of 18 years. J Clin Oncol 7:1239-1251, 1989 (27) JORDAN VC, WOLF DM: Laboratory model to describe the survival advantage observed by patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res. In press (22) VALAOUSSA P, ZAMBETTI M, BONADONNA G: Long-term toxicities of
adjuvant chemotherapy. Recent Results Cancer Res. In press (25) GELBER RD, COLE BF, GOLDHIRSCH A, ET AL; HOW to compare quality
of life of breast cancer patients in clinical trials. Recent Results Cancer Res. In press (24) HILLNER BE: Financial cost, benefits and the role of patient preferences. Recent Results Cancer Res. In press (25) NATIONAL CANCER INSTITUTE: Clinical Alert. Bethesda, Md: NCI,
1988
Join the National Black Leadership Initiative On Cancer FIGHT CANCER IN YOUR COMMUNITY For More Information About A Program In Your Region Call the Cancer Information Service
1-800-4-CANCER A COHIURITT 0UTI1ACH M 0 C I A B OF H E IATIOIAL CARCIt U S T I T u n
Vol. 84, No. 19, October 7, 1992
COMMENTARY 1485
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
(7) Consensus Conference. Adjuvant chemotherapy for breast cancer. JAMA 254:3461-3463, 1985 (2) NIH Consensus Conference. Treatment of early-stage breast cancer. JAMA 265:391-395, 1991 (.?) GUCK JH: Meeting highlights: Adjuvant therapy for breast cancer. J Natl Cancer Inst 80:471-475, 1988 (4) Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339:1-5, 71-85, 1992 (5) CLARK GM, MCGUIRE WL: Prognosis of breast cancer patients: How to use what? Recent Results Cancer Res. In press (6) DRESSLER LG: DNA flow cytometry measurements: Its clinical impact in primary breast cancer. Recent Results Cancer Res. In press (7) SILVESTRINI R: Review of proliferative variables and their predictive value. Recent Results Cancer Res. In press
(77)
use of systemic adjuvant therapy for the treatment of breast cancer. Semin Oncol 19:263-277, 1992 BONADONNA G: Primary chemotherapy for resectable breast cancer. Recent Results Cancer Res. In press HARRIS J: HOW to combine adjuvant chemotherapy with radiation therapy. Recent Results Cancer Res. In press KURTZ JM: Factors which predict breast relapse. Recent Results Cancer Res. In press BONADONNA G: What did we learn from the results of the international overview about the effects of endocrine therapy? Recent Results Cancer Res. In press GELBER RD, GOLDHIRSCH A: From the overview to the patient: How to interpret meta-analysis data. Recent Results Cancer Res. In press ABELOFF MD: High dose chemotherapy for high risk breast cancer? Recent Results Cancer Res. In press TORMEY DC: New aspects of chemoendocrine therapy. Recent Results Cancer Res. In press FISHER B: The recent NSABP experience and strategies. Recent Results Cancer Res. In press
'The proceedings of this meeting will be published in Recent Results in Cancer Research.
Vol. 84, No. 19, October 7, 1992
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
For stage I and II breast cancer, therapies adjuvant to surgery remain in evolution as new data emerge from controlled randomized trials and from the overview analysis by the Early Breast Cancer Trialists' Collaborative Group. The Fourth International Conference on Adjuvant Therapy of Primary Breast Cancer1 held in St. Gallen, Switzerland, in February 1992, brought together breast cancer experts from all over the world to present their most recent data and to discuss the remaining challenges that confront both clinicians and basic scientists. The data presented at the 1992 St. Gallen Conference allow us to revisit the treatment recommendations made at the 1985 and 1990 NIH Consensus Development Conferences, as well as those made at the 1988 St. Gallen meeting (7-5). The timing of the 1992 St. Gallen Conference was fortunate in that the 10-year data from the Early Breast Cancer Trialists' Collaborative Group (the 10-year overview) recently had been published (4). In that study, four distinct overviews were conducted to evaluate whether adjuvant therapy with tamoxifen, chemotherapy, ovarian ablation, or immunotherapy, either alone or as part of combined modality treatment, reduced the risk of recurrence and death. Eligible randomized trials included those started before January 1985 in which the only difference between treatments received by two randomly assigned groups of patients was the modality under study. Data were available for 75 000 women randomly assigned in 133 clinical trials. The specific positive findings that attracted attention were based on 30000 women in tamoxifen trials, 1800 women below age 50 in ovarian ablation trials, and 11000 women in combination chemotherapy trials. It was clear that the 10-year overview data presented by Richard Peto (University of Oxford, Oxford, England) at the 1992 St. Gallen Conference greatly influenced the participants. The overview demonstrated statistically significant reductions in annual rates of both recurrence and death— reductions produced by tamoxifen in both lymph node-
negative and lymph node-positive patients, by ovarian ablation below age 50, and by combination chemotherapy for patients below age 50 and those between 50-69 years of age (4). For tamoxifen and combination chemotherapy, the reduction in recurrence is chiefly during the first 5 years, but the reduction in mortality is highly significant during both the first and second 5 years. Consequently, the cumulative differences in survival are large at 5 and then at 10 years. Indirect comparisons show that long-term tamoxifen use (e.g., 2-5 years) is significantly more effective than tamoxifen treatment programs of shorter duration. Between ages 50 and 69 years, direct comparisons show that chemotherapy plus tamoxifen is superior to chemotherapy alone for both recurrence and mortality and better than tamoxifen alone for recurrence. In women under 50, chemotherapy and ovarian ablation appear, by indirect comparison across two separate overviews, to be of comparable efficacy. The 30%-40% proportional risk reductions that-can be produced by combined chemoendocrine therapy in middle age are similar for node-positive and for node-negative patients, while the absolute improvement in 10year survival is about twice as great for the node-positive patients (4). The timeliness of this conference is illustrated by the remarkable accord among the investigators, who, using their own data and the 10-year overview results, came to similar conclusions regarding the 1992 St. Gallen treatment recommendations.
Conference Highlights Prognostic Factors The role of currently accepted and new prognostic factors was a subject of active debate. There was broad acceptance Received May 8, 1992; revised July 30, 1992; accepted August 6, 1992. J. H. Glick, University of Pennsylvania Cancer Center, Philadelphia, Pa. R. D. Gelber, Dana Farber Cancer Institute, Boston, Mass. A. Goldhirsch, Ospedale Civico, Lugano, Switzerland. H. J. Senn, Kantonsspital Oncology Center, St. Gallen, Switzerland. 'Correspondence to: John H. Glick, M.D., University of Pennsylvania Cancer Center, 6 Penn Tower, 3400 Spruce St., Philadelphia, PA 19104.
COMMENTARY
1479
Primary Therapy
controversy remains as to whether there is a subgroup of patients with small tumors ( « 1 cm) who can be treated with lumpectomy alone and spared the cost and possible morbidity of radiation therapy. Gianni Bonadonna (Istituto Nazionale Tumori, Milan) (12) discussed the Milan trial using primary systemic (neoadjuvant) chemotherapy for operable breast cancer. The principal aim of this trial was to increase the frequency of breast conservation treatment in patients with an initial tumor size greater than or equal to 3 cm. In this series of 227 patients, 82% had tumors measuring 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 three to four cycles of chemotherapy prior to surgery. The surgical technique included either lumpectomy or quadrantectomy for tumors 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, Bernard Fisher (NSABP Operations Office, Pittsburgh, Pa.) observed that 75%-80% of Bonadonna's patients would have been eligible for the NSABP B-06 trial. Thus, the use of neoadjuvant chemotherapy for patients with tumors of 3.0-5.0 cm is not routinely recommended, since these patients are generally candidates for lumpectomy without initial chemotherapy. Jay Harris (Harvard Medical School, Boston, Mass.) (73) discussed the integration of primary radiotherapy and adjuvant chemotherapy. In a small retrospective series of 295 patients, he observed that lengthy delays in the initiation of radiotherapy (to allow the delivery of chemotherapy before radiation) may increase the rate of local recurrence in the treated breast. The small number of patients in this retrospective analysis, however, makes this conclusion tenuous at this time. Thus, the optimal sequencing of definitive radiation and chemotherapy remains an open question. John Kurtz (University Hospital, Geneva, Switzerland) (14) also reviewed factors influencing the risk of breast tumor recurrence following lumpectomy and radiation. He noted that patients less than 35 years of age incurred a significantly increased risk of local recurrence compared with older patients (P25%) and is also detectable in sections of grossly normal adjacent breast tissue.
Data presented at the conference continue to demonstrate that both breast conservation therapy (lumpectomy and radiation therapy) and modified radical mastectomy achieve equivalent 10-year overall survival. Thus, lumpectomy and radiotherapy offer equal efficacy with less morbidity and are the preferred local treatment for most patients with earlystage breast cancer. Richard G. Margolese (Sir Mortimer Davis Jewish Hospital, Montreal) (10), reporting the data from the National Surgical Adjuvant Breast and Bowel Project (NSABP), noted a 40% rate of local recurrence 9 years after treatment with lumpectomy alone. There was no difference in overall survival, however, between patients receiving lumpectomy alone versus those receiving lumpectomy and radiotherapy. A very low incidence of breast tumor recurrence has been observed in recent NSABP trials in which chemotherapy was used in addition to radiotherapy to the conserved Adjuvant Systemic Therapy Overview breast (2.6% recurrences in the chemotherapy group compared with 7.4% in the no-treatment group) (77). For patients Peto reviewed the data from the Early Breast Cancer Trialwith tumor size less than or equal to 1.0 cm, the NSABP trial ists' Collaborative Group (4) and presented the following did not demonstrate a significant difference in local breast conclusions: tumor recurrence rate between patients receiving lumpectomy 1) The definitive effect of adjuvant therapy on 10-year surversus those receiving lumpectomy plus radiotherapy. Thus, vival is clearly demonstrated. 1480
Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
that tumor size, axillary lymph node status, age or menopausal status, hormone receptors, and histopathology are important prognostic factors. Both Gary Clark (University of Texas Health Science Center, San Antonio, Tex.) (5) and Lynn Dressier (University of New Mexico Cancer Center, Albuquerque, N.M.) (6) stressed the importance of determining S-phase fraction 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 nodenegative patients, Rosella Silvestrini (Istituto Nazionale Tumori, Milan, Italy) (7) did not confirm the prognostic value of S-phase fraction as determined by flow cytometry for these patients. Instead, Silvestrini argued that the [3H]thymidine labeling index was the most important indicator of relapse. Clark discussed the prognostic significance of overexpression of the tumor suppressor gene p53 in node-negative patients. He reported studies showing a 50% incidence of p53 mutations (determined by immunohistochemistry) and suggesting that p53 is an independent predictor for early recurrence in node-negative patients (5). Jan Klijn (8) (Dr. Daniel den Hoed Cancer Center, Rotterdam, The Netherlands) 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. He observed, however, 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 axillary lymph nodes involved, tumor size, age or menopausal status, histopathology, and hormone receptor status should be routinely used at this time. Michael Baum (Royal Marsden Hospital, London, England) (9) agreed with the routine use of these well-accepted prognostic factors.
Vol. 84, No. 19, October 7, 1992
by high-dose chemotherapy and bone marrow transplantation, the Duke group observed 72% 5-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 remained investigational and that these techniques should not be used outside the context of the randomized controlled clinical trial. Adjuvant Systemic Therapy Trials Douglas Tormey (University of Wisconsin Clinical Cancer, Center, Madison, Wis.) (18) reviewed the data from several randomized trials conducted by the Eastern Cooperative Oncology Group. These trials addressed particularly the effect of duration of tamoxifen therapy. They demonstrated that longterm tamoxifen regimens (5 years) were associated with a significantly longer time to recurrence than shorter term tamoxifen (1 year) regimens (P70 years of age), node-positive, hormone receptor-positive patient, tamoxifen clearly remains the standard of care. For the elderly patient with node-positive, hormone receptor-negative breast cancer, the option of adjuvant chemotherapy must be considered if the patient's general medical condition warrants the administration of full-dose chemotherapy. Alternatively, tamoxifen could be administered to this subset.
Conclusion It now appears that almost all patients with clinical and pathologic stage I and II breast cancers, regardless of age or menopausal, nodal, or receptor status, will benefit from some Journal of the National Cancer Institute
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
tor status. For estrogen receptor-positive patients, tamoxifen remains the mainstay of treatment. There is increasing evidence both from individual trials and from the overview data that tamoxifen combined with chemotherapy for this subgroup of patients may have additional benefit. Thus, the combination of tamoxifen plus chemotherapy is a reasonable alternative to tamoxifen alone for this subgroup. For postmenopausal patients in the high-risk, node-negative category who are estrogen receptor negative, adjuvant chemotherapy is indicated as standard treatment. The role of tamoxifen when added to chemotherapy in these receptor-negative patients remains controversial and is under investigation. 3) For the elderly patient (>70 years of age) in the highrisk, node-negative group, tamoxifen appears to be of benefit irrespective of estrogen receptor status. Full-dose chemotherapy might also be indicated for selected patients in good general medical condition with excellent performance status who are at high risk for recurrence. It is now apparent that all patients with node-negative breast cancer should have an oncologic consultation at the time of diagnosis to discuss their prognostic profile and the available therapeutic options, as well as to evaluate risks and benefits. Although the patient should be urged to participate in one of the many available clinical trials, it must be recognized that the vast majority of patients are treated outside that context. In this situation, a physician should recommend adjuvant chemotherapy with or without tamoxifen or tamoxifen with or without chemotherapy for all high-risk, node-negative patients, tamoxifen for the overwhelming majority of patients in the good-risk category, and observation versus tamoxifen for patients in the minimal/low-risk subgroup. Thus, the treatment recommendations made at St. Gallen in 1992 support the general recommendations made in the controversial 1988 NCI Clinical Alert (25).
form of adjuvant chemotherapy and/or hormonal therapy, both in terms of improved disease-free survival and overall survival. Thus, the 1992 St. Gallen treatment recommendations confirm and expand on the guidelines suggested at the time of the 1988 St. Gallen Conference (3). Although further clinical investigation is imperative, it is now incumbent upon physicians to apply the known adjuvant therapeutic regimens broadly, so as not to deny any patient the benefits of adjuvant therapy that already have been demonstrated.
(70) MARGOLESE RG: Selection and technique for lumpectomy. Recent Results Cancer Res. In press (77) FISHER B, WICKERHAM DL, REDMOND C: Recent developments in the
(12) (13) (14) (75) (16)
References
(8) KLUN JGM, BERNS PM, BONTENBAL M, ET AL: Critical review of
growth factors as clinical tools. Recent Results Cancer Res. In press (°) BAUM M: What did we learn from the international overview results about the effects of chemotherapy. Recent Results Cancer Res. In press
(18) (79)
(20) ROSEN PP, GROSHEN S, SAIOO PE, ET AL: Pathological prognostic fac-
tors in stage I (T1N0M0) and stage II (T1N1M0) breast carcinoma. A study of 644 patients with median follow-up of 18 years. J Clin Oncol 7:1239-1251, 1989 (27) JORDAN VC, WOLF DM: Laboratory model to describe the survival advantage observed by patients taking adjuvant tamoxifen therapy. Recent Results Cancer Res. In press (22) VALAOUSSA P, ZAMBETTI M, BONADONNA G: Long-term toxicities of
adjuvant chemotherapy. Recent Results Cancer Res. In press (25) GELBER RD, COLE BF, GOLDHIRSCH A, ET AL; HOW to compare quality
of life of breast cancer patients in clinical trials. Recent Results Cancer Res. In press (24) HILLNER BE: Financial cost, benefits and the role of patient preferences. Recent Results Cancer Res. In press (25) NATIONAL CANCER INSTITUTE: Clinical Alert. Bethesda, Md: NCI,
1988
Join the National Black Leadership Initiative On Cancer FIGHT CANCER IN YOUR COMMUNITY For More Information About A Program In Your Region Call the Cancer Information Service
1-800-4-CANCER A COHIURITT 0UTI1ACH M 0 C I A B OF H E IATIOIAL CARCIt U S T I T u n
Vol. 84, No. 19, October 7, 1992
COMMENTARY 1485
Downloaded from http://jnci.oxfordjournals.org/ at Freie Universitaet Berlin on May 6, 2015
(7) Consensus Conference. Adjuvant chemotherapy for breast cancer. JAMA 254:3461-3463, 1985 (2) NIH Consensus Conference. Treatment of early-stage breast cancer. JAMA 265:391-395, 1991 (.?) GUCK JH: Meeting highlights: Adjuvant therapy for breast cancer. J Natl Cancer Inst 80:471-475, 1988 (4) Systemic treatment of early breast cancer by hormonal, cytotoxic, or immune therapy: 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women. Early Breast Cancer Trialists' Collaborative Group. Lancet 339:1-5, 71-85, 1992 (5) CLARK GM, MCGUIRE WL: Prognosis of breast cancer patients: How to use what? Recent Results Cancer Res. In press (6) DRESSLER LG: DNA flow cytometry measurements: Its clinical impact in primary breast cancer. Recent Results Cancer Res. In press (7) SILVESTRINI R: Review of proliferative variables and their predictive value. Recent Results Cancer Res. In press
(77)
use of systemic adjuvant therapy for the treatment of breast cancer. Semin Oncol 19:263-277, 1992 BONADONNA G: Primary chemotherapy for resectable breast cancer. Recent Results Cancer Res. In press HARRIS J: HOW to combine adjuvant chemotherapy with radiation therapy. Recent Results Cancer Res. In press KURTZ JM: Factors which predict breast relapse. Recent Results Cancer Res. In press BONADONNA G: What did we learn from the results of the international overview about the effects of endocrine therapy? Recent Results Cancer Res. In press GELBER RD, GOLDHIRSCH A: From the overview to the patient: How to interpret meta-analysis data. Recent Results Cancer Res. In press ABELOFF MD: High dose chemotherapy for high risk breast cancer? Recent Results Cancer Res. In press TORMEY DC: New aspects of chemoendocrine therapy. Recent Results Cancer Res. In press FISHER B: The recent NSABP experience and strategies. Recent Results Cancer Res. In press
