Correspondence
Radiotherapy and Chemotherapy in High-Risk Breast Cancer
N Engl J Med 1998; 338:329-333January 29, 1998
- Article
To the Editor:
The study by Overgaard et al. (Oct. 2 issue)1 was designed to address the capacity of radiation therapy after mastectomy to reduce the frequency of distant relapse or to delay it significantly in women with stage I or II breast cancer, but the inclusion of patients with stage IIIA and stage IIIB disease creates interpretive difficulties. There are no data concerning the number and distribution of patients with tumor stage T4, nor is it clear how many patients with T3 disease were classified as having N0 (stage II) or N1 (stage III) nodal involvement. Table 1 of the article by Overgaard et al. indicates that there were significantly more patients with tumors more than 5 cm in size in the group treated with chemotherapy alone (n = 135) than in the chemotherapy–radiation group (n = 99), with a P value of 0.03. How many patients with stage IIIA or IIIB disease were there in each treatment group? The need for irradiation after mastectomy for local–regional control in patients with stage III breast cancer is established. Was such irradiation associated with a significant survival advantage among the women in each treatment group with stage II disease?
The results suggest inadequate axillary-node dissection in more than 75 percent of the patients. In 1297 of 1708 women, distributed equally between the treatment groups, fewer than nine nodes were dissected. What was the average number of involved nodes in the stage II and stage III subgroups in each treatment group? Surgical technique is known to affect the incidence of local recurrence.2 The data thus seem more relevant to the role of radiotherapy after total mastectomy, rather than modified radical mastectomy. The value of axillary irradiation in the former case is established; the rate of recurrence in untreated, clinically negative axillae is about 20 percent, as opposed to 1 to 2 percent after axillary-node dissection or irradiation.3
How were the data on patients who underwent treatment for local recurrences and remained free of systemic disease analyzed? Were they censored? The National Surgical Adjuvant Breast and Bowel Project (in protocol B-04) detected no difference in the overall survival of patients who underwent primary or delayed axillary dissection or radiation.4
4 ReferencesMahmoud El-Tamer, M.D.
Peter Homel, Ph.D.
Albert S. Braverman, M.D.
SUNY Health Science Center at Brooklyn, Brooklyn, NY 112031
Overgaard M ,Hansen PS ,Overgaard J , et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955
Full Text | Web of Science | Medline2
Benson EA ,Thorogood J . The effect of surgical technique on local recurrence rates following mastectomy. Eur J Surg Oncol 1986;12:267-271
Web of Science | Medline3
Recht A ,Houlihan MJ . Axillary lymph nodes and breast cancer: a review. Cancer 1995;76:1491-1512
CrossRef | Web of Science | Medline4
Fisher B ,Redmond C ,Fisher ER , et al. Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. N Engl J Med 1985;312:674-681
Full Text | Web of Science | Medline
To the Editor:
We question the appropriateness of extrapolating the data from the recent reports of Ragaz et al. (Oct. 2 issue)1 and Overgaard et al.2 on their postmastectomy studies to medical practice in the United States. The trial by Ragaz et al. from British Columbia, Canada, reports a 5-year local–regional recurrence rate of 21 percent among women who did not undergo radiation therapy and 10 percent among those who received radiation; 10-year rates were 25 percent and 13 percent, respectively.1 Similarly, the Danish trial by Overgaard et al. reports a 114-month rate of local–regional recurrence alone of 26 percent for women given chemotherapy without radiation therapy and 5 percent for those given both chemotherapy and radiation therapy.2
Rates of local–regional recurrence are considerably lower in the United States. Fisher et al. reported a 6.2 percent rate of local–regional recurrence among women treated without radiation therapy at 8 years 3; Lichter et al. reported 7.8 percent at 68 months 4; and Jacobson et al. reported 8.6 percent at 10.1 years.5 Notably, Fisher et al.3 found the same rate of local–regional recurrence in stage I and II disease, which probably reflects a positive effect of adjuvant chemotherapy. Parenthetically, the actuarial eight-year rate of local–regional recurrence at other European centers was 9 percent in patients treated with mastectomy, as reported by van Dongen et al.6
Thus, the incidence of local–regional recurrence after mastectomy reported by Ragaz et al. and Overgaard et al. is extremely high. Beyond this, neither study defined the frequency of follow-up evaluations. In our opinion, early detection of local–regional disease optimizes the likelihood of completely eradicating local recurrences, which may affect survival. This relation is exemplified by the study of Borner et al., which showed a 59 percent rate of disease-free survival five years after resection and radiation therapy followed by tamoxifen for isolated local or regional recurrences.7
We think the aforementioned considerations prevent the application of the results of the Canadian and Danish studies to U.S. patients and perhaps other population groups. Inherent in our concern about the possible misapplication of routine radiotherapy to patients who have undergone mastectomy is the need to explain the extremely high rates of local–regional recurrence encountered by these groups.
7 ReferencesWilliam H. Wolberg, M.D.
H. Ian Robins, M.D., Ph.D.
University of Wisconsin Comprehensive Cancer Center, Madison, WI 53792-00011
Ragaz J ,Jackson SM ,Le N , et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-962
Full Text | Web of Science | Medline2
Overgaard M ,Hansen PS ,Overgaard J , et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955
Full Text | Web of Science | Medline3
Fisher B ,Redmond C ,Poisson R , et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822-828[Erratum, N Engl J Med 1994;330:1467.]
Full Text | Web of Science | Medline4
Lichter AS ,Lippman ME ,Danforth DN Jr , et al. Mastectomy versus breast-conserving therapy in the treatment of stage I and II carcinoma of the breast: a randomized trial at the National Cancer Institute. J Clin Oncol 1992;10:976-983
Web of Science | Medline5
Jacobson JA ,Danforth DN ,Cowan KH , et al. Ten-year results of a comparison of conservation with mastectomy in the treatment of stage I and II breast cancer. N Engl J Med 1995;332:907-911
Full Text | Web of Science | Medline6
van Dongen JA, Bartelink H, Fentiman IS, et al. Randomized clinical trial to assess the value of breast-conserving therapy in stage I and II breast cancer, EORTC 10801 trial. Journal of the National Cancer Institute monographs. No. 11. Washington, D.C.: Government Printing Office, 1992:15-8. (NIH publication no. 90-3187.)
7
Borner M ,Bacchi M ,Goldhirsch A , et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. J Clin Oncol 1994;12:2071-2077
Web of Science | Medline
To the Editor:
Two recent trials have shown that after mastectomy, the addition of irradiation to a chemotherapy regimen containing cyclophosphamide, methotrexate, and fluorouracil (CMF) improved disease-free and overall survival.1,2 An editorial in the same issue of the Journal concluded that “to the 30 percent reduction in breast-cancer deaths attributable to the use of screening mammography and the proven benefit of adjuvant chemotherapy, we can now add the further benefit from regional radiation treatment when combined with such chemotherapy.” 3 Such a conclusion could have a major impact on the management of operable breast cancer. It is therefore disappointing that the editorial did not discuss more critically the evidence on which it was based. It would be doubly unfortunate if changes to treatment policy were to be based on flawed evidence. The critical assumption is that the contribution of CMF is the same regardless of any alterations in the doses and schedules of the drugs. We believe this assumption to be mistaken.
The CMF regimens used in the two trials were altered from the classic CMF regimen first reported as an effective adjuvant therapy more than 20 years ago. This regimen used oral cyclophosphamide on days 1 through 14, with intravenous methotrexate and fluorouracil on days 1 and 8; the cycle was repeated every 28 days.4 No trial has directly compared classic and altered CMF as adjuvant treatment. However, several randomized trials have shown that departure from the classic CMF regimen compromises its efficacy in metastatic breast cancer. The European Organisation for Research and Treatment of Cancer (EORTC) compared classic CMF and an altered CMF regimen similar to the more intensive of the CMF regimens in the current trials.2 The EORTC trial included 254 eligible patients. The altered CMF regimen was inferior in terms of response rate and overall survival.5 Further evidence of the inferiority of altered CMF regimens comes from the seven trials that have compared CMF regimens plus tamoxifen with tamoxifen alone. A benefit of adding CMF was seen in all three trials that used classic CMF, but in none of the trials using CMF schedules given on day 1 every three or four weeks or at a low continuous dose.
The two recent trials published in the Journal do not provide evidence that irradiation of the chest wall or the regional lymph-node sites, or both, adds to the benefit of effective systemic therapies such as classic CMF. The correct, though limited, conclusion from these trials should be that radiation therapy to the chest wall and regional nodes should be considered for premenopausal patients with a high risk of relapse in all cases in which suboptimal systemic therapy is planned.
5 ReferencesAron Goldhirsch, M.D.
European Institute of Oncology, 20141 Milan, ItalyAlan S. Coates, M.D.
University of Sydney, Sydney, NSW 2050, AustraliaMarco Colleoni, M.D.
European Institute of Oncology, 20141 Milan, ItalyRichard D. Gelber, Ph.D.
Dana–Farber Cancer Institute, Boston, MA 021151
Overgaard M ,Hansen PS ,Overgaard J , et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955
Full Text | Web of Science | Medline2
Ragaz J ,Jackson SM ,Le N , et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-962
Full Text | Web of Science | Medline3
Hellman S . Stopping metastases at their source. N Engl J Med 1997;337:996-997
Full Text | Web of Science | Medline4
Bonadonna G ,Brusamolino E ,Valagussa P , et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410
Full Text | Web of Science | Medline5
Engelsman E ,Klijn JC ,Rubens RD , et al. “Classical“ CMF versus a 3-weekly intravenous CMF schedule in postmenopausal patients with advanced breast cancer: an EORTC Breast Cancer Co-operative Group Phase III Trial (10808). Eur J Cancer 1991;27:966-970
CrossRef | Web of Science | Medline
To the Editor:
Why does the editorial1 conclude that radiotherapy stops metastases at their source? The Danish trial2 found that more women in the radiotherapy-plus-chemotherapy group had metastases than in the chemotherapy-alone group.
2 ReferencesA.E. Raffle, M.B., Ch.B.
Avon Health Authority, Bristol BS2 8EE, United Kingdom1
Hellman S . Stopping metastases at their source. N Engl J Med 1997;337:996-997
Full Text | Web of Science | Medline2
Overgaard M ,Hansen PS ,Overgaard J , et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955
Full Text | Web of Science | Medline
To the Editor:
Hellman referred to the B-06 study by the National Surgical Adjuvant Breast and Bowel Project. He noted correctly that patients treated with lumpectomy but without radiation therapy had a marked increase in local recurrences. Hellman states, “These patients already have a statistically significant increase in the number of distant metastases. A reasonable interim conclusion would be that such treatment is not satisfactory, since local recurrence often leads to distant metastases that are likely eventually to decrease overall survival.”
This statement is incorrect. Nine different studies (including four randomized trials) have examined the risk of locally recurrent breast cancer after lumpectomy alone. Every study has concluded that local recurrence is not a threat to survival and that radiation therapy does not prolong survival. The precise words used by the various investigators to express this conclusion are available on the Internet at http://www.texascancercenter.com.
In their 1985 paper, the National Surgical Adjuvant Breast and Bowel Project1 arrived at the conclusion suggested by Hellman. By 1989, the group concluded, “The difference observed earlier between the two lumpectomy groups may be related to `lead-time' bias in the identification of distant disease in the group that underwent lumpectomy alone . . . [because] the patients with a recurrence were subjected to a more thorough examination for the detection of metastatic disease at that time.” 2
It is surprising to me that Hellman would make such a misleading statement on such a fundamentally important subject in this field. For two reasons, it is even more surprising that the Journal would publish it. First, it contradicts a study that was previously published by the Journal. Second, the Journal has already published a very similar erroneous statement on this subject, as well as my correction.3 At this rate, it is going to be many years indeed before American physicians have a clear understanding of the often-innocent behavior of locally recurrent breast cancer after limited surgery.
3 ReferencesRichard A. Evans, M.D.
1011 Augusta Dr., Houston, TX 77057-20151
Fisher B ,Bauer M ,Margolese R , et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med 1985;312:666-6732
Fisher B ,Redmond C ,Poisson R , et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822-828[Erratum, N Engl J Med 1994;330:1467.]
Full Text | Web of Science | Medline3
Evans RA . Adjuvant chemotherapy in breast cancer. N Engl J Med 1995;333:596-597
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: With respect to the letter of El-Tamer et al.: we could not identify any subgroups among high-risk premenopausal women in whom radiotherapy was more beneficial, not even among patients with an advanced primary tumor (tumor size of >5 cm, invasion of pectoral fascia, invasion of skin, or a combination of these factors). The 10-year actuarial overall survival rate was 48 percent in the group receiving radiotherapy plus CMF (260 patients), as compared with 39 percent in the group that received CMF alone (290 patients, P<0.001). Patients without features of an advanced primary tumor had better survival than those with an advanced primary tumor, but the 10-year actuarial survival was 57 percent in the radiotherapy-plus-CMF group (569 patients), as compared with 49 percent in the CMF-alone group (546 patients, P<0.001).
For the entire group of patients, only a median of seven nodes were removed, but the recurrence rate in the axillae decreased among patients who had more nodes removed. However, the majority of locoregional recurrences were localized in the chest wall, and adequate second-line treatment of recurrences in the axilla, the chest wall, or both, in nonirradiated patients did not compensate for inadequate primary therapy in terms of 10-year overall survival.
The seemingly contradictory higher incidence of distant metastases among irradiated as compared with nonirradiated patients can be explained by the concept of competing risks, since we recorded only the site of the first recurrence. Data on a very large number of patients in the nonirradiated group were censored because of locoregional recurrences before distant metastases developed.
With respect to the comments of Goldhirsch et al., we agree that the dose intensity of the CMF regimen we used is lower than that of classic CMF.1 However, there are no data from adjuvant trials proving that classic CMF is superior. The addition of prednisolone to CMF in the Ludwig I trial2 increased the dose intensity of CMF without significant improvement in disease-free and overall survival.
2 ReferencesMarie Overgaard, M.D.
Aarhus University Hospital, DK-8000 Aarhus C, DenmarkCarsten Rose, M.D.
Odense University Hospital, DK-5000 Odense C, DenmarkHenning Mouridsen, M.D.
Rigshospitalet, DK-2100 Copenhagen Ø, Denmark1
Bonadonna G ,Brusamolino E ,Valagussa P , et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294:405-410
Full Text | Web of Science | Medline2
Castiglione-Gertsch M ,Johnsen C ,Goldhirsch A , et al. The International (Ludwig) Breast Cancer Study Group Trials I-IV: 15 years follow-up. Ann Oncol 1994;5:717-724
Web of Science | Medline
Author/Editor Response
Wolberg and Robins, along with Goldhirsch et al., question the appropriateness of extrapolating data from the Vancouver1 and Danish2 trials to present medical practice. Wolberg et al. quote several recent studies showing that rates of locoregional recurrence are considerably lower in the United States than in the Vancouver or Danish trial, implying that the benefit of wide-field radiotherapy would be less in the present patient population in the United States than in Vancouver or Denmark. However, the quoted studies differed substantially from the Vancouver trial. They included a high number of node-negative patients, patients selected for partial mastectomy, or postmenopausal patients. Most studies had a shorter follow-up than ours. All these factors can considerably lower the risk of locoregional or systemic recurrences. In contrast, all patients in the Vancouver study were premenopausal and node-positive, all underwent modified radical mastectomy with a median of 11 nodes removed, and follow-up was 15 years.
Wolberg and Robins also indicate that optimizing treatment for locoregional recurrence may improve outcome, as “exemplified by the study of Borner et al., which showed a 59 percent rate of disease-free survival” after five years, implying again a decreased need for adjuvant radiation therapy. However, Borner et al.3 studied selected patients with recurrent estrogen-receptor–positive tumors, which have a favorable biology. Also, their follow-up was substantially shorter than that in our study. These examples indicate that comparisons of trial results without adjustment for major prognostic factors may be misleading. We believe that our trial reflects true locoregional-recurrence rates for patients with the stages of breast cancer we specified.
Goldhirsch et al. raise the possibility that the less intensive CMF regimen used in our trial may overestimate the effect of radiation as compared with that of the classic CMF regimen, which has a higher dose intensity. The dose intensities of the Danish and Vancouver protocols were indeed different: 0.45 and 0.65, respectively, as compared with 1.0 for classic CMF. Two other trials,4,5 which used either no chemotherapy (dose intensity, 0) or high-dose chemotherapy requiring a bone marrow transplantation (estimated dose intensity, 2 to 3), showed a substantial reduction in recurrences as a result of radiotherapy, with a relative risk of a locoregional event of 0.4 to 0.5, and 0.6 to 0.7 for any recurrence, regardless of the dose intensity of chemotherapy. Furthermore, both the Vancouver and the Danish trials provide recurrence rates for subgroups with one to three and with four or more involved nodes. These subgroups have similar reductions in relative risk due to radiotherapy.
Although absolute rates of recurrence and mortality may vary substantially among cohorts treated according to different approaches, the proportional (relative) reduction in the risk of metastatic events associated with radiation remains constant, analogous to the well-accepted gains due to adjuvant systemic therapy. These observations are relevant to the applicability of our data to the present generation of patients and may influence therapeutic recommendations — for instance, to use radiotherapy for high-risk but not low-risk patients and to initiate trials of radiation therapy in women with borderline risk.
We would like to emphasize that between the extremes of the Halstedian dogma of ignoring the systemic component of breast cancer and the downplaying of locoregional management, we propose a middle position, which recognizes the importance of both the systemic and locoregional approaches.
5 ReferencesJoseph Ragaz, M.D.
Stewart M. Jackson, M.D.
British Columbia Cancer Agency, Vancouver, BC V5Z 4E6, CanadaJohn J. Spinelli, Ph.D.
University of British Columbia, Vancouver, BC V6T 1Z4, Canada1
Ragaz J ,Jackson SM ,Le N , et al. Adjuvant radiotherapy and chemotherapy in node-positive premenopausal women with breast cancer. N Engl J Med 1997;337:956-962
Full Text | Web of Science | Medline2
Overgaard M ,Hansen PS ,Overgaard J , et al. Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. N Engl J Med 1997;337:949-955
Full Text | Web of Science | Medline3
Borner M ,Bacchi M ,Goldhirsch A , et al. First isolated locoregional recurrence following mastectomy for breast cancer: results of a phase III multicenter study comparing systemic treatment with observation after excision and radiation. J Clin Oncol 1994;12:2071-2077
Web of Science | Medline4
Arriagada R ,Rutqvist LE ,Mattsson A ,Kramar A ,Rotstein S . Adequate locoregional treatment for early breast cancer may prevent secondary dissemination. J Clin Oncol 1995;13:2869-2878
Web of Science | Medline5
Marks LB ,Halperin EC ,Prosnitz LR , et al. Post-mastectomy radiotherapy following adjuvant chemotherapy and autologous bone marrow transplantation for breast cancer patients with greater than or equal to 10 positive axillary lymph nodes. Int J Radiat Oncol Biol Phys 1992;23:1021-1026
CrossRef | Web of Science | Medline
Author/Editor Response
Dr. Raffle is concerned about the apparent contradiction between the report by Overgaard et al., indicating that the percentage of patients with distant metastases is seemingly greater in the CMF–radiotherapy group than in the CMF-alone group, and the suggestion in my editorial that the improved survival in the combined group is due to the eradication of residual local disease. I suggest that persistent cancer is the source of distant metastases. This disparity reflects a problem in the method of data presentation. Only distant metastases that were first relapses were scored. Thus, any patient who first had a local recurrence and later distant disease would not be counted as having a distant relapse. Since the local recurrences were almost four times as prevalent in the CMF-alone group (32 percent, vs. 9 percent in the CMF–radiotherapy group), the combined-therapy group would appear to have many fewer local recurrences. Gelman et al.1 have written about the pitfalls of such an analysis, which are even more grievous in a study designed to determine whether persistent local disease gives rise to metastases. One wonders whether Dr. Raffle has any speculation as to an alternative explanation of the salutary effect of improved local treatment on the enhanced survival of the patients so treated.
Dr. Evans reminds us that in Protocol B-06 of the National Surgical Adjuvant Breast and Bowel Project the increase in distant metastases — all were scored — associated with the greater rate of local recurrences has been explained by Fisher et al. as an effect of lead-time bias.2 Although that is possible, the way to determine whether this presumption is more likely than my conclusion — that persistent local disease is the source of distant metastases — is to wait a sufficient time for such metastases to affect survival. In fact, both Overgaard et al. and Ragaz et al. found a marked survival advantage associated with the eradication of residual regional disease. If these two studies had been judged at intermediate periods, there would not have been a statistically significant survival difference.3 Because of the natural history of breast cancer and effective palliative treatment, very long follow-up is required. This emphasizes the need for surrogate markers on which to base clinical decisions while awaiting long-term follow-up (15 years). On the basis of these two studies, physicians would be prudent to assume that any treatment associated with significant increases in local recurrence will also be associated with decreased survival, the intermediate markers of which are increased local recurrence and increased distant metastases.
3 ReferencesSamuel Hellman, M.D.
University of Chicago, Chicago, IL 60637-14701
Gelman R ,Gelber R ,Henderson IC ,Coleman CN ,Harris JR . Improved methodology for analyzing local and distant recurrence. J Clin Oncol 1990;8:548-555
Web of Science | Medline2
Fisher B ,Redmond C ,Poisson R , et al. Eight-year results of a randomized clinical trial comparing total mastectomy and lumpectomy with or without irradiation in the treatment of breast cancer. N Engl J Med 1989;320:822-828[Erratum, N Engl J Med 1994;330:1467.]
Full Text | Web of Science | Medline3
Overgaard M ,Christensen JJ ,Johansen H , et al. Postmastectomy irradiation in high-risk breast cancer patients: present status of the Danish Breast Cancer Cooperative Group trials. Acta Oncol 1988;27:707-714
CrossRef | Web of Science | Medline
- Citing Articles (6)
Citing Articles
1
Christine S. Chung, Jay R. Harris. (2007) Post-mastectomy radiation therapy: Translating local benefits into improved survival. The Breast 16, 78-83
CrossRef2
T. Whelan, M. Levine. (2005) More Evidence That Locoregional Radiation Therapy Improves Survival: What Should We Do?. JNCI Journal of the National Cancer Institute 97:2, 82-84
CrossRef3
J. Ragaz, I. A. Olivotto, J. J. Spinelli, N. Phillips, S. M. Jackson, Kenneth. S. Wilson, M. A. Knowling, C. M. L. Coppin, L. Weir, K. Gelmon, N. Le, R. Durand, A. J. Coldman, M. Manji. (2005) Locoregional Radiation Therapy in Patients With High-Risk Breast Cancer Receiving Adjuvant Chemotherapy: 20-Year Results of the British Columbia Randomized Trial. JNCI Journal of the National Cancer Institute 97:2, 116-126
CrossRef4
Danijela Scepanovic, Nada Bajic, Jovan Babic. (2004) Postmastectomy radiotherapy and locoregional recurrence rate in high-risk breast cancer patients. Archive of oncology 12:1, 39-43
CrossRef5
Blake Cady. (2001) Fundamentals of contemporary surgical oncology: biologic principles and the threshold concept govern treatment and outcomes1 1No competing interests declared.. Journal of the American College of Surgeons 192:6, 777-792
CrossRef6
H. Takei, T. Fukutomi, S. Akashi-Tanaka, T. Nanasawa. (1998) Changes in the Treatment Outcome of Node-positive Breast Cancer Stratified by Menopausal Status: Comparison of Patients Treated in 1965-75 versus Those Treated in 1976-86. Japanese Journal of Clinical Oncology 28:12, 754-757
CrossRef
