Showing papers by "Bernard Fisher published in 1977"

Comparison of radical mastectomy with alternative treatments for primary breast cancer. A first report of results from a prospective randomized clinical trial.

Abstract: In 1971, the National Surgical Adjuvant Breast Project (NSABP) implemented a prospective randomized clinical trial to compare the worth of alternative treatments with radical mastectomy in women with primary operable breast cancer. Information has been obtained from 1,665 patients eligible for follow-up from 34 NSABP member institutions in Canada and the United States. Results from that trial, at present in its sixth year with patients on study for an average of 36 months, (26 to 62 months), fail to demonstrate an advantage for those who had a radical mastectomy. No significant difference in the treatment failure or survival has as yet been observed in clinically negative node patients who have been randomly managed by conventional radical mastectomy, total mastectomy with postoperative regional radiation or total mastectomy followed by axillary dissection of those patients who subsequently develop positive nodes. Similarly, there presently exists no difference between patients with clinically positive nodes treated by radical mastectomy or by total mastectomy followed by radiation. Of particular interest is the observation that based upon findings from radical mastectomy patients, there may be as many as 40% of patients having a total mastectomy who had histologically positive nodes unremoved, to date only 15% have developed positive nodes requiring an axillary dissection. The persistence of such a difference in incidence would have profound biological significance. The discovery that leaving behind positive axillary nodes has as yet not been influential in enhancing the incidence of distant metastases or the overall proportion of treatment failures and that a disproportionate number of treatment failures in the total mastectomy group occurred in those patients who subsequently required axillary dissection provides reinforcement to the view that positive axillary lymph nodes are not the predecessor of distant tumor spread but are a manifestation of disseminated disease.

L-phenylalanine mustard (L-PAM) in the management of primary breast cancer: An update of earlier findings and a comparison with those utilizing L-PAM plus 5-fluorouracil (5-FU)

Abstract: In 1972, a prospective, randomized, multi-institutional, cooperative clinical trial was begun to evaluate the efficacy of prolonged 1-phenylalanine mustard (L-PAM) administration following operation in lengthening the disease free interval of patients with primary breast cancer That protocol using a single agent was the first of a series directed toward evaluating successively more complex chemotherapeutic regimens in an attempt to define subsets of patients which might be responsive to less therapy than others When it was observed that L-PAM prolonged the disease free interval, particularly of premenopausal patients, findings were reported and a new evaluation comparing L-PAM with L-PAM plus 5-fluorouracil (5-FU) was begun Upon completion of patient accrual in that protocol, an additional trial comparing L-PAM and 5-FU with L-PAM, 5-FU and Methotrexate was implemented The present report updates findings from the initial study and presents those from the second It compares results across the first two protocols as well as between groups within a protocol While insufficient time has elapsed for determining the ultimate worth of the modalities employed, findings from the second protocol confirm those previously reported indicating that L-PAM lengthens the disease free interval following mastectomy The combination of L-PAM with 5-FU resulted in a reduction of treatment failure at 12 months which is as good or better than that observed with L-PAM in the first protocol lending further credibility to the earlier findings While at the end of the first year following mastectomy there was alomst a 50% reduction in treatment failures in patients aged 50 or over (post-menopausal), by 18 months the reduction was 23% and at two years, based on small numbers of patients, only 5% Examination of results from the first protocol (placebo vs L-PAM) after two years reveals a most highly significant effect of L-PAM in pre-menopausal women with one to three positive nodes There is an 89% reduction of treatment failures A similar but less striking effect is noted for those under 50 with ≥four positive nodes In older patients in both nodal categories, the early observed effect for L-PAM has decreased with time Inter-protocol comparisons relative to survival are premature At two years survival in L-PAM patients is 36% greater than in those receiving placebo It is somewhat better in every subgroup for those receiving L-PAM Information relative to the effect of these agents on patient toxicity and loco-regional treatment failures is presented All of the findings stress the urgency for obtaining results on subsets of patients rather than on a population as a whole and they lend support to the thesis that since breast cancer is an eponym to describe a heterogeneous group of tumors residing in a heterogeneous group of women, it is unlikely that uniformly qualitative and quantitative systemic regimens of therapy will be required for every patient

Biological and clinical considerations regarding the use of surgery and chemotherapy in the treatment of primary breast cancer.

Abstract: Numerous clinical trials are currently being implemented to evaluate the effectiveness of a variety of therapeutic regimens against primary breast cancer. There must be a rational biologic basis for the use of each component of the therapy. Principles upon which operation and systemic chemotherapy are employed in current trials are presented in this review. The basis for cancer surgery is undergoing a redefinition which is in keeping with present understanding of tumor biology. Anatomical principles of the past are being supplanted as a result of evidence indicating 1) breast cancer is predominantly a systemic disease at the time of diagnosis, 2) removal of a primary tumor affects host immunological mechanisms as well as residual tumor cell kinetics, 3) the role of lymphatics and lymph nodes differ from what had previously been promulgated, and 4) the significance of multicentricity is not as clear as might be presumed. Such considerations are giving rise to a new biological basis for cancer surgery. Several continuing surgical clinical trials being conducted by the National Surgical Adjuvant Breast Project (NSABP) should provide information which will substantiate or refute the justification for a change in oncologic surgical principles. A brief review of information regarding tumor cell kinetics, experiences with adjuvant therapy in animal model systems, and other considerations providing justification for the use of systemic adjuvant chemotherapy has been provided. From the spectrum of combined modality trials in progress throughout the world should come information within the next few years which will verify or repudiate not only concepts and principles upon which the use of adjuvant therapy is based, but the worth of those modalities presently representing our total therapeutic resources and upon which rest hope for the cure of breast cancer. Cancer 40:574–587, 1977.

A perspective concerning the relation of duration of symptoms to treatment failure in patients with breast cancer.

Abstract: Measures of association between the duration of symptoms and 7 clinical and 33 histologic characteristics in 1,539 patients with clinical stage I and II invasive cancer were performed. The relative frequency of highly malignant (histologic grade 3) cancers and tumor necrosis decreased when the duration of symptoms exceeded 9 months. However, tumor size, clinical stage II disease, nipple involvement, and microscopic evidence of involvement of the skin overlying the tumor were significantly increased with longer periods of duration of symptoms. The proportion of patients with axillary nodes containing metastases was suggestively related to duration of symptoms. Despite the relationship of duration of symptoms to these ominous prognostic indices its overall correlation with average monthly treatment failure rate was not statistically significant. Indeed, there was a trend toward a reduction in treatment failure rate in patients whose symptom period was greater than 9 months. The overall lack of association between treatment failure rate and duration of symptoms was sub-stantiated by the results of further analyses of life tables and average monthly treatment failure rates which attempted to assess the interrelationships of these discriminants with duration of symptoms and treatment failure. This information reflects the heterogeneity of tumor characteristics and possibly the importance of host-tumor relationships in the natural history of patients with breast cancer. Although these considerations are not intended to denigrate the sound practice of early diagnosis of breast cancer they do indicate that the time-oriented, conventional view concerning its growth and dissemination may represent a misleading oversimplification. Cancer 40:3160-3167, 1977.

Lobular carcinoma of the breast: an overview.

Abstract: The biologic nature, diagnostic features and therapeutic management of patients with lobular carcinoma in its in situ and invasive forms are discussed. Although recorded studies emphasize that patients with lobular carcinoma in situ are "at risk" for the development of invasive cancer, it has not been unequivocally demonstrated whether such an event represents a persistence of cancer due to inadequate excision or a de novo lesion. In support of the latter is the contention that lobular carcinoma exhibits a propensity for multicentricity and bilaterality. The recognition that the histologic types of the subsequent invasive cancers are not universally lobular invasive might also be cited in this regard. This information also bears upon views purporting a stepwise development of lobular invasive carcinoma from its in situ analog. Analysis of our own material fails to confirm any significant association between invasive lobular carcinoma and multicentric lesions. The diagnostic difficulty in distinguishing lobular hyperplasia from in situ lobular carcinoma and the inadvisability of frozen sections for this purpose is noted. Although the results of some electron microscopic studies of the in situ lesion challenge the propriety of its "pure in situ" nature; this criticism does not appear valid from both a pathological as well as pragmatic standpoints. The various schemes have been proposed concerning the surgical management of patients with lobular carcinoma in situ are presented and discussed. Certain biologic principles prompt consideration of segmental mastectomy and axillary node sampling as an alternative, commodious form of treatment for such lesions. There does not appear to be any unique reason to invoke any different treatment regimen for lobular invasive carcinoma than has been utilized for other invasive breast cancers.

Relationship of pathologic and some clinical discriniinants to the spread of breast cancer

Abstract: Breast cancer, Pathologic discriminants breast cancer, Clinical discriminants breast cancer. Spread breast cancer, Lymph nodes breast cancer, Metastases breast cancer. The conventional view regarding the natural history of breast cancer indicates that the primary tumor spreads to the regional lymph nodes at some given time(s) and subsequently disseminates systemically with further time. The significance of the time factor in this scheme at present is polemical. This concept also ascribes a primary role to lymphatic extension in the spread of the disease. Experimental studies which have demonstrated that tumor cells traverse lymph nodes’ and thus gain access into the general circulation tend to support such a contention. Yet, it is surprising that little attention has been directed to the phenomenon of direct neoplastic venous extension. That such an event occurs might be deduced from the, albeit rare, histopathological evidence of intravascular extension’* as well as from the presence of tumor cells in venous tributaries draining breast cancers in about 0.25 of a small series of cases.” This latter phenomenon was noted with equal frequency in both pathologic Stage I and II cases. Nevertheless, it has been demonstrated repeatedly that regional nodal metastases represent an ominous prognostic discriminant for breast cancer. Indeed, a prevalent view regards nodal metastases as an index of systemic spread. It readily becomes apparent that identification of factors which might influence or reflect the nodal status of patients with breast cancer might provide some insight into the mechanism as well as significance of such an event. Accumulating evidence of decreasing treatment failure rates with the use of adjuvant chemotherapy in patients with Stage II disease indicates the pragmatic value of such information.5*9.” In this communication we shall attempt to identify those pathological and clinical characteristics that were found to be associated with lymph node metastases and treatment failure rates [% failure/(average months followed)] in patients with invasive, operable mammary cancer (clinical Stages I and II) entered in the National Surgical Breast Project, protocol No. 4. These women were randomized prospectively so that those with clinically negative axillae were treated by radical mastectomy or total (simple) mastectomy with or without postoperative irradiation. Those with clinically positive axillae also were randomized and received either radical mastectomy or total mastectomy and irradiation. Information relating to nodal involvement is based upon the 386 patients of the first 1000 entered that were subjected to radical mastectomy regardless of clinical nodal status. These patients were categorized according to whether pathological examination of their axillary nodes revealed 1-3, 4 or more, or no nodal metastases. This stratification was derived from previous studies which indicated that the number rather than proportion of involved nodes were significantly related to survival.” Associations with treatment failure rates were compiled from information obtained from all arms of the study constituting 1665 patients. Treatment failure is defined as the occurrence of local or regional recurrence or systemic metastases or death resulting from breast cancer. The average period of

United States trials of conservative surgery

Abstract: From August 1971 to August 1974, almost 1700 patients with clinically curable breast cancer in 34 institutions in the United States and Canada were entered into the National Surgical Adjuvant Breast Project (NSABP) trial comparing the results of total (simple) mastectomy with those of radical mastectomy. Patients with clinically negative axillary nodes in the total mastectomy group were further randomized to receive postoperative regional radiotherapy or no radiotherapy, but the latter patients underwent an axillary dissection if clinically positive axillary nodes developed after operation. Patients with clinically positive axillary nodes in the total mastectomy group automatically received postoperative regional radiotherapy. After a follow-up period of 2 to 5 years, there are no significant differences in the results of the various types of treatment in either the groups of patients with clinically negative axillary nodes or those with clinically positive axillary nodes.

The Changing Role of Surgery in the Treatment of Cancer

Abstract: When consideration is given to recent advances and progress made in the treatment of cancer, little attention is directed toward those changes taking place that are probably as profound and as far reaching in consequence as are any in our time. To many—particularly those in other disciplines—the surgical approach to cancer is deemed anachronistic in concept. While categorically such may be true, the leading edge of that specialty is attempting to redefine the basis for cancer surgery so that it is in keeping with present understanding of tumor biology.

Surgery of Primary Breast Cancer

Abstract: Whereas for almost 100 years radical mastectomy was virtually unchallenged and accepted as standard therapy for clinically curable female breast cancer, there presently exists great controversy and actual confusion regarding the management of that disease. Women with breast cancers may have surgical procedures ranging from extended radical mastectomy with internal mammary node dissection to “lumpectomy,” depending entirely upon the belief of the surgeon. Unfortunately, more often than not the decision regarding which operation to employ has been based upon information obtained from poorly carried out retrospective analyses of heterogeneous groups of case records (the comparison of data which are worthless because they were acquired from divergent series of patients); peer pressure; emotionalism; and an outmoded concept of tumor biology. It is the latter which this reviewer considers the most significant factor responsible for the present period of clinical uncertainty.

Tumor Specificity, Serum Inhibition, and Influence of Regional Lymph Nodes on Cytotoxic Macrophages from Cultured Bone Marrow

Abstract: Prior investigations from this laboratory have demonstrated that, when bone marrow cells (BMC) from a tumorbearing host are cultured, enhanced macrophage colony production occurs and macrophages from the colonies (CMA) are cytotoxic to tumor cells. The presently reported findings indicate that the cytotoxicity of CMA is highly specific, destroying only cells derived from the immunizing tumor. They support prior observations indicating that the cytotoxicity of the mature macrophage is derived from precursor stem cells and that no peripheral lymphocyte-antigen interaction with the macrophage is required for it to obtain that property. Information is also provided that indicates that cells from lymph nodes regional to a tumor (RLN) may affect stem cells from which CMA are derived. Not only is there decreased macrophage colony production when regional lymph nodes are absent, but also cytotoxicity of the resultant CMA is reduced. Observations indicating that transfer of regional lymph node cells from tumor-bearing mice to normal mice results in the production of cytotoxic CMA by BMC derived from the latter afford further support to this consideration. Findings also indicate that the cytotoxicity of CMA, like that of regional lymph node cells and BMC, is inhibited by serum from tumor-bearing animals and that the degree of inhibition increases with duration of tumor growth in the serum donor. Finally, it was observed that, with progressive tumor growth, BMC result in CMA with decreased cytotoxicity.

Systemic Adjuvant (Combined Modality) Therapy in the Treatment of Primary Breast Cancer

Abstract: Despite the use of expansive surgical procedures on women with primary breast cancers, noteworthy gains relative to survival and freedom from disease have not occurred during the past three or four decades. Elsewhere in this volume, it has been documented that operation alone is all too frequently inadequate to effect a cure. There is increasing acceptance of the consideration that most, if not all, such patients have disseminated disease at the time of diagnosis. Consequently, improvement in survival is only apt to result from the employment of effective systemic therapy in conjunction with those modalities used to control locoregional disease, i.e., operation and radiation. The use of chemo-, mmuno-, or hormonal therapy in conjunction with operation has been inappropriately designated as “adjuvant” therapy. Recent advances in knowledge support the contention that operation and/or radiation, by reducing tumor burden, may actually serve as the “adjuvant” to systemic therapy. Consequently, the term “combined modality” therapy seems more appropriate to describe the various conglomerate treatment regimens. Nonetheless, because of its common usage and the general familiarity with its connotation, the term “adjuvant therapy” will be employed in this review.

United States trials of adjuvant therapy.

Abstract: Beginning in 1958, the first clinical trial of the National Surgical Adjuvant Breast Project compared a brief postoperative course of low dose triethylenethiophosphoramide (TSPA) with no adjuvant therapy or placebo in 826 patients who underwent radical mastectomy for breast cancer. After 5 years, one subset of patients made up of premenopausal women with 4 or more positive axillary lymph nodes had a significantly higher survival rate and longer disease free interval following TSPA therapy than after placebo therapy. After 10 years, these significant differences in survival and incidence of treatment failure between the TSPA-treated patients and the controls persisted. In 1972, the NSABP initiated a trial comparing prolonged postoperative chemotherapy with 1-phenylalanine mustard (L-PAM) with placebo in patients with positive nodes who had undergone radical mastectomy. By 1975 it appeared that premenopausal women who received L-PAM had a significantly lower incidence of treatment failure than those who received placebo. L-PAM therapy produced little alteration in the well-being of the patients. Between February 1975 and March 1976, 700 patients were entered into NSABP Protocol #7 which compares 2 regimens of prolonged postoperative chemotherapy, L-PAM alone and L-PAM plus 5-fluorouracil (5-FU). In June 1976, NSABP Protocol #8 was initiated to compare another 2 regimens of prolonged postoperative chemotherapy, L-PAM plus 5-FU and L-PAM plus 5-FU plus methotrexate. It is too early to evaluate the results of these studies. It seems likely that the many trials of adjuvant chemotherapy being conducted throughout the world will provide significant improvement in the curability of breast cancer, provided these trials are carefully planned and thoroughly executed.