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1.
J Clin Oncol ; 41(10): 1795-1808, 2023 04 01.
Article in English | MEDLINE | ID: mdl-36989610

ABSTRACT

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.

2.
J Clin Oncol ; 19(4): 931-42, 2001 Feb 15.
Article in English | MEDLINE | ID: mdl-11181655

ABSTRACT

PURPOSE: Uncertainty about the relative worth of doxorubicin/cyclophosphamide (AC) and cyclophosphamide/methotrexate/fluorouracil (CMF), as well as doubt about the propriety of giving tamoxifen (TAM) with chemotherapy to patients with estrogen receptor-negative tumors and negative axillary nodes, prompted the National Surgical Adjuvant Breast and Bowel Project to initiate the B-23 study. PATIENTS AND METHODS: Patients (n = 2,008) were randomly assigned to CMF plus placebo, CMF plus TAM, AC plus placebo, or AC plus TAM. Six cycles of CMF were given for 6 months; four cycles of AC were administered for 63 days. TAM was given daily for 5 years. Relapse-free survival (RFS), event-free survival (EFS), and survival (S) were determined by using life-table estimates. Tests for heterogeneity of outcome used log-rank statistics and Cox proportional hazards models to detect differences across all groups and according to chemotherapy and hormonal therapy status. RESULTS: No significant difference in RFS, EFS, or S was observed among the four groups through 5 years (P =.96,.8, and.8, respectively), for those aged < or = 49 years (P =.97,.5, and.9, respectively), or for those aged > or = 50 years (P =.7,.6, and.6, respectively). A comparison between all CMF- and all AC-treated patients demonstrated no significant differences in RFS (87% at 5 years in both groups, P =.9), EFS (83% and 82%, P =.6), or S (89% and 90%, P =.4). There were no significant differences in RFS, EFS, or S between CMF and AC in patients aged < or = 49 or > or = 50 years. No significant difference in any outcome was observed when chemotherapy-treated patients who received placebo were compared with those given TAM. RFS in both groups was 87% (P =.6), 87% in patients aged < or = 49 (P =.9), and 88% and 87%, respectively (P =.4), in those aged > or = 50 years. CONCLUSION: There was no significant difference in the outcome of patients who received AC or CMF. TAM with either regimen resulted in no significant advantage over that achieved from chemotherapy alone.


Subject(s)
Breast Neoplasms/drug therapy , Breast Neoplasms/metabolism , Receptors, Estrogen/metabolism , Tamoxifen/administration & dosage , Age Factors , Antineoplastic Combined Chemotherapy Protocols , Axilla , Breast Neoplasms/pathology , Cisplatin , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Fluorouracil , Humans , Lymphatic Metastasis , Methotrexate , Middle Aged , Patient Compliance , Placebos , Survival Analysis
3.
Ann Surg Oncol ; 7(3): 181-7, 2000 Apr.
Article in English | MEDLINE | ID: mdl-10791847

ABSTRACT

BACKGROUND: Less than two decades ago, early discharge of mastectomy patients was found to be possible while the drains were still in place, without noticeable consequences for patients. Most reported studies focused on surgical complication rates and found no significant evidence of it. The objective of the present study was to compare inpatient to same-day discharge surgery for breast cancer, on unselected patients. METHODS: All interviewed patients (n = 90) had routine level I and II axillary lymph node dissection under general anesthesia, combined with breast surgery for most of them. The outpatient group comprised 55 patients and the inpatient group 35. Psychological distress was assessed, as well as pain, anxiety, quality of life, emotional adjustment, recovery, social relations, stressful life events, and so on. RESULTS: The sociodemographic characteristics of both surgery groups was quite similar, except that time from surgery to interview was about 1 year longer for inpatients. Outpatients and hospitalized patients report similar levels of pain, fear, anxiety, health assessment, and quality of life. Ambulatory patients manifest a significantly better emotional adjustment and fewer psychological distress symptoms. Inpatients reported that it took an average of 27 days to feel that they had recovered from surgery, about 10 days longer than outpatients. Inpatient return to usual activities was also about 11 days later. CONCLUSIONS: Same-day discharge patients are not at a disadvantage compared to hospitalized patients; i.e., they report faster recovery and better psychological adjustment. Outpatient surgery may thus foster patient emotional well-being better than routine hospitalization.


Subject(s)
Ambulatory Surgical Procedures , Breast Neoplasms/surgery , Mastectomy/methods , Adaptation, Psychological , Anxiety/etiology , Breast Neoplasms/psychology , Female , Humans , Inpatients , Mastectomy/psychology , Middle Aged , Pain Measurement , Pain, Postoperative , Patient Satisfaction , Quality of Life , Surveys and Questionnaires , Treatment Outcome
4.
Surg Clin North Am ; 79(5): 1031-46, 1999 Oct.
Article in English | MEDLINE | ID: mdl-10572549

ABSTRACT

The 1992 NIH Consensus Development Conference reported that "breast conservation treatment is an appropriate method of primary therapy for the majority of women with stage I and II breast cancer and is preferable because it provides survival equivalent to total mastectomy and axillary dissection while preserving the breast." This conclusion has been solidly confirmed by recent updates of all of the prospective clinical trials performed. The uneven utilization of this BCS indicates the personal discomfort of some surgeons in recommending it or in communicating their recommendations to patients. The appropriate candidate for mastectomy is the patient in whom it is evident that BCS will not control the tumor. This conclusion may be drawn after one or even two attempts at revision have shown more extensive microscopic disease. The experience with preoperative chemotherapy programs such as NSABP Protocol B-18 shows that even for larger tumors primary excision or excision after preoperative chemotherapy provides reasonable rates of local control with no evidence of diminished distant control or survival. Very large tumors, often accompanied by other grave signs, are best treated by primary chemotherapy, because they are essentially not stage I or stage II disease. Although recognizing that better long-term cure rates are a function of the treatment of micrometastases with adjuvant chemotherapy, surgeons should remember the need to balance cosmetic factors with techniques required for good local control. Cosmetic factors are always important, but the primary concern is adequate removal of the primary tumor with pathologically negative margins. The best way to prevent the need for a salvage mastectomy following local recurrence is to obtain adequate control at the initial procedure, but this does not mean that aggressive local surgery is needed, and it certainly does not mean that a primary mastectomy is needed except in unusual cases.


Subject(s)
Breast Neoplasms/surgery , Attitude of Health Personnel , Chemotherapy, Adjuvant , Clinical Trials as Topic , Consensus Development Conferences, NIH as Topic , Esthetics , Female , Humans , Lymph Node Excision , Mastectomy, Segmental , Mastectomy, Simple , Neoplasm Invasiveness , Neoplasm Recurrence, Local/prevention & control , Neoplasm Staging , Prospective Studies , Salvage Therapy , United States
5.
Lancet ; 353(9169): 1993-2000, 1999 Jun 12.
Article in English | MEDLINE | ID: mdl-10376613

ABSTRACT

BACKGROUND: We have shown previously that lumpectomy with radiation therapy was more effective than lumpectomy alone for the treatment of ductal carcinoma in situ (DCIS). We did a double-blind randomised controlled trial to find out whether lumpectomy, radiation therapy, and tamoxifen was of more benefit than lumpectomy and radiation therapy alone for DCIS. METHODS: 1804 women with DCIS, including those whose resected sample margins were involved with tumour, were randomly assigned lumpectomy, radiation therapy (50 Gy), and placebo (n=902), or lumpectomy, radiation therapy, and tamoxifen (20 mg daily for 5 years, n=902). Median follow-up was 74 months (range 57-93). We compared annual event rates and cumulative probability of invasive or non-invasive ipsilateral and contralateral tumours over 5 years. FINDINGS: Women in the tamoxifen group had fewer breast-cancer events at 5 years than did those on placebo (8.2 vs 13.4%, p=0.0009). The cumulative incidence of all invasive breast-cancer events in the tamoxifen group was 4.1% at 5 years: 2.1% in the ipsilateral breast, 1.8% in the contralateral breast, and 0.2% at regional or distant sites. The risk of ipsilateral-breast cancer was lower in the tamoxifen group even when sample margins contained tumour and when DCIS was associated with comedonecrosis. INTERPRETATION: The combination of lumpectomy, radiation therapy, and tamoxifen was effective in the prevention of invasive cancer.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma, Intraductal, Noninfiltrating/drug therapy , Tamoxifen/therapeutic use , Antineoplastic Agents, Hormonal/adverse effects , Breast Neoplasms/mortality , Breast Neoplasms/pathology , Breast Neoplasms/therapy , Carcinoma in Situ/drug therapy , Carcinoma in Situ/therapy , Carcinoma, Intraductal, Noninfiltrating/mortality , Carcinoma, Intraductal, Noninfiltrating/secondary , Carcinoma, Intraductal, Noninfiltrating/therapy , Carcinoma, Lobular/drug therapy , Carcinoma, Lobular/therapy , Combined Modality Therapy , Double-Blind Method , Female , Humans , Mastectomy, Segmental , Middle Aged , Survival Rate , Tamoxifen/adverse effects
6.
J Clin Oncol ; 16(8): 2672-85, 1998 Aug.
Article in English | MEDLINE | ID: mdl-9704717

ABSTRACT

PURPOSE: To determine, in women with primary operable breast cancer, if preoperative doxorubicin (Adriamycin) and cyclophosphamide (Cytoxan; AC) therapy yields a better outcome than postoperative AC therapy, if a relationship exists between outcome and tumor response to preoperative chemotherapy, and if such therapy results in the performance of more lumpectomies. PATIENTS AND METHODS: Women (1,523) enrolled onto National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18 were randomly assigned to preoperative or postoperative AC therapy. Clinical tumor response to preoperative therapy was graded as complete (cCR), partial (cPR), or no response (cNR). Tumors with a cCR were further categorized as either pathologic complete response (pCR) or invasive cells (pINV). Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were estimated through 5 years and compared between treatment groups. In the preoperative arm, proportional-hazards models were used to investigate the relationship between outcome and tumor response. RESULTS: There was no significant difference in DFS, DDFS, or survival (P = .99, .70, and .83, respectively) among patients in either group. More patients treated preoperatively than postoperatively underwent lumpectomy and radiation therapy (67.8% v 59.8%, respectively). Rates of ipsilateral breast tumor recurrence (IBTR) after lumpectomy were similar in both groups (7.9% and 5.8%, respectively; P = .23). Outcome was better in women whose tumors showed a pCR than in those with a pINV, cPR, or cNR (relapse-free survival [RFS] rates, 85.7%, 76.9%, 68.1%, and 63.9%, respectively; P < .0001), even when baseline prognostic variables were controlled. When prognostic models were compared for each treatment group, the preoperative model, which included breast tumor response as a variable, discriminated outcome among patients to about the same degree as the postoperative model. CONCLUSION: Preoperative chemotherapy is as effective as postoperative chemotherapy, permits more lumpectomies, is appropriate for the treatment of certain patients with stages I and II disease, and can be used to study breast cancer biology. Tumor response to preoperative chemotherapy correlates with outcome and could be a surrogate for evaluating the effect of chemotherapy on micrometastases; however, knowledge of such a response provided little prognostic information beyond that which resulted from postoperative therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/mortality , Breast Neoplasms/surgery , Combined Modality Therapy/adverse effects , Cyclophosphamide/administration & dosage , Disease-Free Survival , Doxorubicin/administration & dosage , Female , Humans , Middle Aged , Prognosis , Proportional Hazards Models , Survival Rate
8.
Am J Ophthalmol ; 125(4): 493-501, 1998 Apr.
Article in English | MEDLINE | ID: mdl-9559735

ABSTRACT

PURPOSE: To estimate the prevalence of abnormalities in visual function and ocular structures associated with the long-term use of tamoxifen citrate. METHODS: A single-masked, cross-sectional study involving multiple community and institutional ophthalmologic departments was conducted with a volunteer sample of 303 women with breast cancer currently taking part in a randomized clinical trial to determine the efficacy of tamoxifen (20 mg/day) in preventing recurrences. Participants included women who had never been on drug (n=85); women who had taken tamoxifen for an average of 4.8 years, then been off the drug for an average of 2.7 years (n=140); and women who had been on tamoxifen continuously for an average of 7.8 years (n=78). Women were evaluated by questionnaire, psychophysical testing, and clinical examination to determine any abnormalities in visual function and the comparative prevalences of corneal, lens, retinal, and optic nerve pathology. RESULTS: There were no cases of vision-threatening ocular toxicity among the tamoxifen-treated participants. Compared with nontreated participants, the tamoxifen-treated women had no differences in the activities of daily vision, visual acuity measurements, or other tests of visual function except for color screening. Intraretinal crystals (odds ratio [OR]=3.58, P=.178) and posterior subcapsular opacities (OR=4.03, P=.034) were more frequent in the tamoxifen-treated group. CONCLUSIONS: Women should have a thorough baseline ophthalmic evaluation within the first year of initiating tamoxifen therapy and receive appropriate follow-up evaluations.


Subject(s)
Antineoplastic Agents, Hormonal/adverse effects , Eye Diseases/chemically induced , Tamoxifen/adverse effects , Vision, Ocular/drug effects , Aged , Antineoplastic Agents, Hormonal/therapeutic use , Breast Neoplasms/prevention & control , Cataract/chemically induced , Cross-Sectional Studies , Female , Humans , Lens, Crystalline/drug effects , Longitudinal Studies , Middle Aged , Neoplasm Recurrence, Local/prevention & control , Prevalence , Retina/drug effects , Retinal Diseases/chemically induced , Single-Blind Method , Tamoxifen/therapeutic use , Vision Tests
9.
J Clin Oncol ; 16(2): 441-52, 1998 Feb.
Article in English | MEDLINE | ID: mdl-9469327

ABSTRACT

PURPOSE: In 1993, findings from a National Surgical Adjuvant Breast and Bowel Project (NSABP) trial to evaluate the worth of radiation therapy after lumpectomy concluded that the combination was more beneficial than lumpectomy alone for localized intraductal carcinoma-in-situ (DCIS). This report extends those findings. PATIENTS AND METHODS: Women (N = 818) with localized DCIS were randomly assigned to lumpectomy or lumpectomy plus radiation (50 Gy). Tissue was removed so that resected specimen margins were histologically tumor-free. Mean follow-up time was 90 months (range, 67 to 130). Size and method of tumor detection were determined by central clinical, mammographic, and pathologic assessment. Life-table estimates of event-free survival and survival, average annual rates of occurrence for specific events, relative risks for event-specific end points, and cumulative probability of specific events comprising event-free survival are presented. RESULTS: The benefit of lumpectomy plus radiation was virtually unchanged between 5 and 8 years of follow-up and was due to a reduction in invasive and noninvasive ipsilateral breast tumors (IBTs). Incidence of locoregional and distant events remained similar in both treatment groups; deaths were only infrequently related to breast cancer. Incidence of noninvasive IBT was reduced from 13.4% to 8.2% (P = .007), and of invasive IBT, from 13.4% to 3.9% (P < .0001). All cohorts benefited from radiation regardless of clinical or mammographic tumor characteristics. CONCLUSION: Through 8 years of follow-up, our findings continue to indicate that lumpectomy plus radiation is more beneficial than lumpectomy alone for women with localized, mammographically detected DCIS. When evaluated according to the mammographic characteristics of their DCIS, all groups benefited from radiation.


Subject(s)
Breast Neoplasms/therapy , Carcinoma in Situ/therapy , Carcinoma, Ductal, Breast/therapy , Mastectomy, Segmental , Breast Neoplasms/mortality , Breast Neoplasms/radiotherapy , Carcinoma in Situ/mortality , Carcinoma in Situ/radiotherapy , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/radiotherapy , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Middle Aged , Survival Rate
10.
Recent Results Cancer Res ; 152: 193-201, 1998.
Article in English | MEDLINE | ID: mdl-9928558

ABSTRACT

Primary systemic chemotherapy for breast cancer was initially directed at downsizing tumors to make them acceptable candidates for breast-conserving surgery. Later trials used this approach in the hope of improving disease-free survival and overall survival. Results from NSABP protocol B-18 indicate significant initial tumor response and downstaging of lymph nodes in 30% of patients. Patients with small tumors were more likely to experience complete clinical response and complete pathologic response. Patients with larger tumors whose surgeons would have chosen mastectomy often responded with tumor decrease to a size at which lumpectomy was considered feasible. The local recurrence rate in these patients was higher than in those patients selected for lumpectomy primarily. Nevertheless, even with a higher rate of ipsilateral breast tumor recurrence, approximately 90% of women older than 50 years and 83% of younger women had successful breast-conserving surgery. There was no difference in disease-free survival or overall survival between preoperative and postoperative chemotherapy groups. The response of patients to initial chemotherapy can be a useful tool in exploring the biology of breast cancer.


Subject(s)
Breast Neoplasms/therapy , Preoperative Care/methods , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Clinical Trials as Topic , Disease-Free Survival , Female , Humans , Mastectomy, Segmental , Middle Aged , Neoplasm Recurrence, Local
11.
J Natl Cancer Inst ; 89(22): 1673-82, 1997 Nov 19.
Article in English | MEDLINE | ID: mdl-9390536

ABSTRACT

BACKGROUND: The B-20 study of the National Surgical Adjuvant Breast and Bowel Project (NSABP) was conducted to determine whether chemotherapy plus tamoxifen would be of greater benefit than tamoxifen alone in the treatment of patients with axillary lymph node-negative, estrogen receptor-positive breast cancer. METHODS: Eligible patients (n = 2306) were randomly assigned to one of three treatment groups following surgery. A total of 771 patients with follow-up data received tamoxifen alone; 767 received methotrexate, fluorouracil, and tamoxifen (MFT); and 768 received cyclophosphamide, methotrexate, fluorouracil, and tamoxifen (CMFT). The Kaplan-Meier method was used to estimate disease-free survival, distant disease-free survival, and survival. Reported P values are two-sided. RESULTS: Through 5 years of follow-up, chemotherapy plus tamoxifen resulted in significantly better disease-free survival than tamoxifen alone (90% for MFT versus 85% for tamoxifen [P = .01]; 89% for CMFT versus 85% for tamoxifen [P = .001]). A similar benefit was observed in both distant disease-free survival (92% for MFT versus 87% for tamoxifen [P = .008]; 91% for CMFT versus 87% for tamoxifen [P = .006]) and survival (97% for MFT versus 94% for tamoxifen [P = .05]; 96% for CMFT versus 94% for tamoxifen [P = .03]). Compared with tamoxifen alone, MFT and CMFT reduced the risk of ipsilateral breast tumor recurrence after lumpectomy and the risk of recurrence at other local, regional, and distant sites. Risk of treatment failure was reduced after both types of chemotherapy, regardless of tumor size, tumor estrogen or progesterone receptor level, or patient age; however, the reduction was greatest in patients aged 49 years or less. No subgroup of patients evaluated in this study failed to benefit from chemotherapy. CONCLUSIONS: Findings from this and other NSABP studies indicate that patients with breast cancer who meet NSABP protocol criteria, regardless of age, lymph node status, tumor size, or estrogen receptor status, are candidates for chemotherapy.


Subject(s)
Antineoplastic Agents, Hormonal/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Estrogen Antagonists/therapeutic use , Receptors, Estrogen , Tamoxifen/therapeutic use , Antimetabolites, Antineoplastic/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Lymphatic Metastasis , Methotrexate/administration & dosage , Middle Aged , Neoplasm Recurrence, Local , Receptors, Estrogen/drug effects , Risk , Survival Analysis , Treatment Failure , Treatment Outcome
12.
J Clin Oncol ; 15(7): 2483-93, 1997 Jul.
Article in English | MEDLINE | ID: mdl-9215816

ABSTRACT

PURPOSE: To determine whether preoperative doxorubicin and cyclophosphamide (AC) permits more lumpectomies to be performed and decreases the incidence of positive nodes in women with primary breast cancer. PATIENTS AND METHODS: Women (n = 1,523) were randomized to National Surgical Adjuvant Breast and Bowel Project (NSABP) B-18; 759 eligible patients received postoperative AC and 747, preoperative AC. The clinical size of breast and axillary tumors was determined before each of four cycles of AC and before surgery. Tumor response to preoperative therapy was clinically complete (cCR), partial (cPR), stable (cSD), or progressive disease (cPD). Tissue from patients with a cCR was evaluated for a pathologic complete response (pCR). RESULTS: Breast tumor size was reduced in 80% of patients after preoperative therapy; 36% had a cCR. Tumor size and clinical nodal status were independent predictors of cCR. Twenty-six percent of women with a cCR had a pCR. Clinical nodal response occurred in 89% of node-positive patients: 73% had a cCR and 44% of those had a pCR. There was a 37% increase in the incidence of pathologically negative nodes. Before randomization, lumpectomy was proposed for 86% of women with tumors < or = 2 cm, 70% with tumors 2.1 to 5.0 cm, and 3% with tumors > or = 5.1 cm. Clinical tumor size and nodal status influenced the physician's decision. Overall, 12% more lumpectomies were performed in the preoperative group; in women with tumors > or = 5.1 cm, there was a 175% increase. CONCLUSION: Preoperative therapy reduced the size of most breast tumors and decreased the incidence of positive nodes. The greatest increase in lumpectomy after preoperative therapy occurred in women with tumors > or = 5 cm, since women with tumors less than 5 cm were already lumpectomy candidates. Preoperative therapy should be considered for the initial management of breast tumors judged too large for lumpectomy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Mastectomy, Segmental , Neoplasm Recurrence, Local/prevention & control , Antibiotics, Antineoplastic/administration & dosage , Antineoplastic Agents, Alkylating/administration & dosage , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Humans , Lymphatic Metastasis , Middle Aged , Preoperative Care , Treatment Outcome
13.
J Natl Cancer Inst ; 88(21): 1529-42, 1996 Nov 06.
Article in English | MEDLINE | ID: mdl-8901851

ABSTRACT

BACKGROUND: In 1982, the National Surgical Adjuvant Breast and Bowel Project initiated a randomized, double-blinded, placebo-controlled trial (B-14) to determine the effectiveness of adjuvant tamoxifen therapy in patients with primary operable breast cancer who had estrogen receptor-positive tumors and no axillary lymph node involvement. The findings indicated that tamoxifen therapy provided substantial benefit to patients with early stage disease. However, questions arose about how long the observed benefit would persist, about the duration of therapy necessary to maintain maximum benefit, and about the nature and severity of adverse effects from prolonged treatment. PURPOSE: We evaluated the outcome of patients in the B-14 trial through 10 years of follow-up. In addition, the effects of 5 years versus more than 5 years of tamoxifen therapy were compared. METHODS: In the trial, patients were initially assigned to receive either tamoxifen at 20 mg/day (n = 1404) or placebo (n = 1414). Tamoxifen-treated patients who remained disease free after 5 years of therapy were then reassigned to receive either another 5 years of tamoxifen (n = 322) or 5 years of placebo (n = 321). After the study began, another group of patients who met the same protocol eligibility requirements as the randomly assigned patients were registered to receive tamoxifen (n = 1211). Registered patients who were disease free after 5 years of treatment were also randomly assigned to another 5 years of tamoxifen (n = 261) or to 5 years of placebo (n = 249). To compare 5 years with more than 5 years of tamoxifen therapy, data relating to all patients reassigned to an additional 5 years of the drug were combined. Patients who were not reassigned to either tamoxifen or placebo continued to be followed in the study. Survival, disease-free survival, and distant disease-free survival (relating to failure at distant sites) were estimated by use of the Kaplan-Meier method; differences between the treatment groups were assessed by use of the logrank test. The relative risks of failure (with 95% confidence intervals [CIs]) were determined by use of the Cox proportional hazards model. Reported P values are two-sided. RESULTS: Through 10 years of follow-up, a significant advantage in disease-free survival (69% versus 57%, P < .0001; relative risk = 0.66; 95% CI = 0.58-0.74), distant disease-free survival (76% versus 67%, P < .0001; relative risk = 0.70; 95% CI = 0.61-0.81), and survival (80% versus 76%, P = .02; relative risk = 0.84; 95% CI = 0.71-0.99) was found for patients in the group first assigned to receive tamoxifen. The survival benefit extended to those 49 years of age or younger and to those 50 years of age or older. Tamoxifen therapy was associated with a 37% reduction in the incidence of contralateral (opposite) breast cancer (P = .007). Through 4 years after the reassignment of tamoxifen-treated patients to either continued-therapy or placebo groups, advantages in disease-free survival (92% versus 86%, P = .003) and distant disease-free survival (96% versus 90%, P = .01) were found for those who discontinued tamoxifen treatment. Survival was 96% for those who discontinued tamoxifen compared with 94% for those who continued tamoxifen treatment (P = .08). A higher incidence of thromboembolic events was seen in tamoxifen-treated patients (through 5 years, 1.7% versus 0.4%). Except for endometrial cancer, the incidence of second cancers was not increased with tamoxifen therapy. CONCLUSIONS AND IMPLICATIONS: The benefit from 5 years of tamoxifen therapy persists through 10 years of follow-up. No additional advantage is obtained from continuing tamoxifen therapy for more than 5 years.


Subject(s)
Antineoplastic Agents, Hormonal/administration & dosage , Breast Neoplasms/drug therapy , Estrogen Antagonists/administration & dosage , Receptors, Estrogen , Tamoxifen/administration & dosage , Antineoplastic Agents, Hormonal/adverse effects , Breast Neoplasms/metabolism , Breast Neoplasms/pathology , Chemotherapy, Adjuvant , Disease-Free Survival , Double-Blind Method , Endometrial Neoplasms/etiology , Estrogen Antagonists/adverse effects , Female , Follow-Up Studies , Humans , Lymphatic Metastasis , Middle Aged , Risk , Tamoxifen/adverse effects , Time Factors
14.
J Clin Oncol ; 14(7): 1982-92, 1996 Jul.
Article in English | MEDLINE | ID: mdl-8683228

ABSTRACT

PURPOSE: To compare sequential methotrexate (M) and fluorouracil (F) (M-->F) with surgery (National Surgical Adjuvant Breast and Bowel Project [NSABP] B-13) and cyclophosphamide (C), M, and F with M-->F (NSABP B-19), in patients with estrogen receptor (ER)-negative tumors and negative axillary nodes. PATIENTS AND METHODS: A total of 760 patients were randomized to B-13; 1,095 patients with the same eligibility requirements were randomized to B-19. Disease-free survival (DFS), distant disease-free survival (DDFS), and survival were determined using life-table estimates. RESULTS: A significant benefit in overall DFS (74% v 59%; P < .001) was demonstrated at 8 years in all B-13 patients who received M-->F (69% v 56% [P = .006] in those or= 50 years). A survival advantage was evident in older patients (89% v 80%; P = .03). In B-19, through 5 years, an overall DFS advantage (82% v 73%; P < .001) and a borderline survival advantage (88% v 85%; P = .06) were evident with CMF. The DFS (84% v 72%; P < .001) and survival (89% v 84%; P = .04) benefits from CMF were greater in women aged F or CMF after lumpectomy and breast irradiation resulted in a low probability of ipsilateral breast tumor recurrence (IBTR). In B-13, the frequency of IBTR was 2.6% following M-->F versus 13.4% in women treated by lumpectomy; it was 0.6% following CMF in B-19. Toxicity >or= grade 3 was more frequent among CMF patients in B-19. The age-related difference in CMF benefit was not related to amount of drug received. CONCLUSION: M-->F and CMF are effective for node-negative patients with ER-negative tumors. The incidence of local-regional or distant metastases and IBTR decreased after either therapy. The benefit from either therapy was evident in all patients, but the CMF advantage was greater in those F may be used in patients with medical problems that would preclude CMF administration.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Receptors, Estrogen/analysis , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/chemistry , Breast Neoplasms/surgery , Chemotherapy, Adjuvant , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Fluorouracil/adverse effects , Humans , Leucovorin/administration & dosage , Lymphatic Metastasis , Mastectomy , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local , Survival Rate
18.
Can J Surg ; 38(5): 402-8, 1995 Oct.
Article in English | MEDLINE | ID: mdl-7553462

ABSTRACT

Cancer treatment in the past has been based on contemporary biologic understanding of the disease process. For most of this century cancer was viewed as an anatomic problem, and the treatment was surgical, with radical and extended radical operations viewed as appropriate. With improved understanding of the true biologic nature of cancer, the extent of surgery has been modified, and clinical trials have confirmed the suitability of breast-conserving surgery. At the same time, adjuvant chemotherapies have extended disease-free survival and survival for many categories of patient. Unfortunately, these gains have been of limited clinical dimensions. More recently, the genetic model of cancer has led to attempts at cancer prevention. In the biologic sense we have entered an era in which surgery is the adjuvant therapy, and systemic treatments have increased breast cancer cure rates. We must now move from a strategy that tries to kill cancer cells to one that seeks to control their growth, which may, if successful provide an approach for true cancer prevention.


Subject(s)
Breast Neoplasms/surgery , Breast Neoplasms/etiology , Breast Neoplasms/prevention & control , Chemotherapy, Adjuvant , Female , Humans
20.
Hum Genet ; 95(5): 545-50, 1995 May.
Article in English | MEDLINE | ID: mdl-7759076

ABSTRACT

We have examined 26 Canadian families with hereditary breast or ovarian cancer for linkage to markers flanking the BRCA1 gene on chromosome 17q12-q21. Of the 15 families that contain cases of ovarian cancer, 94% were estimated to be linked to BRCA1. In contrast, there was no overall evidence of linkage in the group of 10 families with breast cancer without ovarian cancer. A genetic recombinant in a breast-ovarian cancer family indicates a placement of BRCA1 telomeric to D17S776, and helps to define the region of assignment of the cancer susceptibility gene. Other cancers of interest that appeared in the BRCA1-linked families included primary peritoneal cancer, cancer of the fallopian tube, and malignant melanoma.


Subject(s)
Breast Neoplasms/genetics , Chromosomes, Human, Pair 17 , DNA, Neoplasm/analysis , Genetic Linkage/genetics , Neoplasm Proteins/genetics , Ovarian Neoplasms/genetics , Transcription Factors/genetics , Adult , BRCA1 Protein , Biomarkers, Tumor , Canada , Chromosome Mapping , Female , Humans , Lod Score , Melanoma/genetics , Middle Aged , Pedigree
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