title: The combination of radiotherapy, adjuvant chemotherapy (cyclophosphamide-doxorubicin-ftorafur) and tamoxifen in stage II breast cancer. Long-term follow-up results of a randomised trial. Postsurgical adjuvant chemotherapy with or without radiotherapy in women with breast cancer and positive axillary nodes: a South-Eastern Cancer Study Group (SEG) Trial. Clinical practice guidelines for the care and treatment of breast cancer: 11. Lymphedema. Tangential breast irradiation with or without internal mammary chain irradiation: results of a randomized trial. A randomized trial of chemotherapy (L-PAM vs CMF) and irradiation for node positive breast cancer The total incidence of loco-regional recurrence in a randomized trial of breast cancer TNM stage II. The South Sweden Breast Cancer Trial. Adjuvant treatment of postmenopausal patients with high risk primary breast cancer. Results from the Danish adjuvant trials DBCG 77 C and DBCG 82 C. The role of radiotherapy in the management of operable locally advanced breast carcinoma Radiotherapy-related lung fibrosis enhanced by tamoxifen. Long-term cardiac morbidity and mortality in a randomized trial of pre- and postoperative radiation therapy versus surgery alone in primary breast cancer. The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. Cardiac effects of adjuvant doxorubicin and radiation therapy in breast cancer patients. Concurrent paclitaxel and radiation therapy for breast cancer. Late treatment-related morbidity in breast cancer patients randomized to postmastectomy radiotherapy and systemic treatment versus systemic treatment alone. The dissection of internal mammary nodes does not improve the survival of breast cancer patients. 30-year results of a randomised trial. Treatment-related toxicity from a randomized trial of the sequencing of doxorubicin and radiation therapy in patients treated for early stage breast cancer. Locoregional failure 10 years after mastectomy and adjuvant chemotherapy with or without tamoxifen without irradiation: experience of the Eastern Cooperative Oncology Group. The 5-year results of a randomized trial of adjuvant radiation therapy after chemotherapy in breast cancer patients treated with mastectomy. A randomized comparative trial of chemotherapy and irradiation therapy for stage ii breast cancer Effects of tamoxifen on pulmonary fibrosis after cobalt-60 radiotherapy in breast cancer patients. Locoregional recurrence patterns after mastectomy and doxorubicin-based chemotherapy: implications for postoperative irradiation. Postoperative radiotherapy following mastectomy for high-risk breast cancer. A randomised trial. Adjuvant radiotherapy and chemotherapy in breast cancer Postoperative radiotherapy in high-risk postmenopausal breast-cancer patients given adjuvant tamoxifen: Danish Breast Cancer Cooperative Group DBCG 82c randomised trial Radiation-induced brachial plexopathy: neurological follow-up in 161 recurrence-free breast cancer patients. Adjuvant postoperative radiotherapy, chemotherapy, and immunotherapy in stage III breast cancer Long-term cardiac sequelae in operable breast cancer patients given adjuvant chemotherapy with or without doxorubicin and breast irradiation. Patterns of tumor relapse following mastectomy and adjuvant systemic therapy in patients with axillary lymph node‐positive breast cancer. Impact of clinical, histopathologic, and flow cytometric factors Cardiovascular mortality in a randomized trial of adjuvant radiation therapy versus surgery alone in primary breast cancer. Adjuvant postoperative radiotherapy, chemotherapy, and immunotherapy in stage III breast cancer. II. 5‐year results and influence of levamisole Radical mastectomy versus radical mastectomy plus internal mammary dissection. Five‐year results of an international cooperative study Ten-year results of a randomized clinical trial comparing radical mastectomy and total mastectomy with or without radiation. Twenty-five-year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by irradiation. A preliminary assessment of factors associated with recurrent disease in a surgical adjuvant clinical trial for patients with breast cancer with special emphasis on the aggressiveness of therapy Postoperative radiotherapy in high-risk premenopausal women with breast cancer who receive adjuvant chemotherapy. Danish Breast Cancer Cooperative Group 82b Trial. Chronic arm morbidity after curative breast cancer treatment: prevalence and impact on quality of life. Risk factors for locoregional recurrence among breast cancer patients: results from International Breast Cancer Study Group Trials I through VII. Randomized trial on the effect of radiotherapy in addition to 6 cycles CMF in node-positive breast-cancer patients. The German Breast-Cancer Study Group.
abstract: Two hundred patients with node positive stage II breast cancer were r and omised to four groups after radical mastectomy and axillary evacuation : ( 1 ) Postoperative radiotherapy , ( 2 ) Adjuvant chemotherapy with eight courses of CAFt ( cyclophosphamide 500 mg m-2 + doxorubicin 40 mg/m-2 + ftorafur 20 mg kg-1 orally day 1 - 14 ) every fourth week , ( 3 ) Postoperative radiotherapy and adjuvant chemotherapy and ( 4 ) postoperative radiation , adjuvant chemotherapy and tamoxifen 40 mg daily for 2 years . Thirty-two per cent of the patients discontinued treatment due to GI-toxicity , while 26 % required dose reductions due to leukopenia . Radiation pneumonitis was more frequent after the combination of postoperative radiotherapy with chemotherapy . There was a better relapse-free survival in the groups receiving chemotherapy compared to radiotherapy alone ( P = 0.05 ) , which was highly significant in a multivariate Cox analysis ( P = 0.004 ) . No significant survival differences were seen . Tamoxifen had no clear overall effect but there were better relapse-free ( P = 0.04 ) and overall ( P = 0.004 ) survival with tamoxifen in estrogen receptor positive patients , while estrogen receptor negative patients had a somewhat poorer survival ( P = 0.07 ) after tamoxifen .  Local control was better ( NS ) after the combination ( 93 % ) radiotherapy and chemotherapy compared to either treatment alone ( 76 % with radiotherapy and 74 % with chemotherapy at 5 years ) In a prospect i ve study of 622 women with breast cancer , those with one to three histologically positive axillary lymph nodes were r and omised after mastectomy  to receive cyclophosphamide 100 mg/m2 orally on days 1 - 14 , methotrexate 40 mg/m2 intravenously on days 1 and 8 , and fluorouracil 600 mg/m2 intravenously on days 1 and 8 every 28 days for six cycles ( CMF x six ) , or for twelve cycles of the same chemotherapy ( CMF x 12 ) . Those with > or = four positive nodes were r and omised to one of these two groups or to 5000 cGy of postmastectomy regional radiotherapy ( RT ) followed by six cycles of the same chemotherapy ( RT + CMF x six ) . With about 10 years median follow-up , there was no significant difference in survival or disease-free survival among the three groups . There was evidence of decreased locoregional recurrence in patients with > or = four nodes who received RT + CMF x six ( relative risk 0.53 , P = 0.067 ) . Multivariate analysis indicated that the presence of > or = four positive nodes ( negatively ) and the percentage of ideal ( full ) dose of CMF received ( positively ) were the strongest factors predictive of survival . This study shows no advantage for 12 over six cycles of CMF chemotherapy in women with breast cancer and positive axillary nodes . There was a suggestion of decreased locoregional recurrence but no improvement in survival with radiotherapy for women with > or = four positive nodes OBJECTIVE To provide information and recommendations for women and their physicians when making decisions about the management of lymphedema related to breast cancer . OPTIONS Compression garments , pneumatic compression pumps , massage and physical therapies , other physical therapy modalities , pharmaceutical treatments . OUTCOMES Symptom control , quality of life , cosmetic results . EVIDENCE Systematic review of English- language literature retrieved primarily from MEDLINE ( 1966 to April 2000 ) and CANCERLIT ( 1985 to April 2000 ) . Non systematic review of breast cancer literature published to October 2000 . RECOMMENDATIONS Pre- and postoperative measurements of both arms are useful in the assessment and diagnosis of lymphedema . Circumferential measurements should be taken at 4 points : the metacarpal-phalangeal joints , the wrists , 10 cm distal to the lateral epicondyles and 15 cm proximal to the lateral epicondyles . Clinicians should elicit symptoms of heaviness , tightness or swelling in the affected arm . A difference of more than 2.0 cm at any of the 4 measurement points may warrant treatment of the lymphedema , provided that tumour involvement of the axilla or brachial plexus , infection and axillary vein thrombosis have been ruled out . Practitioners may want to encourage long-term and consistent use of compression garments by women with lymphedema . One r and omized trial has demonstrated a trend in favour of pneumatic compression pumps  compared with no treatment . Further r and omized trials are required to determine whether pneumatic compression provides additional benefit over compression garments alone . Complex physical therapy , also called complex decongestive physiotherapy , requires further evaluation in r and omized trials . In one r and omized trial no difference in outcomes was detected between compression garments plus manual lymph drainage versus compression garments alone . Clinical experience supports encouraging patients to consider some practical advice regarding skin care , exercise and body weight . [ A patient version of these guidelines appears in Appendix 2 . ] VALIDATION An initial draft of this document was developed by a task force sponsored by the BC Cancer Agency . It was up date d and revised substantially by a writing committee and then su bmi tted for further review , revision and approval by the Steering Committee for Clinical Practice Guidelines for the Care and Treatment of Breast Cancer . SPONSOR The steering committee was convened by Health Canada . COMPLETION DATE : October 2000 UNLABELLED A prospect i ve r and omized study was made of 270 patients with unilateral stage I or II invasive breast cancer treated by segmental resection , axillary dissection and radiation at the University Hospital of Tampere , Finl and , between 1989 and 1991 . The aim of the study was to determine whether there is any advantage or disadvantage if the internal mammary chains ( IMC ) are included in the radiation target volume . The medial and lateral two-field technique was used and the target volumes were determined r and omly either to include the internal mammary chain ( IMC-RT ) or not ( no-IMC-RT ) . The prevalence of radiation pneumonitis was 16 % and there was no significant difference between the IMC- and no-IMC-groups ( 18 vs. 14 % ) . Skin reactions were equal in both groups . Lung fibrosis was more common in the IMC-RT group . IN CONCLUSION radiation of internal mammary chain after conservative surgery does not lead to an increase in clinical ly important skin or pulmonary complications . Whether it prevents recurrences or new primaries of the opposite breast is too early to say because of the short follow-up time Summary 158 evaluable patients with stage II , lymph node positive , carcinoma of the breast were r and omized to adjuvant therapy with either melphalan ( L-PAM ) or cyclophosphamide , methotrexate , and fluorouracil ( CMF ) after mastectomy . In addition , patients were r and omized to be treated with or without post-operative irradiation therapy ( RT ) in addition to their chemotherapy . At a median follow-up time of 11 years , there is no difference in time to relapse ( P=0.69 ) or survival ( P=0.55 ) among the four treatment groups . Multivariate analysis including treatment arm , age , race , tumor size , histologic type , performance status , time to onset of treatment , menopausal status , and number of positive nodes , revealed that only the number of positive nodes ( < 4 vs ≥ 4 ) was related to disease-free and overall survival . Ten year relapse-free survival for patients with < 4 positive nodes compared to those with ≥4 positive nodes was 63 % versus 30 % , and overall survival 63 % versus 41 % , respectively . Patients who received post-operative radiation therapy had significantly less local recurrence than those treated with chemotherapy alone ( P=0.03 ) but without improvement in relapse-free or overall survival . In this trial , post-operative radiation therapy when added to chemotherapy  decreased the risk of local recurrence without adverse effects on survival . Treatment outcome was not influenced by chemotherapy regimen , but differences may have been obscured by the small sample size We studied loco-regional recurrence during follow-up ( median observation time 8 years ) in 1,153 patients , who underwent modified mastectomy and were r and omly assigned to one of the following postoperative treatments ; Premenopausal patients : radiotherapy , cyclophosphamide , or both ; Post-menopausal patients : radiotherapy , tamoxifen , or both .  Recurrence occurred in a total of 419 patients , 123 of whom had loco-regional recurrence with or without distant metastasis . The loco-regional recurrence rate was 7 % in the irradiated subgroups and 17 % in the non-irradiated subgroups , the corresponding cure rates being 43 % and 58 % . Complete remission of all local recurrence was obtained after the first treatment in 67 % of the cases , and was persistent in 67 % of them ( 44 % overall ) . Complete remission was obtained in all patients with local recurrence who received local treatment only , and was persistent in 65 % . Of local recurrences treated with a combination of surgery , radiotherapy and hormone therapy , complete response was obtained in 94 % of the patients , and was persistent in 94 % of them ( 88 % overall ) . Complete remission of all regional recurrence was obtained after the first treatment in 58 % of the patients and was persistent in 67 % of them ( 39 % overall ) . Postoperative radiotherapy reduced not only the total number of loco-regional recurrences but also the number of uncontrolled loco-regional recurrences . Aggressive local treatment would appear to yield both satisfactory initial control and , when combined with the hormone therapy , a high rate of persistent loco-regional control The efficacy of adjuvant treatment with tamoxifen was evaluated in protocol DBCG 77 C. Postmenopausal high risk patients ( tumor greater than 5 cm , positive axillary nodes , or invasion to skin/fascia ) were r and omized after total mastectomy and axillary sampling to postoperative radiotherapy ( control ) or to radiotherapy plus treatment with tamoxifen ( TAM ) , 30 mg daily for 1 year . A total of 1,716 patients entered the study . At 8 years of follow-up , ( 7 years median time of observation ) , we observed a significant increase of recurrence-free survival for the TAM treated group and a reduction in mortality , which is significant for patients less than 70 years of age . Retrospectively , an increased recurrence-free survival in TAM treated patients was significant in the following subgroups : tumor less than 5 cm , positive lymph nodes , anaplasia grade II and estrogen receptor level greater than 100 fmol/mg cytosol protein . In the subsequent trial ( DBCG 82 C ) , 1,347 postmenopausal patients less than 70 years were r and omized to one of the following 3 regimens : radiotherapy + tamoxifen , 30 mg daily for 1 year ( TAM ) , TAM alone , or TAM + CMF ( CMF i.v . day 1 every 4 weeks x 9 ) . The survival is similar in the 3 groups at 4 years ( 2 years median time of observation ) The purpose of this study was to test the role of radiotherapy following total mastectomy , axillary dissection , and adjuvant systemic therapy in the management of operable locally advanced breast carcinoma BACKGROUND Tamoxifen is an anti-estrogen with proven efficacy and low toxicity in the treatment of breast cancer . However , tamoxifen has been shown to exert a number of nonhormonal as well as hormonal effects . One nonhormonal effect of tamoxifen is the induction of transforming growth factor-beta ( TGF-beta ) secretion . TGF-beta has been implicated in the pathogenesis of radiation-induced fibrosis . PURPOSE We investigated the development of lung fibrosis in breast cancer patients who were treated after mastectomy with radiotherapy , with or without simultaneous adjuvant treatment with tamoxifen .  METHODS Data from 196 women were included in the analysis . Eighty-four women were postmenopausal patients who participated in a r and omized trial testing tamoxifen as an adjuvant to postmastectomy radiotherapy .  The radiotherapy technique employed an 8-MV photon field covering the axillary and the infraclavicular and supraclavicular regions of the affected side of the chest ; the chest wall was treated with an abutted electron field . Optical density changes in pretreatment and post-treatment chest x-ray films were used to monitor the development of lung fibrosis ; lung reactions were assessed in the photon-irradiated field only . Logistic regression analysis was used to explore relationships between radiation dose and the development of lung fibrosis in patients either receiving or not receiving tamoxifen . All P values are from two-sided tests . RESULTS Among the 84 women who participated in the r and omized trial of radiotherapy plus tamoxifen ( n = 38 ) versus radiotherapy alone ( n = 46 ) , there was a significant association between tamoxifen treatment and the incidence of marked lung fibrosis ( relative risk = 2.0 ; 95 % confidence interval [ CI ] = 1.2 - 3.5 ; P = .01 ) . When logistic regression analysis was used to evaluate data from all 196 patients , a highly significant relationship was found between the incidence of lung fibrosis and total radiation dose ( P = .0005 ) . In the full analysis , an increased risk of marked lung fibrosis was found again for patients who received tamoxifen simultaneously with radiotherapy ( with patients receiving radiotherapy alone as the referent , odds ratio = 2.9 ; 95 % CI = 1.3 - 6.3 ; P = .007 ) . Patient age and menopausal status did not significantly influence the results . CONCLUSION Tamoxifen treatment during postmastectomy radiotherapy enhances the risk of radiation-induced lung fibrosis . IMPLICATION S In view of pre-existing data , we hypothesize that tamoxifen mediates the enhancement of radiation-induced lung fibrosis through the induction of TGF-beta secretion . If this hypothesis is correct , new strategies might be devised for preventing or reducing radiation-induced fibrosis . Because we studied a relatively small portion of the irradiated lung , we can not recommend changes in current therapeutic measures ; however , we strongly encourage additional studies of lung fibrosis in patients receiving tamoxifen and radiotherapy BACKGROUND AND PURPOSE Some types of radiation therapy have been associated with an increased risk of cardiac mortality and morbidity in patients with early-stage breast cancer . A relationship has been observed between cardiac radiation dose-volume and the level of excess risk of cardiac mortality . However , relatively few data are available on the morbidity from myocardial infa rct ion associated with adjuvant radiotherapy . PATIENTS AND METHODS From 1971 to 1976 , a total of 960 patients with operable breast cancer were r and omly allocated to  preoperative radiation therapy , postoperative radiation therapy or to surgery alone . A previous analysis of the cardiac dose-volumes with the treatment techniques used in the trial indicated that the irradiated patients could roughly be divided into three groups . Information on the number of myocardial infa rct ions was obtained through computerized record linkage with a population -based registry of myocardial infa rct ions in Stockholm County . Information on cause-specific mortality was obtained from the Swedish Cause-of-Death Registry . The median follow-up was 20 years ( range 17 - 23 years ) . RESULTS A total of 58 patients developed an acute myocardial infa rct ion during the period of follow-up . The number of myocardial infa rct ion cases was not significantly different between the three treatment groups . When analyzed according to estimated cardiac radiation dose-volumes , patients in the highest dose-volume subgroup exhibited a hazard of myocardial infa rct ion of 1.3 ( 95 % CI 0.7 - 2.6 ) relative to that of the surgical controls , whereas the corresponding relative hazard for the intermediate and low dose-volume subgroups was below unity . Data on death due to cardiovascular disease showed that patients in the high dose-volume group exhibited a hazard of 2.0 ( 95 % CI 1.0 - 3.9 , P = 0.04 ) relative to that of the surgical controls . Concerning death due to ischemic heart disease , the relative hazard for the same subgroup was 2.5 ( 95 % CI 1.1 - 5.7 , P = 0.03 ) . The difference between the groups was established after 4 - 5 years . The cumulative incidence curves continued to diverge up to about 10 - 12 years . No further divergence appeared after 12 years , but the number of events was low . CONCLUSIONS This analysis confirms and extends previous results from the trial . Cardiac mortality was positively correlated with the cardiac dose-volume . Patients receiving high dose-volumes exhibited an increased mortality of ischemic heart disease , but not of myocardial infa rct ion , which implies another mechanism , e.g. radiation-induced microvascular damage to the heart BACKGROUND Patients with early-stage breast cancer who are at substantial risk for systemic metastases are increasingly treated with breast-conserving therapy and adjuvant chemotherapy . However , the optimal sequencing of chemotherapy and radiation therapy is not clear . METHODS Two hundred forty-four patients with stage I or II breast cancer who were at substantial risk for distant metastases were r and omly assigned to receive a 12-week course of chemotherapy either before or after radiation therapy .  All had had breast-conserving surgery .  The median length of follow-up in surviving patients was 58 months ( range , 10 to 124 ) . RESULTS The five-year actuarial rates of cancer recurrence at any site and of distant metastases in the radiotherapy-first group and the chemotherapy-first group were 38 percent and 31 percent ( P = 0.17 ) and 36 percent and 25 percent ( P = 0.05 ) , respectively . Overall survival was 73 percent and 81 percent ( P = 0.11 ) , respectively . The five-year crude rates of first recurrence according to site in the radiotherapy-first and chemotherapy-first groups , respectively , were 5 percent and 14 percent for local recurrence and 32 percent and 20 percent for distant or regional recurrence or both . This difference in the pattern of recurrence was of borderline statistical significance ( P = 0.07 ) . CONCLUSIONS This study suggests that for patients ar substantial risk for systemic metastases , it is preferable to give a 12-week course of chemotherapy followed by radiation therapy , rather than radiation therapy followed by chemotherapy PURPOSE To assess the cardiac effects of two different cumulative doses of adjuvant doxorubicin and radiation therapy ( RT ) in breast cancer patients . PATIENTS AND METHODS Two hundred ninety-nine breast cancer patients were prospect ively r and omized to receive either five cycles ( CA5 ) or 10 cycles ( CA10 ) of adjuvant treatment with cyclophosphamide ( 500 mg/ m2 ) and doxorubicin ( 45 mg/m2 ) administered by intravenous bolus every 21 days . One hundred twenty-two of these patients also received RT . Estimates of the cardiac RT dose-volume were retrospectively categorized as low , moderate , or high . The risk of major cardiac events ( congestive heart failure , acute myocardial infa rct ion ) was assessable in 276 patients ( 92 % ) , with a median follow-up time of 6.0 years ( range , 0.5 to 19.4 ) . RESULTS The estimated risk ( 95 % confidence interval ) of cardiac events per 100 patient-years was significantly higher for CA10 than for CA5 [ 1.7 ( 1.0 to 2.8 ) v 0.5 ( 0.1 to 1.2 ) ; P=.02 ] . The risk of cardiac events in CA5 patients , irrespective of the cardiac RT dose-volume , did not differ significantly from rates of cardiac events predicted for the general female population by the Framingham Heart Study . In CA10 patients , the incidence of cardiac events was significantly increased ( relative risk ratio , 3.6 ; P < .00003 ) compared with the Framingham population , particularly in groups that also received moderate and high dose-volume cardiac RT . CONCLUSION Conventional-dose adjuvant doxorubicin as delivered in the CA5 regimen by itself , or in combination with locoregional RT , was not associated with a significant increase in the risk of cardiac events . Higher doses of adjuvant doxorubicin ( CA10 ) were associated with a threefold to fourfold increased risk of cardiac events . This appears to be especially true in patients treated with higher dose-volumes of cardiac RT . Larger studies with longer follow-up periods are needed to confirm these results Few studies have evaluated the role of concurrent chemoradiation therapy in the management of locally advanced breast cancer .  The availability of radiosensitizing chemotherapeutic agents that are effective in breast cancer and the encouraging results achieved by concurrent chemoradiation in other malignancies have prompted us to investigate this approach . Paclitaxel is a promising agent for use with concurrent radiotherapy because of its single-agent efficacy profile and its radiosensitizing effects . A clinical protocol of preoperative paclitaxel and radiation in locally advanced breast cancer is ongoing at our institution to test feasibility , measure pathologic response at mastectomy , and explore association of pathologic response with molecular tumor markers . Initially , the study was design ed to test weekly paclitaxel at a dose of 60 mg/m2 during radiation therapy , delivered 5 days a week at 200 cGy fractions to a total dose of 50 Gy over 5 weeks . Due to severe skin toxicity in the first two patients , the protocol was amended to change the scheduling of paclitaxel to 30 mg/m2 twice weekly and to reduce the radiation to 180 cGy fractions to a total dose of 45 Gy , delivered 5 days a week over 5 weeks . Presently , 13 patients have been accrued ; preliminary data indicate good tolerance to twice-weekly paclitaxel , and four of eight evaluable patients have achieved pathologic response ( one patient who received the weekly regimen and three who received the twice-weekly regimen ) . In addition , sequential fine-needle aspirations of palpable breast cancers were obtained in patients enrolled in a parallel study of preoperative single-agent paclitaxel ( 200 mg/m2 every 2 weeks , for a total of four cycles before breast surgery ) . Preliminary results suggest that a steep increase in the mitotic index occurs during the first day after paclitaxel administration and plateaus between the second and the third day , then decreases to pretreatment values . The peak apoptotic index occurs at approximately 72 hours after paclitaxel administration and decreases at approximately 98 hours . These initial findings suggest that twice-weekly dosing of paclitaxel may optimize recruitment of cells into the G2/M phase of the cell cycle , the most radiosensitive phase Late treatment-related morbidity after  mastectomy and adjuvant systemic treatment with and without postoperative irradiation was assessed in 84 patients r and omized in the Danish Breast Cancer Cooperative Group Trials 82b and c. A structured interview and physical examination , using a st and ardized assessment sheet , constructed on the basis of the late effects normal tissues ( LENT ) scoring system , was used . The median length of follow-up from mastectomy was 9 years ( range 6 - 13 years ) . Lymphedema was measured in 14 % , of the irradiated patients versus 3 % of the non-irradiated patients ( NS ) . Slightly decreased shoulder morbidity was measured in 45 % of the irradiated women versus 15 % of the non-irradiated patients , but moderate or more severe impairment was seen in only 5 % of the irradiated patients and in none of the non-irradiated patients ( p = 0.004 ) . Seventeen percent of the irradiated patients and 2 % of the non-irradiated patients found that impairment of shoulder movement caused symptoms ( p = 0.001 ) The lymph nodes of the internal mammary chain represent a primary station draining the lymph from the breast and their removal or their irradiation has been considered an important step in breast cancer treatment . From January 1964 to January 1968 , 737 patients with breast cancer were r and omised at the National Cancer Institute in Milan to undergo either Halsted mastectomy or extended mastectomy with internal mammary node dissection . Patients with non-disseminated carcinoma classified as T1 , T2 , T3 , N0 , N1 were eligible for the study . No patients received postoperative radiotherapy or systemic therapy . After 30 years of follow-up , the overall survival curves and the specific survival curves do not show any difference between the patients of the two groups . Among the 558 patients who died in the 30 year interval period , 395 ( 71 % ) died from breast carcinoma ( 201 in the Halsted group and 194 in the extended mastectomy group ) and 163 from other causes . This study shows that the removal of internal mammary nodes does not improve the survival of patients treated for breast carcinoma . This finding supports the theory that treatment of regional nodes does not influence the survival of cancer patients . The prognostic value of internal mammary node status is , however , high and a biopsy on a selected lymph node should be considered for staging purpose PURPOSE There is concern that breast cancer patients treated with  left-sided radiation therapy ( XRT ) and doxorubicin ( DOX ) may have an increased risk of cardiac toxicity . In addition , the effect of different sequencing of XRT and chemotherapy ( CT ) on the likelihood of cardiotoxicity , as well as cellulitis , arm edema , or brachial plexopathy , is not well understood . We review ed the records of patients treated on a r and omized trial testing the sequencing of CT and XRT  to determine if there was an increase in cardiac events or other complications in patients treated with a total dose of DOX of 180 mg/m2 and XRT , comparing patients with treatment to the left breast and the right breast , and comparing patients treated with initial CT and initial RT . MATERIAL S AND METHODS From June 1984 to December 1992 , 244 patients with clinical stage I or II breast cancer were r and omized following conservative surgery to receive CT ( 4 cycles of CAMFP at 3 week intervals ) either before or after XRT ( 45 Gy to the entire breast , followed by a boost of 16 Gy ; nodal radiation therapy was optional ) . Two hundred thirty-one patients were evaluable for the development of cardiac toxicity . The median age at diagnosis was 45 years ( range , 20 - 68 ) . CT doses were : doxorubicin , 45 mg/m2 IV bolus , d 3 ; methotrexate , 200 mg/m2 IV , d 1 and 15 ; 5-fluorouracil , 500 mg/m2 IV , d 1 ; cyclophosphamide , 500 mg/m2 IV , d 1 ; prednisone 40 mg p.o . , d 1 - 5 . A cardiac event was defined as a myocardial infa rct ion or clinical evidence of congestive heart failure . Median follow-up time was 53 months . RESULTS No cardiac events were observed for patients with either left- or right-sided breast cancer . The sequencing of CT and XRT had no significant effect on the risk of cardiac toxicity , cellulitis , arm edema or brachial plexopathy . CONCLUSIONS We observed no evidence of an increased risk of cardiac toxicity from the addition of left breast tangential irradiation to DOX at a total dose of 180 mg/m2 . Additional follow-up is needed to exclude possible late events . In addition , the sequencing of CT and XRT does not appear to affect the risk of cellulitis , arm edema , or brachial plexopathy PURPOSE To assess patterns of failure and how selected prognostic and treatment factors affect the risks of locoregional failure ( LRF ) after mastectomy in breast cancer patients with histologically involved axillary nodes treated with chemotherapy with or without tamoxifen without irradiation .  PATIENTS AND METHODS The study population consisted of 2,016 patients entered onto four r and omized trials conducted by the Eastern Cooperative Oncology Group . The median follow-up time for patients without recurrence was 12.1 years ( range , 0.07 to 19.1 years ) . RESULTS A total of 1,099 patients ( 55 % ) experienced disease recurrence . The first sites of failure were as follows : isolated LRF , 254 ( 13 % ) ; LRF with simultaneous distant failure ( DF ) , 166 ( 8 % ) ; and distant only , 679 ( 34 % ) . The risk of LRF with or without simultaneous DF at 10 years was 12.9 % in patients with one to three positive nodes and 28.7 % for patients with four or more positive nodes . Multivariate analysis showed that increasing tumor size , increasing numbers of involved nodes , negative estrogen receptor protein status , and decreasing number of nodes examined were significant for increasing the rate of LRF with or without simultaneous DF . CONCLUSION LRF after mastectomy is a substantial clinical problem , despite the use of chemotherapy with or without tamoxifen . Prospect i ve r and omized trials will be necessary to estimate accurately the potential disease-free and overall survival benefits of postmastectomy radiotherapy for patients in particular prognostic subgroups treated with presently used and future systemic therapy regimens The use of adjuvant radiation therapy in breast cancer patients treated with mastectomy and adjuvant chemotherapy  has been controversial . In order to assess the necessity and effectiveness of adjuvant radiation therapy in this setting , we review ed the results in 510 patients with T1-T3 tumors and pathologically positive nodes or tumors larger than 5 cm and negative nodes who were treated with adjuvant chemotherapy . Patients with four or more positive nodes or at least one positive apical node were r and omized to receive either five or ten cycles of cyclophosphamide/Adriamycin ( Adria Laboratories , Columbus , OH ) ( CA ) and patients with one to three positive nodes or operable tumors larger than 5 cm and pathologically negative nodes were r and omized to receive eight cycles of either cyclophosphamide , methotrexate , and 5-fluorouracil ( 5-FU ) ( CMF ) or methotrexate and 5-FU ( MF ) chemotherapy .  Two hundred six of these patients were subsequently rer and omized to receive either no further treatment or adjuvant radiotherapy .  Thirty-five patients withdrew after r and omization , including 34 who declined to receive radiotherapy .  Radiation therapy consisted of 4,500 cGy in 5 weeks to the chest wall and appropriate draining lymph nodes . Median follow-up from chemotherapy r and omization is 45 months for patients in the CA arm and 53 months for those in the CMF/MF arm . The crude rate of local failure ( chest wall or draining lymph node areas ) as first site of failure for patients r and omized to receive chemotherapy only was 14 % ; for those r and omized to receive both chemotherapy and radiotherapy it was 5 % ( P = .03 ) . For patients in the CMF/MF arm , the rate of local failure as the first site of failure was nearly the same for patients r and omized to chemotherapy only as for those r and omized to adjuvant radiotherapy as well ( 5 % v 2 % ) . For patients in the CA arm , the crude rate of local failure was 20 % for patients r and omized to receive chemotherapy only , and 6 % for those r and omized to both types of adjuvant treatment ( P = .03 ) . Among the 43 patients treated with CA who actually received radiotherapy , there was only one local failure , compared with 12 local failures among the 59 patients ( 20 % ) who actually did not receive radiotherapy ( P = .007 ) . No significant difference was seen in disease-free survival or overall survival in either the CA or the CMF/MF arm between patients r and omized to receive radiation therapy and those r and omized to no further treatment . ( ABSTRACT TRUNCATED AT 400 WORDS One hundred fifty‐eight evaluable patients with Stage II carcinoma of the breast with positive lymph nodes were treated either with adjuvant chemotherapy or irradiation therapy followed by chemotherapy . Patients were r and omized to test the effectiveness of L‐phenylalanine mustard ( L‐PAM ) with and without postoperative irradiation therapy ( R.T. ) against cyclophosphamide , 5‐fluorouracil , and methotrexate ( CMF ) with and without postoperative irradiation therapy in decreasing the frequency of recurrence . No significant difference was observed between L‐PAM as compared with R.T. plus L‐PAM ( P = 0.85 ) . The difference between CMF and R.T. plus CMF was significant in support of CMF alone ( P = 0.04 ) . The frequency of recurrence between R.T. plus L‐PAM and R.T. plus CMF showed no difference . A comparison of the chemotherapy only regimens showed an advantage of CMF over L‐PAM ( P = 0.05 ) . Both the delay in starting chemotherapy and the significant decrease in percent optimal drug dosage during the first six cycles of therapy are factors that may influence the high frequency of relapse observed in the R.T. plus chemotherapy groups . Of the four treatments , CMF has the lowest frequency of recurrence BACKGROUND AND PURPOSE This study was performed to investigate whether the tamoxifen ( TAM ) induced the development of pulmonary fibrosis after post-mastectomy cobalt-60 ( Co-60 ) irradiation of chest wall and regional lymphatics in patients with breast cancer along with patient age , menopausal status , body weight , observation time and adjuvant chemotherapy regimens . MATERIAL S AND METHODS In this prospect i ve study , 74 patients treated with post-mastectomy adjuvant radiotherapy ( RT ) and TAM and 37 patients treated with RT were evaluated by axial computerized tomography ( CT ) . CT was first performed before initiation of radiotherapy and TAM treatment . A total of 824 thorax CT sections were evaluated by a radiologist blindly . Comparison of pre-treatment and post-treatment CT sections was used to monitor the development of pulmonary fibrosis . RESULTS Pulmonary fibrosis developed in 26 of 74 patients who were treated with RT and TAM combination . It was found in five of 37 women treated only with RT . The difference was statistically significant ( P<0.01 ) . The median time for the development of pulmonary fibrosis was 8 months in TAM-treated patients whereas it was 10 months in non-TAM-treated patients . Among 111 patients who participated in that study , 65 were in the post-menopausal state and 46 in pre-menopausal state . In the multivariate analysis , the independent prognostic factors were age ( P=0.010 ) and menopausal status ( P=0.019 ) . Advanced age and post-menopausal status predisposed to pulmonary fibrosis . The time interval in the development of lung fibrosis and body weight did not significantly influence the results . The time interval which is one independent prognostic factor was found to be associated with lung fibrosis under only-RT group in multivariate analysis ( P<0.01 ) . CONCLUSION TAM treatment during post-mastectomy RT in breast cancer patients significantly increases the risk of the development of lung fibrosis along with the patient age and menopausal status PURPOSE The objective of this study was to determine locoregional recurrence ( LRR ) patterns after mastectomy and doxorubicin-based chemotherapy to define subgroups of patients who might benefit from adjuvant irradiation .  PATIENTS AND METHODS A total of 1,031 patients were treated with mastectomy and doxorubicin-based chemotherapy without irradiation on five prospect i ve trials . Median follow-up time was 116 months . Rates of isolated and total LRR ( + /- distant metastasis ) were calculated by Kaplan-Meier analysis . RESULTS The 10-year actuarial rates of isolated LRR were 4 % , 10 % , 21 % , and 22 % for patients with zero , one to three , four to nine , or > /= 10 involved nodes , respectively ( P < .0001 ) . Chest wall ( 68 % ) and supraclavicular nodes ( 41 % ) were the most common sites of LRR . T stage ( P < .001 ) , tumor size ( P < .001 ) , and > /= 2-mm extranodal extension ( P < .001 ) were also predictive of LRR . Separate analysis was performed for patients with T1 or T2 primary disease and one to three involved nodes ( n = 404 ) . Those with fewer than 10 nodes examined were at increased risk of LRR compared with those with > /= 10 nodes examined ( 24 % v 11 % ; P = .02 ) . Patients with tumor size greater than 4.0 cm or extranodal extension > /= 2 mm experienced rates of isolated LRR in excess of 20 % . Each of these factors continued to significantly predict for LRR in multivariate analysis by Cox logistic regression . CONCLUSION Patients with tumors > /= 4 cm or at least four involved nodes experience LRR rates in excess of 20 % and should be offered adjuvant irradiation . Additionally , patients with one to three involved nodes and large tumors , extranodal extension > /= 2 mm , or inadequate axillary dissections experience high rates of LRR and may benefit from postmastectomy irradiation Grade III , node-positive breast cancer carries a high risk of loco-regional relapse after simple mastectomy . A r and omised trial was conducted to assess whether this would be significantly reduced by postoperative radiotherapy .  Between 1985 and 1991 , 76 patients who had undergone a simple mastectomy and axillary sampling , and whose tumours had been found to be grade III and node-positive , were r and omised to receive postoperative radiotherapy to the chest wall and axilla or no further loco-regional treatment . Radiotherapy was delivered with 8 MV X-rays to the axilla and supraclavicular fossa and with 8 MeV electrons to the chest wall , to a dose of 45 Gy in 15 fractions over 3 weeks . All patients have been followed-up until death , or for a minimum of 10 years . All loco-regional recurrences occurred within the first 4 years after mastectomy . There were 26 such events in the 40 patients r and omised to the ' watch ' policy ( 65 % ) , as opposed to 9 out of 36 ( 25 % ) who received radiotherapy ( P<0.01 ) . Ten-year survival was 39 % in the radiotherapy arm as opposed to 25 % in the no radiotherapy arm . Recruitment to the trial was closed in 1991 , when a preliminary safety analysis revealed the size of the effect of radiotherapy , and from then on all node-positive patients with grade III tumours have routinely been given this treatment . Further follow-up has confirmed this finding , as borne out by these 10-year results , which shows that radiotherapy has a significant impact on reducing loco-regional recurrence in patients at high risk after mastectomy . There is an apparent survival benefit although , because of the small numbers in this trial , this has not reached statistical significance Three hundred and twenty‐two women with involvement of axillary lymph nodes following surgery for operable breast cancer were r and omized to receive either postoperative radiotherapy , chemotherapy ( CMF ) or radiotherapy followed by chemotherapy . There was an increase in disease free interval in pre‐ and postmenopausal patients receiving radiotherapy and chemotherapy regardless of the number of nodes involved . However , there was a trend towards an improvement in disease related survival only in those patients with more than three nodes involved BACKGROUND Postmastectomy radiotherapy is associated with a lower locoregional recurrence rate and improved disease-free and overall survival when combined with chemotherapy in premenopausal high-risk breast-cancer patients . However , whether the same benefits apply also in postmenopausal women treated with adjuvant tamoxifen for similar high-risk cancer is unclear . In a r and omised trial among postmenopausal women who had undergone mastectomy , we compared adjuvant tamoxifen alone with tamoxifen plus postoperative radiotherapy . METHODS Between 1982 and 1990 , postmenopausal women with high-risk breast cancer ( stage II or III ) were r and omly assigned  adjuvant tamoxifen ( 30 mg daily for 1 year ) alone ( 689 ) or with postoperative radiotherapy to the chest wall and regional lymph nodes ( 686 ) . Median follow-up was 123 months . The endpoints were first site of recurrence ( locoregional recurrence , distant metastases , or both ) , and disease-free and overall survival . FINDINGS Locoregional recurrence occurred in 52 ( 8 % ) of the radiotherapy plus tamoxifen group and 242 ( 35 % ) of the tamoxifen only group ( p<0.001 ) . In total there were 321 ( 47 % ) and 411 ( 60 % ) recurrences , respectively . Disease-free survival was 36 % in the radiotherapy plus tamoxifen group and 24 % in the tamoxifen alone group ( p<0.001 ) . Overall survival was also higher in the radiotherapy group ( 385 vs 434 deaths ; survival 45 vs 36 % at 10 years , p=0.03 ) . INTERPRETATION Postoperative radiotherapy decreased the risk of locoregional recurrence and was associated with improved survival in high-risk postmenopausal breast-cancer patients after mastectomy and limited axillary dissection , with 1 year of adjuvant tamoxifen treatment . Improved survival in high-risk breast cancer can best be achieved by a strategy of both locoregional and systemic tumour control PURPOSE The purpose was to assess the incidence and clinical manifestations of radiation-induced brachial plexopathy in breast cancer patients , treated according to the Danish Breast Cancer Cooperative Group protocol s. METHODS AND MATERIAL S One hundred and sixty-one recurrence-free breast cancer patients were examined for radiation-induced brachial plexopathy after a median follow-up period of 50 months ( 13 - 99 months ) . After total mastectomy and axillary node sampling , high-risk patients were r and omized to adjuvant therapy .  One hundred twenty-eight patients were treated with postoperative radiotherapy with 50 Gy in 25 daily fractions over 5 weeks . In addition , 82 of these patients received cytotoxic therapy ( cyclophosphamide , methotrexate , and 5-fluorouracil ) and 46 received tamoxifen . RESULTS Five percent and 9 % of the patients receiving radiotherapy had disabling and mild radiation-induced brachial plexopathy , respectively . Radiation-induced brachial plexopathy was more frequent in patients receiving cytotoxic therapy ( p = 0.04 ) and in younger patients ( p = 0.04 ) . The clinical manifestations were paraesthesia ( 100 % ) , hypaesthesia ( 74 % ) , weakness ( 58 % ) , decreased muscle stretch reflexes ( 47 % ) , and pain ( 47 % ) . CONCLUSION The brachial plexus is more vulnerable to large fraction size . Fractions of 2 Gy or less are advisable . Cytotoxic therapy adds to the damaging effect of radiotherapy . Peripheral nerves in younger patients seems more vulnerable . Radiation-induced brachial plexopathy occurs mainly as diffuse damage to the brachial plexus One hundred twenty pathologically confirmed operable Stage III ( T3N0–2 ) breast cancer patients were r and omized to receive either postoperative radiotherapy or chemotherapy , or a combination of these , with or without levamisole immunotherapy . Radiotherapy was given to regional lymph node areas and chest wall . Chemotherapy consisted of 6 cycles of Adriamycin ( doxorubicin ) ( 45 mg/m2 ) , vincristine ( 1.2 mg/m2 ) intravenously , and cyclophosphamide ( 200 mg/m2 for 5 days ) perorally every 4 weeks . Peroral levamisole , 150 mg a day , 2 days weekly , was given as an immunotherapy . The 3‐year results are described in this article . The effect of levamisole on the prognosis can not be evaluated yet because of the short follow‐up period . The disease‐free survival was almost equal in each patient group , however , some benefit was achieved by levamisole ( a shift of disease‐free survival from 12 to 18 months ) . The patients receiving radiotherapy alone had the poorest prognosis : 68 % had a recurrent tumor , and 57 % were alive . In the chemotherapy group , the figures were 53 % and 72 % , respectively . Patients who received a combined treatment had the best prognosis : 13 % had a recurrent tumor , and 90 % survived 3 years . There was a statistically significant difference in the recurrence rate between any single therapy and the combined treatment ( radiotherapy to combined treatment , P < 0.001 , chemotherapy to combined treatment , P ± 0.01 chi‐square test ) . In overall survival , a statistically significant difference was reached between radiotherapy and combination treatment groups ( P < 0.01 , chi‐square test ) . Radiotherapy gave a good local control of the tumor , and chemotherapy  decreased the number of metastases . The nonmetastatic axillary lymph node status and secondary amenorrhea or severe menstrual disturbances were of positive prognostic value . The side effects due to radiotherapy and chemotherapy were moderate and tolerable . The dose of Adriamycin had to be reduced only in four patients . All of the patients receiving chemotherapy had a transient total alopecia . Three of them had nonlethal arrhythmias , and one had skin rash .  Levamisole was found very toxic with 9 cases of transient agranulocytosis , leading to the discontinuation of immunotherapy in 22 of 59 patients . Our results show that radiotherapy controls the tumor only locally and chemotherapy systematic ally , but the best patient‐saving results are achieved with a combination of radiotherapy and chemotherapy . The disease‐free and overall survival are statistically significant , and favor the combined therapy PURPOSE To investigate long-term cardiac sequelae associated with anthracycline use in adjuvant chemotherapy of patients with early breast cancer . PATIENTS AND METHODS All 1,000 patients from three prospect i ve trials of adjuvant chemotherapy containing doxorubicin ( n = 637 , median total dose of 294 mg/m(2 ) ) or not containing the anthracycline ( cyclophosphamide , methotrexate , and fluorouracil [ CMF ] regimen alone , n = 363 ) were analyzed for the relative incidence of congestive heart failure ( CHF ) and myocardial infa rct ion ( MI ) during 14 years of follow-up . The 462 women continuously free of disease as of February 1996 were recalled , and 355 consented to undergo evaluation including 12-lead ECG  and cardiac ultrasound with determination of left ventricular ejection fraction ( LVEF ) to assess the relative incidence of abnormalities in long-term survivors . RESULTS Among the 1,000 patients , there were six cases of CHF and three cases of MI . Cumulative cardiac mortality accounted for 0.4 % ( doxorubicin-treated = 0.6 % ; CMF-treated = 0 ) . Eighteen ( 5 % ) of the 355 patients undergoing cardiac evaluation after median 11 years of follow-up presented systolic dysfunction as defined by pathologic ( < 50 % , n = 8) or borderline ( 50 % to 55 % , n = 10 ) LVEF . Systolic dysfunction was higher in doxorubicin-treated ( 15 of 192 ; 8 % ) than in CMF-treated patients ( three of 150 ; 2 % ) . Breast irradiation had a significant impact on the occurrence of early CHF ( four of 116 ; 3 % ) , but not on systolic dysfunctions . CONCLUSION At longer than 10 years of follow-up , the use of doxorubicin at a total dose commonly applied in regimens of adjuvant chemotherapy does not lead to cardiac clinical sequelae that counter-balance the benefit of treatment in patients with operable breast cancer who may be cured of their disease Background . This analysis was conducted to evaluate the impact of selected clinical , histopathologic , and flow cytometric factors on sites of initial tumor relapse after postmastectomy adjuvant systemic therapy One concern with adjuvant radiation therapy for early breast cancer is the potential risk of increasing intercurrent mortality due to radiation-induced damage of the myocardium . The paper presents an analysis of long-term survival among 960 patients with primary breast cancer included in a r and omized trial of pre- or postoperative radiation therapy ( 45 Gy/5 weeks ) versus surgery alone . All patients were treated with a modified radical mastectomy .  The mean follow-up was 16 years ( range : 13 - 19 years ) . During the entire follow-up period there was an overall survival difference in favor of the irradiated patients that was of borderline significance ( p = 0.09 ) . There was no increase in intercurrent mortality due to any cause . However , when the results were analyzed according to estimated doses of radiation to the myocardium , the subset of patients who received the highest doses , that is , those treated with tangential 60Co fields for left-sided tumors , were found to have a significantly increased risk of death due to ischemic heart disease compared to the surgical controls ( relative hazard : 3.2 , p less than 0.05 ) . No such increase was observed among the patients who received less radiation to the myocardium , that is , whose chest wall and internal mammary nodes were treated with electrons or those with right-sided tumors , irrespective of the treatment technique . It is concluded that cardiovascular mortality associated with radiation therapy for early breast cancer is correlated with the biological dose of radiation to the heart and the irradiated volume . All of the following factors are thus important : laterality of the tumor , portal arrangements , radiation energy , fractionation , and total dose . The study illustrates that an increased cardiovascular mortality can be avoided by the use of appropriate techniques and avoidance of excessive treatment One hundred twenty pathologically confirmed operable Stage III breast cancer patients were r and omized to receive either postoperative radiotherapy or chemotherapy , or a combination of these , with or without levamisole immunotherapy . Radiotherapy was given to regional lymph nodes and chest wall . Chemotherapy consisted of six cycles of vincristine , doxorubicin , and cyclophosphamide . Radiotherapy provided local and chemotherapy systemic control over the tumor , but the best patient‐saving results were achieved with a combination of radiotherapy and chemotherapy . This clinical trial was commenced in 1976 , and the first 60 of 120 patients also received oral levamisole , 150 mg/day , on 2 consecutive days weekly as immunotherapy .  All patients were followed for at least 5 years . At this stage levamisole seems to increase disease‐free and overall survival in all three treatment arms ( radiotherapy , chemotherapy , combined treatment ) . Significance is reached in disease‐free survival ( P = 0.035 ) and overall survival , adjusted for all other treatment modalities ( P = 0.019 ) From 1963 to 1968 , the international group collected 1580 cases of breast cancer , r and omized into two therapeutic groups : radical mastectomy and extended mastectomy .  The data were processed on the UNIVAC 1107 computer of the I.N.S.E.R.M. Computing Center . No significant difference was observed between the two groups in the overall five‐year survival rate . However , a more detailed analysis , according to certain prognostic features , showed that extended mastectomy improved the results in one subgroup : cancers of inner or medial quadrants , axillary N+ . Within this group the difference was highly significant for a smaller subgroup ( 190 patients ) including only tumors T1 and T2 . In conclusion , there is no indication for  extended mastectomy  in any cancers of the outer quadrants or in those of the inner or medial quadrants without axillary involvement . A limited indication for extended mastectomy may be provisionally retained for T1 and T2 cancers of the inner or medial quadrants with axillary involvement In 1971 we began a r and omized trial to compare alternative local and regional treatments of breast cancer , all of which employ breast removal . Life-table estimates were obtained for 1665 women enrolled in the study for a mean of 126 months . There were no significant differences among three groups of patients with clinical ly negative axillary nodes , with respect to disease-free survival , distant-disease -- free survival , or overall survival ( about 57 per cent ) at 10 years . The patients were treated by radical mastectomy , total ( " simple " ) mastectomy without axillary dissection but with regional irradiation , or total mastectomy without irradiation plus axillary dissection only if nodes were subsequently positive . Similarly , no differences were observed between patients with clinical ly positive nodes treated by radical mastectomy or by total mastectomy without axillary dissection but with regional irradiation .  Survival at 10 years was about 38 per cent in both groups . Our findings indicate that the location of a breast tumor does not influence the prognosis and that irradiation of internal mammary nodes in patients with inner-quadrant lesions does not improve survival . The data also demonstrate that the results obtained at five years accurately predict the outcome at 10 years . We conclude that the variations of local and regional treatment used in this study are not important in determining survival of patients with breast cancer BACKGROUND In women with breast cancer , the role of radical mastectomy , as compared with less extensive surgery , has been a matter of debate . We report 25-year findings of a r and omized trial initiated in 1971 to determine whether less extensive surgery with or without radiation therapy was as effective as the Halsted radical mastectomy . METHODS A total of 1079 women with clinical ly negative axillary nodes underwent radical mastectomy , total mastectomy without axillary dissection but with postoperative irradiation , or total mastectomy plus axillary dissection only if their nodes became positive . A total of 586 women with clinical ly positive axillary nodes either underwent radical mastectomy or underwent total mastectomy without axillary dissection but with postoperative irradiation . Kaplan-Meier and cumulative-incidence estimates of outcome were obtained . RESULTS No significant differences were observed among the three groups of women with negative nodes or between the two groups of women with positive nodes with respect to disease-free survival , relapse-free survival , distant-disease-free survival , or overall survival . Among women with negative nodes , the hazard ratio for death among those who were treated with total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.08 ( 95 percent confidence interval , 0.91 to 1.28 ; P=0.38 ) , and the hazard ratio for death among those who had total mastectomy without radiation as compared with those who underwent radical mastectomy was 1.03 ( 95 percent confidence interval , 0.87 to 1.23 ; P=0.72 ) . Among women with positive nodes , the hazard ratio for death among those who underwent total mastectomy and radiation as compared with those who underwent radical mastectomy was 1.06 ( 95 percent confidence interval , 0.89 to 1.27 ; P=0.49 ) . CONCLUSIONS The findings vali date earlier results showing no advantage from radical mastectomy . Although differences of a few percentage points can not be excluded , the findings fail to show a significant survival advantage from removing occult positive nodes at the time of initial surgery or from radiation therapy Two HUNDRED NINETY-THREE PATIENTS were r and omly assigned to three treatment regimens following mastectomy for operable but prognostically unfavorable breast cancer :  L-PAM , CFP , or CFP with radiation therapy . For premenopausal patients an increased risk of recurrence was associated with the presence of unfavorable local signs , large number of lymph nodes involved , greater body weight , younger age , and L-PAM treatment . For the postmenopausal patients only three factors were associated with an increased risk of recurrent disease : large tumor size , large number of lymph nodes involved , and inner/ central location of the primary lesion . Specifically , the treatment employed has shown no effect . Of particular importance is the fact that for neither group of patients does our experience presently demonstrate clear association of recurrent disease with the level of drug dose administered . Furthermore , evidence suggests that although patients who experience little or no myelosuppression have significantly worse disease-free intervals than patients who experience moderate or severe myelosuppression , there is no benefit for severe myelosuppression over moderate , myelosuppression BACKGROUND Irradiation after mastectomy can reduce locoregional recurrences in women with breast cancer , but whether it prolongs survival remains controversial . We conducted a r and omized trial of radiotherapy after mastectomy in high-risk premenopausal women , all of whom also received adjuvant systemic chemotherapy with cyclophosphamide , methotrexate , and fluorouracil ( CMF ) . METHODS A total of 1708 women who had undergone mastectomy for pathological stage II or III breast cancer were r and omly assigned to receive eight cycles of CMF plus irradiation of the chest wall and regional lymph nodes ( 852 women ) or nine cycles of CMF alone ( 856 women ) . The median length of follow-up was 114 months . The end points were locoregional recurrence , distant metastases , disease-free survival , and overall survival . RESULTS The frequency of locoregional recurrence alone or with distant metastases was 9 percent among the women who received radiotherapy plus CMF and 32 percent among those who received CMF alone ( P<0.001 ) . The probability of survival free of disease after 10 years was 48 percent among the women assigned to radiotherapy plus CMF and 34 percent among those treated only with CMF ( P<0.001 ) . Overall survival at 10 years was 54 percent among those given radiotherapy and CMF and 45 percent among those who received CMF alone ( P<0.001 ) . Multivariate analysis demonstrated that irradiation after mastectomy significantly improved disease-free survival and overall survival , irrespective of tumor size , the number of positive nodes , or the histopathological grade . CONCLUSIONS The addition of postoperative irradiation to mastectomy and adjuvant chemotherapy reduces locoregional recurrences and prolongs survival in high-risk premenopausal women with breast cancer PURPOSE To determine the prevalence of and contributing factors for chronic arm morbidity including lymphedema in breast cancer patients after treatment and to assess the impact of arm morbidity on quality of life ( QOL ) . PATIENTS AND METHODS A four- question screening question naire was developed and mailed to a r and om sample of 744 breast cancer patients treated curatively in two cancer centers from 1993 to 1997 . Patients were without recurrence and at least 2 years from diagnosis . Respondents were classified as with or without arm-related symptoms on the basis of the survey . Stratified r and om sample s from each group were then invited for a detailed assessment of their symptoms and signs , including the presence of lymphedema . Their QOL was assessed by the European Organization for Research and Treatment of Cancer QOL Question naire C-30  and by a detailed arm problem question naire that assessed various aspects of daily arm functioning . RESULTS Approximately half of all screened patients were symptomatic and 12.5 % of all assessed patients had lymphedema . Axillary dissection ( AD ) and axillary radiotherapy ( RT )  after dissection were statistically significantly related to the occurrence of arm symptoms ( odds ratio for AD = 3.3 , P < .001 ; odds ratio for RT = 3.1 , P < .001 ) . Symptomatic patients and patients with lymphedema both had impaired QOL compared with asymptomatic patients . CONCLUSION Treatment for breast cancer is associated with considerable arm morbidity , which has a negative impact on QOL . Arm morbidity should be carefully monitored in future studies involving local treatment modalities for breast cancer PURPOSE To explore prognostic factors for locoregional failures ( LRF ) among women treated for invasive breast cancer within clinical trials of adjuvant therapies . PATIENTS AND METHODS The study population consisted of 5,352 women who were treated with a modified radical mastectomy and enrolled in one of seven International Breast Cancer Study Group r and omized trials . A total of 1,275 women with node-negative disease received either no adjuvant therapy or a single cycle of perioperative chemotherapy , and 4,077 women with node-positive disease received adjuvant chemotherapy of at least 3 months ' duration and /or tamoxifen . Median follow-up is 12 to 15.5 years . RESULTS In women with node-negative disease , factors associated with increased risk of LRF were vascular invasion ( VI ) and tumor size greater than 2 cm for premenopausal and VI for postmenopausal patients . Of the 1,275 patients , 345 ( 27 % ) met criteria for the highest risk groups , and the 10-year cumulative incidences of LRF with or without distant metastases were 16 % for premenopausal and 19 % for postmenopausal women . For the node-positive cohort , number of nodes and tumor grade were factors for both menopausal groups , with additional prediction provided by VI for premenopausal and tumor size for postmenopausal patients . Of the 4,077 patients , 815 ( 20 % ) met criteria for the highest risk groups , and 10-year cumulative incidences were 35 % for premenopausal and 34 % for postmenopausal women . CONCLUSION LRFs are a significant problem after mastectomy alone even for some patients with node-negative breast cancer , as well as after mastectomy and adjuvant treatment for some subgroups of patients with node-positive disease . In addition to number of positive lymph nodes , predictors of LRF include tumor-related factors , such as vascular invasion , higher grade , and larger size In 1984 the GBSG started a multicenter r and omized trial to compare the effectiveness of 6 cycles of cyclophosphamide , methotrexate and fluorouracil ( CMF ) with or without radiotherapy ( RT ) as adjuvant treatment in node-positive breast-cancer patients treated by mastectomy .  During 5 years , 199 patients were r and omized . After a median follow-up of about 9 years , the treatment groups 6 x CMF and 6 x CMF + RT were compared regarding time to recurrence and death . As the first event of failure , we observed locoregional recurrence in 22 patients , distant metastases in 66 patients , a secondary malignancy in 9 patients and death without previous event in 5 patients . For event-free survival ( EFS ) , no significant difference was observed [ relative risk ( RR ) 6 x CMF + RT vs. 6 x CMF 0.82 , 95 % confidence interval ( CI ) 0.55 - 1.21 ] . Event-specific analysis showed a significant decreased risk after radiotherapy for locoregional recurrence . The risk for distant metastases was estimated as slightly decreased and the risk for secondary malignancy and for death without previous event was estimated as increased in treatment group 6 x CMF + RT in comparison with treatment group 6 x CMF , but these effects were not significant . For overall survival ( OS ) and breast-cancer-specific survival ( BCS ) , no significant treatment effect could be demonstrated . There is a beneficial effect of radiotherapy on locoregional recurrence . For EFS and BCS , a tendency in favour of radiotherapy is observed , but this is not significant ; for OS , no difference can be demonstrated , but the power of the study is too low to detect small treatment effects
target: Locoregional PMRT is recommended for women with 4 or more positive axillary lymph nodes .
  The role of PMRT in women with 1 to 3 positive axillary lymph nodes is unclear .
  Locoregional PMRT is generally not recommended for women who have tumours that are less than 5 cm in diameter and who have negative axillary nodes .
background: OBJECTIVE To provide information and recommendations to assist women with breast cancer and their physicians in making decisions regarding the use of locoregional post-mastectomy radiotherapy ( PMRT ) .
  OUTCOMES Locoregional control , disease-free survival , overall survival and treatment-related toxicities .
  To reduce the risk of lymphedema , radiation of the entire axilla should not be used routinely after complete axillary dissection of level I and II lymph nodes .
  The use of modern techniques in radiotherapy planning is recommended to minimize excessive normal tissue exposure , particularly to the cardiac and pulmonary structures .
  Common short-term side effects of PMRT , including fatigue and skin erythema , are generally tolerable and not dose-limiting .
  Severe long-term side effects , including lymphedema , cardiac and pulmonary toxicities , brachial plexopathy , rib fractures and secondary neoplasms , are relatively rare .