Radiation therapy in management of breast cancer.

Randomized trials have demonstrated the efficacy of radiation therapy in the treatment of breast cancer. A reduction in the risk of recurrence has been shown in breast conservation for ductal carcinoma in situ and in invasive cancers after breast conservation and mastectomy. The importance of local control in breast cancer is becoming more apparent. Defining the groups of patients who most benefit from the therapy and improving treatment delivery systems to enhance the therapeutic index are ongoing challenges.

Significance of axillary lymph node extranodal soft tissue extension and indications for postmastectomy irradiation.

BACKGROUND: Extranodal soft tissue extension of axillary lymph node metastases (ETE) has been considered an indication for postmastectomy radiotherapy, including the axilla. However, it is unclear whether patients with ETE are at an increased risk of axillary recurrence. METHODS: From a single institutional database of 2362 patients with breast carcinoma treated between 1974-1994, a total of 487 patients who underwent mastectomy for lymph node positive, infiltrating (T1-T3) breast carcinoma was found. All the patients had pathologically confirmed axillary lymph node metastases and negative surgical margins; none had received postoperative irradiation. Of these patients, 50 had histologically documented axillary ETE. Forty-three patients had a minimum follow-up of at least 1 year and comprise the study population. The median follow-up time of surviving ETE positive patients was 79 months. Twenty-five patients (58.1%) received adjuvant systemic therapy. Sites of first failure were local or distant. Local failure was categorized further as chest wall failure, axillary failure, supraclavicular lymph node failure, or internal mammary lymph node failure. RESULTS: For the 43 patients with ETE, the median patient age was 59.5 years (range, 38-81 years) and the median tumor size was 3.6 cm (range, 0.5-12.0 cm). The median number of positive axillary lymph nodes was 6 (range, 1-36 lymph nodes) versus 2 (range, 1-30 lymph nodes) for all T1-T3 ETE positive patients compared with ETE negative patients (P < 0. 001). The risk of ETE increased significantly with increasing numbers of axillary lymph node metastases (P < 0.001). Of the patients with ETE, 16 (37.2%) developed recurrent disease. ETE positive patients with disease recurrence had significantly greater numbers of positive axillary lymph nodes (median, 10 lymph nodes) than those patients who were recurrence free (median, 4 lymph nodes) (P = 0.02). The site of first failure was local in 7 patients (16. 3%) and distant in 9 patients (20.9%). All patients with local recurrence had chest wall failures; there were no isolated lymph node recurrences. The only simultaneous local and distant failure was in one patient presenting with supraclavicular and intraabdominal metastases. CONCLUSIONS: The risk of axillary recurrence, either as an isolated event or as part of simultaneous failure, is extremely low, even in patients with ETE. These data suggest that patients with ETE frequently have higher numbers of positive axillary lymph nodes and on that basis are at risk for local recurrence and as a rule would be considered for postmastectomy irradiation. However, these data suggest that the presence of ETE is not an indication for routine postmastectomy axillary lymph node irradiation.

Radiation therapy and breast cancer.

The role of radiation therapy in the management of breast cancer is well established. Questions remain, however, regarding: 1) which patients derive the most benefit from the addition of radiation in breast conservation for ductal carcinoma in situ (DCIS) and after mastectomy for node-positive invasive cancer; 2) what is the role of brachytherapy in the management of invasive disease, either as primary therapy or as a boost after external beam therapy; and 3) whether radiation fields can be modified given the low rates of local-regional recurrence reported after breast conserving therapy in patients receiving systemic therapy.

Predictors of breast recurrence after conservative surgery and radiation therapy for invasive breast cancer.

The majority of women with breast cancer are adequately treated with breast-conserving surgery and radiation therapy. Although most women need very limited surgery, some require a larger volume of resection to attain a high level of local control, and some might even require a mastectomy. This article summarizes the current state of knowledge concerning the assessment of the adequacy of excision.

Skin recurrences after breast-conserving therapy for early-stage breast cancer.

PURPOSE: To assess the frequency and prognosis of skin recurrences after breast-conserving therapy (BCT) compared with other breast recurrences. MATERIALS AND METHODS: From 1968 to 1986, 1,624 patients with unilateral stage I or II breast cancer treated with BCT at the Joint Center for Radiation Therapy (Boston, MA) underwent gross tumor excision and received a dose of > or = 60 Gy to the tumor bed. Skin recurrences (SR) were defined as breast recurrences without associated parenchymal disease. An invasive breast recurrence with any parenchymal disease noted clinically or radiographically was scored as an other breast recurrence (OBR). Median follow-up for survivors was 137 months. RESULTS: SR represented 8% (18 of 229) of all breast recurrences and occurred in 1.1% of all patients. The outcome after local recurrence was different for patients with SR and invasive OBR. Patients with SR more frequently had uncontrolled local failure (50%; 9 of 18) than did patients with OBR (14%; 26 of 188) (P = .0007). Forty-four percent (8 of 18) of patients with SR had distant metastasis simultaneously or within 2 months of the recurrence compared with 5% (9 of 188) of invasive OBR patients (P < .0001). For patients without distant metastasis at the time of recurrence, the 5-year actuarial rate of development of distant metastasis was 60% for SR patients compared with 39% for invasive OBR patients (P = .07), and the corresponding 5-year actuarial survival rates beyond the time of local failure were 51% and 79%, respectively (P = .06). CONCLUSION: In contrast to other types of invasive breast recurrence after breast-conserving therapy, skin recurrences are rare and are associated with a significantly higher rate of distant metastasis and uncontrolled local disease as well as a lower rate of survival.

Radiation therapy and breast cancer.

Although the role of radiation therapy in the management of ductal carcinoma in situ is somewhat controversial, the benefit of radiation therapy in breast-conserving treatment of early stage invasive breast cancer is well established. Patients undergoing tumor excision with clear margins have low rates of recurrence with radiation therapy whether there is an extensive intraductal component or not. In all patients, there is a significantly higher risk of recurrence without radiation therapy. In patients receiving systemic therapy, the optimal sequence of chemotherapy and radiation therapy is still being defined; however, in patients with positive nodes and negative margins it is now clear that it is preferable to start chemotherapy first.

Effects of exercise on fatigue, physical functioning, and emotional distress during radiation therapy for breast cancer.

PURPOSES/OBJECTIVES: To test the hypothesis that women participating in a walking exercise program during radiation therapy treatment for breast cancer would demonstrate more adaptive responses as evidenced by higher levels of physical functioning and lower levels of symptom intensity than women who did not participate. DESIGN: Experimental, two-group pretest, post-test. SETTING: Two university teaching hospital outpatient radiation therapy departments. SAMPLE: 46 women beginning a six-week program of radiation therapy for early stage breast cancer. METHODS: Following random assignment, subjects in the exercise group maintained an individualized, self-paced, home-based walking exercise program throughout treatment. The control group received usual care. Dependent variables were measured prior to and at the end of radiation therapy. In addition, symptoms were assessed at the end of three weeks of treatment. MAIN RESEARCH VARIABLES: Participation in the walking exercise program, physical functioning fatigue, emotional distress, and difficulty sleeping. FINDINGS: Hypothesis testing by multivariate analysis of covariance, with pretest scores as covariates, indicated significant differences between groups on outcome measures (p < 0.001). The exercise group scored significantly higher than the usual care group on physical functioning (p = 0.003) and symptom intensity, particularly fatigue, anxiety, and difficulty sleeping. Fatigue was the most frequent and intense subjective symptom reported. CONCLUSIONS: A self-paced, home-based walking exercise program can help manage symptoms and improve physical functioning during radiation therapy. IMPLICATIONS FOR NURSING PRACTICE: Nurse-prescribed and -monitored exercise is an effective, convenient, and low-cost self-care activity that reduces symptoms and facilitates adaptation to breast cancer diagnosis and treatment.

Is machine energy (4-8 MV) associated with outcome for stage I-II breast cancer patients?

PURPOSE: To assess the relationship between machine energy (4-8 MV) and treatment outcome in patients treated with conservative surgery and radiation therapy. METHODS AND MATERIALS: Between 1968 and 1985, 1624 patients were treated for clinical Stage I or II invasive breast cancer. The study population was limited to 1380 patients who underwent complete gross excision and received greater than or equal to 60 Gy to the tumor bed. Of these, 1125 were treated on a 4 MV, 153 on a 6 MV, and 102 on an 8 MV linear accelerator. Patients were selected for treatment on the 8 MV machine based on chest wall separations greater than 24 cm. Of patients treated on the 8 MV, netting was used for 42% and bolus was used for 26%. The median dose with bolus was 14 Gy in seven fractions (range: 2-34.2 Gy). Patients treated on the 8 MV accelerator were older, had a higher percentage of clinical T2 tumors, a higher percentage of pathologically positive nodes, and a lower incidence of extensive intraductal component (EIC). Median follow-up times were 130, 153, and 102 months, respectively, for survivors treated on the 4, 6, and 8 MV machines. RESULTS: We analyzed the site and 5-year crude incidence of first failure by machine energy and found the pattern of first failure site (local, nodal, or distant) to be virtually identical for each energy group. Of the local failures, 12 were in the skin of the treated breast, and these failures were evenly distributed by machine energy. We performed a multivariate analysis to adjust for factors known to predict for treatment failure. When adjusted for these other variables, machine energy was not associated with an increased (or decreased) risk of recurrence (RR for 8 MV vs. 4 MV = 0.94, p = 0.7; RR for 6 MV vs. 4 MV = 1.0, p = 0.9). We also analyzed the nature and incidence of treatment complications (rib fracture, radiation pneumonitis, soft tissue necrosis, and brachial plexopathy) and found no significant differences among the three treatment groups when stratified by treatment technique (tangents only vs. three-field). There was also no significant difference in cosmetic outcome at 5 years among the three groups. CONCLUSIONS: We conclude that machine energy over the range of 4 to 8 MV does not significantly affect treatment outcome. Specifically, it was feasible to treat patients with large chest wall separations using an 8 MV machine without an increase in skin recurrences and with the improved dose homogeneity afforded by 8 MV machines as compared with those of lower energies.

Pathologic margin involvement and the risk of recurrence in patients treated with breast-conserving therapy.

BACKGROUND: The relationship between the microscopic margins of resection and ipsilateral breast recurrence (IBR) after breast-conserving therapy for carcinomas with or without an extensive intraductal component (EIC) has not been adequately defined. METHODS: Of 1,790 women with unilateral clinical Stage I or II breast carcinoma treated with radiation therapy as part of breast-conserving therapy, 343 had invasive ductal histology evaluable for an extensive intraductal component (EIC), had inked margins that were evaluable for an review of their pathology slides, and received > or = 60 Gray to the tumor bed; these 343 women constitute the study population. The median follow-up was 109 months. All available slides were reviewed by one of the study pathologists. Final inked margins of excision were classified as negative > 1 mm (no invasive or in situ ductal carcinoma within 1 mm of the inked margin); negative-1 mm, or close carcinoma < or = 1 mm from the inked margin but not at the margin); or positive (carcinoma at the inked margin). A focally positive margin was defined as invasive or in situ ductal carcinoma at the margin in three or fewer low-power fields. The first site of recurrent disease was classified as either ipsilateral breast recurrence (IBR) or distant metastasis/regional lymph node failure. RESULTS: Crude rates for the first site of recurrence were calculated first for all 340 patients evaluable at 5 years, then separately for the 272 patients with EIC-negative cancers and the 68 patients with EIC-positive cancers. The 5-year rate of IBR for all patients with negative margins was 2%; and for all patients with positive margins, the rate was 16%. Among patients with negative margins, the 5-year rate of IBR was 2% for all patients with close margins (negative < or = 1 mm) and 3% for those with negative > 1 mm margins. For patients with close margins, the rates were 2% and 0% for EIC-negative and EIC-positive tumors, respectively; the corresponding rates for patients with negative margins > 1 mm were 1% and 14%. The 5-year rate of IBR for patients with focally positive margins was 9% (9% for EIC-negative and 7% for EIC-positive patients). The 5-year crude rate of IBR for patients with greater than focally positive margins was 28% (19% for EIC-negative and 42% for EIC-positive patients). CONCLUSIONS: Patients with negative margins of excision have a low rate of recurrence in the treated breast, whether the margin is > 1 mm or < or = 1 mm and whether the carcinoma is EIC-negative or EIC-positive. Among patients with positive margins, those with focally positive margins have a considerably lower risk of local recurrence than those with more than focally positive margins, and could be considered for breast-conserving therapy.

Relationship of tumor grade to other pathologic features and to treatment outcome of patients with early stage breast carcinoma treated with breast-conserving therapy.

BACKGROUND: Although histologic grade has previously been described as a predictor of distant failure, it is uncertain whether histologic grade should be used to decide which patients should undergo axillary lymph node dissection and whether grade should be considered as a selection factor for breast-conserving therapy. METHODS: The authors retrospectively analyzed data from 1081 patients with American Joint Committee on Cancer Stage I or II infiltrating ductal carcinoma treated with breast-conserving therapy at the Joint Center for Radiation Therapy between 1970 and 1986. All patients had pathology slides reviewed by one of two study pathologists. Using the Elston modification of the Bloom-Richardson grading system, patients were divided by histologic grade into 3 groups (219 with Grade I, 482 with Grade II, and 380 with Grade III). The median follow-up time for 716 survivors was 134 months. The incidence of various pathologic features was examined with respect to histologic grade. In addition, the 10-year crude rates of failure (by first site) were examined as they related to grade. A polychotomous logistic regression model was used to determine the effect of grade on local and distant failure. RESULTS: High grade tumors tended to be larger, to exhibit more mononuclear cellular reaction and necrosis, and were more likely to be estrogen receptor negative. Patients with high grade tumors were also younger than those with lower grade tumors. The incidence of an extensive intraductal component and lymphatic vessel invasion did not vary significantly by histologic grade. The incidence of pathologic lymph node metastases also did not vary by grade, even when stratified by tumor size. In both univariable and multivariable analyses, the 10-year crude rate of local recurrence was not related to histologic grade (P = 0.44). Distant recurrence rates, however, were significantly higher as grade increased (p = 0.002). CONCLUSIONS: Higher histologic grade predicted an increased incidence of distant recurrence, but not a greater likelihood of axillary lymph node metastases or local recurrence after breast-conserving therapy. The authors conclude that grade should not be used to make decisions regarding local management.

Age-related differences in patients with nonpalpable breast carcinomas.

BACKGROUND: The survival benefit of screening mammography may be influenced by the age of the screened population. The current series examines the influence of age on the clinical, histopathologic, and prognostic features of nonpalpable breast carcinoma. METHODS: Needle localization and biopsy of suspicious mammographic lesions identified 173 breast carcinomas that were occult by physical examination. The mammographic appearance, the tumor histology and size, as well as axillary lymph node and estrogen receptor status of these carcinomas were reviewed. RESULTS: Mammographic findings of a mass or density (without calcifications) were most common (46%) and the majority of tumors were invasive ductal carcinoma (70%). The median age of the patients was 59 years. Tumor histology and mammographic findings varied by age: women with ductal carcinoma in situ (DCIS) had a median age of 50 years, whereas patients with invasive ductal carcinoma without associated intraductal tumor had a median age of 65 years. Both younger age (P = 0.001) and microcalcifications (P = 0.0001) were strongly correlated with DCIS. The mean greatest tumor dimension was 1.34 cm. Axillary metastases were found in 21%, 15%, and 50% of invasive tumors with sizes of < 1 cm, < 2 cm, and > 2 cm, respectively, and were uninfluenced by age. Estrogen receptor analysis of invasive tumors was > 10 fmol/mg in 47% and 84% of women aged < 50 years and > 50 years, respectively. CONCLUSIONS: Mammographically detected lesions in younger women are typified by a higher incidence of DCIS or tumors with an intraductal component. Nonpalpable invasive carcinomas in women < or = 50 years and > 50 years appear to be biologically similar by virtue of axillary lymph node status, although estrogen receptor positive tumors are more common in older patients. These age-related differences may partially account for age-related variations in the survival impact of mammographic screening programs.

Long-term outcome following breast-conserving surgery and radiation therapy.

PURPOSE: To examine the long-term pattern and frequency of recurrences after breast-conserving therapy and whether the outcome was influenced by the era of treatment. METHODS AND MATERIALS: From 1968 to 1986, 1870 patients with unilateral Stage I or II breast cancer were treated at the Joint Center for Radiation Therapy. Of these, 1628 underwent gross tumor excision and received a dose of > 60 Gy to the tumor bed and constituted the study population. Patients were classified as without evidence of disease, dead from other causes (DOC), or by their first site of recurrence. First sites of recurrent disease were categorized as distant/regional (DF/RNF) or local (LR). Local recurrence was defined as the detection of any invasive or in situ carcinoma occurring in the ipsilateral breast and was further categorized as: true recurrence (TR), marginal miss (MM), skin recurrence (S), or elsewhere in the breast (E). Median follow-up in survivors was 116 months. Eighty patients (4.9%) were lost to follow-up at 3-175 months. The population was divided into two time cohorts: 1968-1982 (n = 810), with a median follow-up time of 143 months, and 1983-1986 (n = 792), with a median follow-up time of 95 months. RESULTS: The overall crude rates of ipsilateral breast recurrence were 7.4 and 13.3% at 5 and 10 years, respectively. Crude rates at 5 and 10 years were 5.7 and 9.3% for TR/MM and were 0.9 and 2.8% for E recurrences, respectively. The annual incidence rates for all LR ranged from 0.5-2.4% and was relatively constant after the first year. The annual incidence rates for TR/MM ranged from 0.4 to 1.9%, whereas for E recurrences the range was 0.1-0.7%. The crude rates of DF/RNF were 16.6 and 23.1% at 5 and 10 years, respectively. The annual incidence rates for DF/RNF ranged from 1-5% over all years. Although the magnitude of the incidence was different, DF/RNF recurrence predominated in years 1-3 for both node-positive and node-negative patients. For the 1968-1982 and 1983-1986 cohorts, the 5-year crude rates of ipsilateral breast recurrence were 8.8 and 5.9%, respectively. CONCLUSIONS: Distant and regional nodal failures were the predominant form of recurrence. The annual incidence rate of LR was relatively constant over the first decade. True recurrence/marginal miss was the most frequent type of ipsilateral breast recurrence and was highest during years 2 through 7. The risk of a recurrence elsewhere in the breast increased with longer follow-up and was highest during years 8 through 10. The 5-year crude rate of ipsilateral breast recurrence appeared lower in the 1983-1986 patient cohort compared to the 1968-1982 patient cohort (8.8% vs. 5.9%), but the distributions of site of first failure did not differ significantly (p = 0.13). Any decrease in ipsilateral breast recurrence likely reflects improvements in mammographic and pathologic evaluation, patient selection, and the increased use of reexcision.

Who is being screened for melanoma/skin cancer? Characteristics of persons screened in Massachusetts.

We conducted a survey of persons who voluntarily attended melanoma/skin cancer screenings in Massachusetts in 1987. Of 1219 persons asked to fill out a questionnaire, 1116 (92%) completed it. Our study demonstrates that persons attending the melanoma/skin cancer screening program were, for the most part, at risk for the disease and appropriately selected themselves to be screened. Most were women, well educated (with college or advanced degrees), and white. More than 86% had at least one risk factor for melanoma/skin cancer whereas 78% had at least two risk factors. Future studies are necessary to determine whether our experience can be verified. Additional efforts should try to attract those who are at risk but perhaps are less willing to attend screening programs--men and those of lower socioeconomic status. These efforts can help target screening to those at highest risk and maximize the yield of these public health efforts.

Evaluation of melanoma/skin cancer screening in Massachusetts. Preliminary results.

Although screening for melanoma/skin cancer is theoretically of value, few data are available to evaluate its effectiveness or the value of a visual exam by a dermatologist as a cancer screening tool. From the 2560 persons screened for melanoma/skin cancer in Massachusetts in 1986 and 1987, the authors followed the positive screenees to determine their final diagnosis. The authors obtained information on 85% of these persons, and found nine malignant melanomas, 91 non-melanoma skin cancers, 39 dysplastic nevi, and three congenital nevi. The sensitivity of the visual exam by a dermatologist was 89% to 97% and the predictive value positive was 35% to 75% for skin cancer. The authors conclude that the yield of screening is equivalent to that of other major cancer screening efforts and that the sensitivity and predictive value of the visual examination by the dermatologist is appropriate for a cancer screening tool.

Prophage-mediated production of a bacteriocinlike substance by SP beta lysogens of Bacillus subtilis.

Cultures of Bacillus subtilis lysogenic for the temperature bacteriophage SP beta release "betacin", a bacteriocinlike substance that inhibits B. subtilis strains which do not carry this phage. Production of betacin is blocked by mutations in the bet gene on the prophage and a second phage gene, tol, is apparently involved in making the lysogen itself tolerant to betacin. Mutations in a bacterial gene betR, located on the B. subtilis chromosome between metC and pyrD, render nonlysogens tolerant to betacin.