Second cancers after conservative surgery and radiation for stages I-II breast cancer: identifying a subset of women at increased risk

PURPOSE: To assess the risk and patterns of second malignancy in a group of women treated with conservative surgery and radiation in a relatively contemporary manner for early-stage invasive breast cancer, and to identify a subgroup of these women at increased risk for a second cancer. METHODS AND MATERIALS: From 1978 to 1994, 1,253 women with unilateral Stage I-II breast cancer underwent wide excision, axillary dissection, and radiation. The median follow-up was 8.9 years, with 446 patients followed for >or= 10 years. The median age was 55 years. Sixty-eight percent had T1 tumors and 74% were axillary-node negative. Radiation was directed to the breast only in 78%. Adjuvant therapy consisted of chemotherapy in 19%, tamoxifen in 19%, and both in 8%. Factors analyzed for their association with the cumulative incidence of all second malignancies, contralateral breast cancer, and non-breast cancer malignancy were: age, menopausal status, race, family history, obesity, smoking, tumor size, location, histology, pathologic nodal status, region(s) treated with radiation, and the use and type of adjuvant therapy. RESULTS: One hundred seventy-six women developed a second malignancy (87 contralateral breast cancers at a median interval of 5.8 years, and 98 non-breast cancer malignancies at a median interval of 7.2 years). Nine women had both a contralateral breast cancer and non-breast cancer second malignancy. The 5- and 10-year cumulative incidences of a second malignancy were 5% and 16% for all cancers, 3% and 7% for contralateral breast cancer, 3% and 8%, for all second non-breast cancer malignancies, and 1% and 5%, respectively, for second non-breast cancer malignancies, excluding skin cancers. Patient age was a significant factor for contralateral breast cancer and non-breast cancer second malignancy. Young age was associated with an increased risk of contralateral breast cancer, while older age was associated with an increased the risk of a second non-breast cancer second malignancy. A positive family history increased the risk of contralateral breast cancer, but not non-breast cancer malignancies. The risk of a contralateral breast cancer increased as the number of affected relatives increased. Tamoxifen resulted in a nonsignificant decrease in contralateral breast cancer and an increase in non-breast cancer second malignancies. The 5-and 10-year cumulative incidences for leukemia and lung cancer were 0.08% and 0.2%, and 0.8% and 1%, respectively. There was no significant effect of chemotherapy or the regions treated with radiation on contralateral breast cancer or non-breast cancer second malignancy. The most common types of second non-breast cancer malignancies were skin cancers, followed by gynecologic malignancies (endometrial), and gastrointestinal malignancies (colorectal and pancreas). CONCLUSION: The 10-years cumulative incidence of a second cancer in this study was 16%. Young age and family history predicted for an increased risk of contralateral breast cancer, and older age predicted for an increased risk of non-breast cancer malignancy. The majority of patients treated with conservative surgery and radiation with or without adjuvant systemic therapy will not develop a second cancer. Long-term follow-up is important to document the risk and patterns of second cancer, and knowledge of this risk and the patterns will influence surveillance and prevention strategies.     

Second primary in the contralateral breast after treatment of breast cancer.

PURPOSE: To study the potential risk factors for contralateral breast cancer (CBC) in women after treatment of the primary breast cancer. PATIENTS AND METHODS: Between January 1985 and December 1995, records of 1084 breast cancer patients at our institution were analyzed for incidence of CBC. In all the patients a detailed analysis was carried out with respect to age, disease stage, radiation therapy technique, dose, the use of chemotherapy or hormone therapy, and other clinical and/or pathologic characteristics. The Kaplan-Meier method was used to estimate the acturial rate of CBC. The Cox proportional hazard regression model was used to estimate the relative risk (RR) of CBC. RESULTS: Up to December 2005, the median follow up was 12 years. Overall incidence of CBC was 4%. The 10 and 20 year acturial rate of CBC was 5.6% and 11.3%, respectively. The CBC rate at 10 and 20 year was 5.4% and 10.2%, respectively, for patients with mastectomy only and 5.1% and 9.7%, respectively, in the mastectomy plus RT group (p=0.3). In the subset of patients <45 years of age at the time of treatment, 10 and 20 year acturial rate of CBC was 5% and 9%, respectively, for patients who underwent mastectomy only and 6.3% and 11%, respectively, for patients treated with mastectomy plus RT (RR=1.4, 95% CI: 1.14-1.45, p=0.003). There was statistically significant lower rate of CBC in patients given adjuvant hormonal therapy (8.5%) as compared to those without hormonal therapy (14.3%, p=0.004) at 20 year. Women with family history of breast cancer had highest rate (15.3%) of CBC (RR=1.6, 95% CI: 1.12-1.27) at 20 years. The adjuvant use of chemotherapy did not significantly affect the risk of second malignancy. CONCLUSION: There seems to be little risk of second malignancies in patients treated with mastectomy plus RT using modern techniques, compared with mastectomy only, that was only prevalent in patients <45 years of age. Family history of breast cancer seems to be the highest risk factor for CBC.     

Prognosis after local recurrence after conservative surgery and radiation for early-stage breast cancer

PURPOSE: To determine the long-term prognosis of patients who develop a local recurrence (LR) after conservative surgery (CS) and radiation therapy (RT) for early-stage invasive breast cancer. METHODS AND MATERIALS: Between 1970 and 1987, 2102 patients with clinical Stage I-II breast cancer were treated with CS+RT. LR was defined as any recurrence within the ipsilateral breast with or without simultaneous regional nodal or distant metastasis. Patients were at risk for a LR until the first of distant metastases, second nonbreast malignancy, or death (DF/S/D). The final study population comprised 341 patients with LR. The median time to LR was 72 months. The median follow-up time after LR was 85 months. A proportional hazards model of time from LR to DF/S/D was done to investigate the influence of factors at initial diagnosis and at LR on subsequent outcome. RESULTS: The actuarial freedom from DF/S/D 5 years after LR was 65% and the survival was 81%. Variables significantly associated with time to DF/S/D were: LR histology (invasive vs. ductal carcinoma in situ, hazard ratio [HR] = 4.1, p < 0.0001); local therapy for LR (none vs. mastectomy or unknown, HR = 3.2, p < 0.0001; and CS +/- RT vs. mastectomy or unknown, HR = 2.0, p = 0.02); time to LR (< or =2 years vs. >5 years, HR = 2.6, p < 0.0001; and 2-5 years vs. >5 years, HR = 1.8, p = 0.006); and age at initial diagnosis (> or =60 vs. <60, HR = 1.6, p = 0.01). CONCLUSIONS: Many patients with LR after CS+RT have prolonged distant disease-free survival, particularly those able to be treated with mastectomy. Patients with a noninvasive LR, longer interval to LR, or age <60 had a longer time to distant failure, second malignancy, or death than other patients.     

Second malignancies after prostate brachytherapy: incidence of bladder and colorectal cancers in patients with 15 years of potential follow-up

PURPOSE: To report the incidence of second bladder and colorectal cancers after prostate brachytherapy. METHODS AND MATERIALS: This review included 125 patients treated with I-125 brachytherapy alone, and 223 patients who received supplemental external beam radiation therapy. Median follow-up was 10.5 years. Patients were followed for the development of lower genitourinary and colorectal cancers. Second malignancies arising five years after radiation therapy were defined as being potentially associated with treatment; observed rates were then compared with age-matched expected rates according to Surveillance, Epidemiology, and End Results data. RESULTS: Five years out of treatment, there were 15 patients with a second solid tumor, including bladder cancer (n = 11), colorectal cancer (n = 3), and prostatic urethra cancer (n = 1). The incidence of second malignancy was no different in patients treated with brachytherapy alone (1.6%) vs. those receiving external beam radiotherapy (5.8%, p = 0.0623). There were more observed bladder cancers compared with those expected (relative risk, 2.34, 95% confidence interval 0.96-3.72; absolute excess risk 35 cancers per 10,000 patients). Relative risk did not significantly change over increasing follow-up intervals up to 20 years after treatment. CONCLUSIONS: There may be an increased but small risk of developing a second malignancy after radiation therapy for prostate cancer. This outcome could be related to radiation carcinogenesis, but more vigilant screening and thorough workup as a result of radiation side effects and predisposing conditions (e.g., genetic and environmental factors) in many of the patients found to have second malignancies likely contributed to the higher number of observed malignancies than expected.     

High-dose therapy and autologous hematopoietic stem-cell transplantation does not increase the risk of second neoplasms for patients with Hodgkin's lymphoma: a comparison of conventional therapy alone versus conventional therapy followed by autologous hematopoietic stem-cell transplantation.

PURPOSE: To determine the incidence of second malignancies among patients with Hodgkin's lymphoma (HL) treated with autologous hematopoietic stem cell transplantation (AHSCT) compared with patients receiving conventional therapy alone and to identify potential risk factors for their occurrence. PATIENTS AND METHODS: We analyzed data on 1,732 consecutive patients with HL treated at the British Columbia Cancer Agency from 1976 to 2001, including 202 patients undergoing AHSCT. The median follow-up duration was 9.8 years for the whole cohort, 9.7 years for those patients treated with conventional therapy, and 7.8 years from AHSCT. RESULTS: The cumulative incidence of developing any second malignancy 15 years after therapy for HL was 9% (risk ratio = 3.5; P < .001); however, the incidence did not differ between those patients receiving conventional therapy alone compared with those undergoing AHSCT (10% and 8%, respectively; P = .48). In multivariate analysis, the only factor significantly associated with an increased risk of developing any second neoplasm or solid tumor was age > or = 35 years (P < .0001). An increased risk of therapy-induced acute myeloid leukemia and therapy-induced myelodysplastic syndrome was seen for patients aged > or = 35 years (P = .03) and stage III/IV (P = .04). CONCLUSION: Patients with HL are at increased risk of developing a second neoplasm. However, those patients undergoing AHSCT do not seem to be at greater risk compared with those patients receiving conventional therapy alone, at least during the first decade after therapy.     

Long-term outcome after postmastectomy radiation therapy for the treatment of ductal carcinoma in situ of the breast.

Postmastectomy radiation therapy may be recommended for patients with a high risk for local recurrence after mastectomy for ductal carcinoma in situ (DCIS). However, long-term outcomes after postmastectomy radiation therapy are not well described. This study was performed to determine long-term outcomes in patients treated with radiation therapy after mastectomy for DCIS. The authors reviewed the records of all patients with breast cancer treated with postmastectomy radiation therapy between 1978 and 1992. Of 287 total patients treated, three (1%) were for DCIS. These three patients had diffuse microcalcifications on screening mammography. The reason for postmastectomy radiation therapy was a potentially increased risk for local recurrence because of a positive resection margin after mastectomy for DCIS. Surgery consisted of a total mastectomy (n = 2) or a modified radical mastectomy (n = 1). Radiation therapy consisted of 4275-5000 cGy to the chest wall in 200-225 cGy fractions. The energy used was 6-MV photons (n = 2) or 15-MV photons (n = 1). No regional nodal irradiation was used. Bolus was applied to the chest wall every other day in one of the three patients. One patient was treated with a scar boost after chest wall irradiation (boost dose, 1000 cGy; total dose, 5275 cGy). The median age for the three patients was 46 years (range, 41-68 years). No patient received adjuvant chemotherapy or hormonal therapy. With a minimum follow-up of 7.1 years (median, 7.4 years; range, 7.1-19.4 years), no local-regional recurrence or evidence of metastatic disease developed in any of the patients. No long-term complication from radiation therapy was noted, and no contralateral breast cancer developed. All patients were alive and free of relapse at the last follow-up. The use of radiation therapy in this group of three patients has shown no evidence of relapse with a minimum of 7.1 years of follow-up. The authors conclude that radiation therapy may be indicated after mastectomy for DCIS to reduce the risk of recurrence for high-risk patients.     

Supraclavicular radiation for breast cancer does not increase the 10-year risk of stroke

BACKGROUND: Modern radiation techniques, which limit the radiation dose to the heart during treatment for breast cancer, have greatly reduced the risk of radiation-induced cardiac injury. However, the risk of radiation damage to the carotid artery, which is often incidentally included in the supraclavicular radiation field for breast cancer treatment, is not routinely examined, and the technique used to treat this field has not changed significantly from early radiation trials. The purpose of the current study was to compare the incidence of hospitalization for stroke among women with breast cancer treated with supraclavicular radiation with those who received radiation therapy to the breast but not the supraclavicular fossa. METHODS: Data from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database for 5752 women who were diagnosed with American Joint Committee on Cancer (AJCC) Stage I-III nonmetastatic breast cancer between 1988 and 1997 were analyzed. Women included were age > or = 66 years, had known lymph node (LN) status, had tumors measuring < or = 5 cm, underwent breast surgery, and received adjuvant radiation therapy (with or without supraclavicular irradiation). Patients with < 5 years of follow-up were excluded because events in the first 5 years after radiation were unlikely to be radiation induced. A Cox proportional hazards model was used to compare patients with 0 positive LNs (surrogate group for no supraclavicular radiation, n = 5281) with patients with > 4 positive LNs (surrogate for supraclavicular radiation group, n = 471) for the endpoint of hospitalization for stroke. Time-to-event curves were calculated using the conditional Kaplan-Meier method. RESULTS: The median follow-up for the 0 and 4+ LN cohorts were 92 months and 90 months, respectively (minimum of 60 months). The 10-year and 15-year actuarial freedom from hospitalization for stroke was 91% (0 LN) versus 89.5% (4+ LN) and 79% (0 LN) versus 81.6% (4+ LN), respectively (P = .28). Estrogen receptor status was balanced between the 2 cohorts. As expected, the 4+ cohort had more advanced tumors, higher stage, larger tumor size, and higher grade (P < .0001). In multivariate analysis including LN group, year of diagnosis, age, race, type of surgery, stage, tumor size, grade, estrogen receptor status, and Charlson comorbidity score, only increased age (hazard ratio [HR] for ages 70-74 years, 1.6; HR for ages 75-79 years, 2.1; and HR for age 80 + years, 2.7) and increasing comorbidity score were predictive of an increased risk of hospitalization for stroke. CONCLUSIONS: Although patients with nonbreast malignancies treated with higher doses to the carotid arteries have been shown to have an increased risk of carotid injury, no evidence was found that radiation to the carotid delivered during supraclavicular irradiation for breast cancer increases the risk of hospitalization for stroke.     

Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma.

PURPOSE: Although the risk of myelodysplastic syndrome (MDS) has been well-described following autologous bone marrow transplantation (ABMT), the risk of solid tumors has been poorly characterized. We report the incidence and outcome of solid tumors at 10-year follow-up in a large cohort of uniformly treated patients who underwent ABMT for non-Hodgkin's lymphoma (NHL). PATIENTS AND METHODS: Between 1982 and 1997, 605 patients underwent ABMT for B-cell NHL, with uniform conditioning with cyclophosphamide and total-body irradiation followed by reinfusion of autologous bone marrow purged with anti-B-cell monoclonal antibodies. Current information on relapse of disease and second malignancies was obtained via an institutional review board-approved questionnaire sent to the referring oncologists. RESULTS: Forty-two solid tumors, six non-MDS hematologic malignancies, 39 nonmelanoma skin cancers, and 68 cases of MDS/acute myelogenous leukemia (AML) were observed at a median follow-up of 9.5 years. A cumulative incidence model using death as a competing risk found that the 10-year incidence of second malignancy is 21%, with 10.0% non-MDS malignancies. The projected incidence of all malignancies at 15 years is 29%. The principal risk factor for second malignancy is increased age at ABMT (P = .0002). In the entire cohort, 9.6% of patients have died of second malignancy. CONCLUSION: Lengthy follow-up demonstrates a significant incidence of second malignancies after ABMT for NHL. Although the incidence of MDS/AML starts to plateau, the incidence of solid tumors continues to rise. Second malignancies are responsible for a significant fraction of overall mortality following ABMT.     

High risk of subsequent neoplasms continues with extended follow-up of childhood Hodgkin's disease: report from the Late Effects Study Group.

PURPOSE: We present an update of a previously reported Late Effects Study Group cohort of 1,380 children with Hodgkin's disease (HD) diagnosed between 1955 and 1986 in patients aged 16 years or younger. We describe the pattern and incidence of subsequent neoplasms (SNs) occurring with extended follow-up. PATIENTS AND METHODS: Median age at diagnosis of HD was 11.7 years (range, 0.3 to 16.9 years) and at last follow-up was 27.8 years. Median length of follow-up was 17.0 years. RESULTS: An additional 103 SNs were ascertained (total SNs = 212). The cohort was at an 18.5-fold increased risk of developing SNs compared with the general population (standardized incidence ratio [SIR], 18.5, 95% CI, 15.6 to 21.7). The cumulative incidence of any second malignancy was 10.6% at 20 years, increasing to 26.3% at 30 years; and of solid malignancies was 7.3% at 20 years, increasing to 23.5% at 30 years. Breast cancer was the most common solid malignancy (SIR, 56.7). Other commonly occurring solid malignancies included thyroid cancer (SIR, 36.4), bone tumors (SIR, 37.1), and colorectal (SIR, 36.4), lung (SIR, 27.3), and gastric cancers (SIR, 63.9). Risk factors for solid tumors included young age at HD and radiation-based therapy. Thirty-two patients developed third neoplasms, with the cumulative incidence approaching 21% at 10 years from diagnosis of second malignancy. CONCLUSION: Additional follow-up of this large cohort of HD survivors documents an increasing occurrence of known radiation-associated solid tumors, (breast and thyroid cancers), as well as emergence of epithelial neoplasms common in adults, (colon and lung cancers) at a younger age than expected in the general population, necessitating ongoing surveillance of this high risk population.     

Thymoma is associated with an increased risk of second malignancy.

BACKGROUND: An association between thymoma and second malignancy has been suggested but has not been validated. Whether the relation is due to treatment or to other thymoma-associated conditions is unclear. METHODS: The authors studied 192 consecutive patients with thymoma and compared the incidence of second malignancies with those of 206 patients who underwent thymectomy for nonthymomatous conditions and 1426 patients with nasopharyngeal carcinoma (NPC). Detailed clinicopathologic features of thymoma patients with second malignancies were described. RESULTS: Additional malignancies were detected in 15 of 192 patients (8%) during their clinical courses. The risk for those patients was significantly greater compared with the risk for patients with nonthymomatous conditions (adjusted odds ratio [OR], 3.81; 95% confidential intervals [95%CI], 1.05-13.81; P = 0.042) and patients with NPC (adjusted OR, 4.89; 95%CI, 2.26-10.53; P < 0.0001) after adjustment for age, gender, length of follow-up, myasthenia gravis, and radiation therapy. The occurrence of second malignancies did not correlate with histologic type or stage of thymoma, radiation therapy, or myasthenia gravis. CONCLUSIONS: Thymoma is associated with an increased risk of second malignancy. The association cannot be attributed to the effect of thymectomy or radiation therapy. Patients with thymoma, even if it is benign, should be followed regularly to facilitate the early detection of other malignancies.     

BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patients after lumpectomy and radiation therapy: implications for breast-conserving management in patients with BRCA1/BRCA2 mutations.

PURPOSE: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. PATIENTS AND METHODS: Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences. RESULTS: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P =.03). The median time to IBTR for patients with BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease. CONCLUSION: In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.     

The risk of multiple primary breast and thyroid carcinomas

BACKGROUND: Some studies have suggested that there is an association between breast carcinoma and thyroid carcinoma. Because ionizing radiation is a well known risk factor for breast and thyroid carcinomas, the authors studied the effect of the radiation dose delivered for the treatment of each of these two malignancies on the risk of subsequently developing the other malignancy. METHODS: The risk of developing thyroid carcinoma subsequent to treatment for breast carcinoma was analyzed in 8 patients (cases) and 192 matched control patients (controls) nested in a cohort of 7711 women who were treated at Institut Gustave Roussy between 1954 and 1983. The risk of developing breast carcinoma after treatment for thyroid carcinoma was studied in a cohort of 2365 women who were treated in 3 French cancer centers between 1934 and 1995. RESULTS: Six of 8 patients with breast carcinoma (75%) who developed thyroid carcinoma and 71% of patients in the control group received radiation therapy during their treatment. The median dose to the thyroid was 6.6 grays (Gy) in the case group and 9.4 Gy in the control group. The overall relative risk of thyroid carcinoma associated with radiation therapy was 1.2 (95% confidence interval, 0.2-6.2). No relation was observed between the radiation dose and the risk of thyroid carcinoma (P = 0.8). Among 2365 women who were treated for thyroid carcinoma, 48 women developed a subsequent breast carcinoma. A significant excess of breast carcinoma was observed among women younger than 59 years at the time of diagnosis of breast carcinoma compared with women in the same age group in the general population. The mean absorbed dose delivered to the breasts by (131)I and external radiation therapy was 0.7 Gy. No relation was found between the radiation dose and the risk of breast carcinoma (P = 0.8). CONCLUSIONS: The previously reported excess incidence of breast carcinoma after thyroid carcinoma was not related to radiation treatment with (131)I and/or external radiation therapy. Radiation therapy for breast carcinoma did not increase the risk of subsequent thyroid carcinoma.     

Long-term outcome after postmastectomy radiation therapy for breast cancer patients at high risk for local-regional recurrence

PURPOSE: Postmastectomy radiation therapy is often recommended for patients at high risk for local-regional recurrence after mastectomy. However, long-term outcomes after radiation therapy are not well described. PATIENTS AND METHODS: Between 1977 and 1992, 221 patients at high risk for local-regional recurrence of breast cancer after mastectomy were treated with radiation therapy, with or without adjuvant systemic therapy. Patients were classified as high risk because of T3 or T4 tumors (14%), positive lymph nodes (29%), close or positive margins of resection (15%), or multiple risk factors (39%); 4% did not meet current criteria for radiation therapy. The median age of patients was 51 years. Radiation therapy consisted of 45 to 50.4 Gy to the chest wall in 1.8 to 2.0 Gy fractions. The regional lymph nodes were treated in 187 patients (85%). There were 151 patients (68%) who received adjuvant chemotherapy. Patients who received chemotherapy were younger (median age, 48 years vs 64 years) and had more positive lymph nodes (median, 5 vs 1) than patients not receiving chemotherapy. Adjuvant hormonal therapy was utilized in 116 patients (53%). The median follow-up was 4.3 years. RESULTS: The actuarial 10-year local-regional failure rate was 11% (95% CI: 6.5% to 16.7%). The site of first failure was distant metastases in 75 patients (34%), local-regional recurrence in 11 patients (5%), and both sites in three patients (1%); 60% had no evidence of disease at last follow-up. Of the patients who presented with local-regional recurrence as first failure, nine patients (82%) subsequently developed metastatic disease. The median time to local-regional first failure was 1.3 years. The median time to distant metastases after local-regional first failure was 0.3 years. DISCUSSION: Postmastectomy radiation therapy is associated with an 89% rate of local-regional control in this high-risk population. Patients who experience a local-regional recurrence after radiation therapy are at a very high risk for metastatic disease. Radiation therapy after mastectomy is recommended to optimize local-regional control for high-risk breast cancer patients.     

Cardiovascular death and second non-breast cancer malignancy after postmastectomy radiation and doxorubicin-based chemotherapy

PURPOSE: To assess the incidence of long-term toxicity after postmastectomy radiation and doxorubicin-based adjuvant chemotherapy. METHODS: Records of 470 patients treated with mastectomy, doxorubicin-based chemotherapy, and postmastectomy radiation in five institutional prospective trials were retrospectively reviewed. Actuarial toxicity rates were compared with those of 1031 patients treated with mastectomy and doxorubicin-based chemotherapy who did not receive postmastectomy radiation. For those treated with radiation, the chest wall received a median dose of 55 Gy with Co-60 (42%) or electrons (51%). Adjuvant chemotherapy consisted of a doxorubicin-based regimen, often followed by 2 years of cyclophosphamide, methotrexate, and fluorouracil. RESULTS: Median follow-up was 10 years. The overall 10-year actuarial rates of RTOG toxicity Grade >1 and >or=3 after radiation were 4% and 2%, respectively. The overall 10- and 15-year actuarial rates of second non-breast cancer malignancy were 3.8% and 7%, respectively. There was no statistical difference between the rates of non-breast cancer second malignancy in the radiated and unirradiated cohorts (3.4% vs. 4.7% 10-year actuarial rates). Increasing age and treatment with >10 cycles of chemotherapy were associated with higher rates of second malignancy (p = 0.025, p = 0.016). The 10-year actuarial rate of death from myocardial infarction (MI) was 2.4% (eight events) and 0.5% (five events) in the radiated and unirradiated groups, respectively (p = 0.058). Of the 8 irradiated patients who died of MI, 2 patients had left-sided breast cancer. CONCLUSIONS: We found very low rates of serious sequelae after postmastectomy radiation, including death from myocardial infarction and non-breast cancer second malignancy. The rate of second non-breast cancer malignancy was increased among patients treated with >10 cycles of cyclophosphamide-containing chemotherapy.     

Second nonbreast malignancies after conservative surgery and radiation therapy for early-stage breast cancer

PURPOSE: Breast cancer patients treated with conservative surgery and radiation therapy are at risk of developing second nonbreast malignancies (SNBMs). The purpose of this study was to determine the incidence of all SNBMs and SNBMs by specific location among long-term survivors and to compare the risk of these events to the age-specific incidence of malignancies as first cancers in the Surveillance Epidemiology and End-Results Program (SEER) population. METHODS AND MATERIALS: We analyzed the likelihood of SNBM development for 1884 patients with clinical Stage I or II breast cancer treated with gross excision and > or = 60 Gy (median 63) to the breast between 1970 and 1987. Fifty-seven percent received supraclavicular/axillary radiation (median dose 45 Gy, range 20-60) and 28% received systemic therapy. The median age at diagnosis was 52 years. The median clinical tumor size was 2 cm. Patients were considered at risk of an SNBM until the development of the first of distant metastases or contralateral breast cancer or death or, if alive and disease-free, until the last follow-up visit. The expected numbers of cancers were obtained from the SEER database, using the age-specific incidence for white women within 5-year age groups and 5-year calendar intervals. The median time at risk for an SNBM was 10.9 years (range 0.2-27.9). RESULTS: By 8 years of follow-up, 432 patients (23%) had developed distant metastases, 295 patients (16%) a local/regional recurrence, and 159 (8%) a contralateral primary. Of the 1884 patients in our cohort, 147 (8%) developed an SNBM compared with the 127.7 expected from SEER. This corresponds to an absolute excess of 1% of the study population and a relative increase of 15% greater than that expected from SEER (p = 0.05). Within the first 5 years, the observed and expected rates of SNBMs were identical (47 vs. 46.9). After 5 years, 24% more SNBMs were observed than expected (100 vs. 80.8, p = 0.02). Among patients <50 years old at breast cancer diagnosis, 43% more observed SNBMs occurred than expected (40 vs. 28, p = 0.02). For patients > or = 50 years, 7% more SNBMs were observed than expected (107 vs. 99.7, p = 0.25). Lung SNBMs were observed in 33 women, 52% more than the 21.67 predicted by SEER (p = 0.01). Most of the lung SNBMs occurred >5 years after treatment (n = 23) and in women who were >50 years at the time of their breast cancer diagnosis (n = 27). The observed incidence of ovarian cancer was significantly greater than expected among patients <50 years (7 vs. 1.96, p = 0.004) but was not different than expected for patients > or = 50 years (5 vs. 5.3, p = 0.61). Among the 7 sarcomas, 3 developed in the radiation field. CONCLUSIONS: SNBMs occur in a substantial minority (8%) of patients treated with conservative surgery and radiotherapy. However, the absolute excess risk compared with the general population is very small (1%). This excess risk is only evident after 5 years. In particular, a slightly increased incidence of lung SNBMs and a somewhat larger increase in ovarian cancer among younger patients was found. Our data suggest that preventive strategies to reduce the incidence of certain cancers (e.g., smoking cessation and prophylactic oophorectomy) and/or continued monitoring for SNBMs to increase the likelihood of early detection and treatment may be prudent in this population.     

A prospective study of conservative surgery without radiation therapy in select patients with Stage I breast cancer

PURPOSE: The effectiveness of radiation therapy (RT) in reducing local recurrence after breast-conserving surgery (BCS) in unselected patients with early stage invasive breast cancer has been demonstrated in multiple randomized trials. Whether a subset of women can achieve local control without RT is unknown. In 1986, we initiated a prospective one-arm trial of BCS alone for highly selected breast-cancer patients. This report updates those results. METHODS AND MATERIALS: Eighty-seven (of 90 planned) patients enrolled from 1986 until closure in 1992, when a predefined stopping boundary was crossed. Patients were required to have a unicentric, T1, pathologic node-negative invasive ductal, mucinous, or tubular carcinoma without an extensive intraductal component or lymphatic-vessel invasion. Surgery included local excision with margins of at least 1 cm or a negative re-excision. No RT or systemic therapy was given. RESULTS: Results are available on 81 patients (median follow-up, 86 months). Nineteen patients (23%) had local recurrence (LR) as a first site of failure (average annual LR: 3.5 per 100 patient-years of follow-up). Other sites of first failure included 1 ipsilateral axilla, 2 contralateral breast cancers, and 4 distant metastases. Six patients developed other (nonbreast) malignancies. Nine patients have died, 4 of metastatic breast cancer and 5 of unrelated causes. CONCLUSIONS: Even in this highly selected cohort, a substantial risk of local recurrence occurred after BCS alone with margins of 1.0 cm or more. These results suggest that with the possible exception of elderly women with comorbid conditions, radiation therapy after BCS remains standard treatment.     

Local-regional radiation therapy after breast reconstruction: what is the appropriate target volume? A case-control study of patients treated with electron arc radiotherapy and review of the literature

The oncologic safety and cosmetic outcome of immediate breast reconstruction in breast cancer patients requiring radiation therapy remains ill-defined. Between 1980 and 1998, 18 patients were treated at the University of Utah Medical Center with mastectomy, immediate breast reconstruction, and adjuvant radiation therapy delivered via an electron arc technique. A case-control study was performed matching reconstructed patients in a 1:2 ratio with patients undergoing mastectomy without reconstruction, using number of lymph nodes and tumor size. Median follow-up was 61 months for the reconstructed group. Five-year local-regional control, disease-free survival, and overall survival rates were 87%, 58%, and 74% respectively in the reconstructed group, versus 88%, 57%, and 67% respectively in the matched control group. Cosmesis was good/excellent in 11 of 13 living patients (85%). Significant capsular contraction occurred in 18% of prosthetic reconstruction patients, and revisional surgery was required in 24% of prosthetic reconstruction patients. Utilizing the electron arc technique, the median radiation dose to the chest wall at the midlevel of the ribs was 20% of the prescribed dose, and no patient failed deep to the implant. These results suggest that in appropriately selected patients, structures deep to the reconstruction are not at high risk for local-regional recurrence, and immediate breast reconstruction yields comparable local-regional control, disease-free survival, and overall survival rates to nonreconstructed patients, with acceptable cosmetic results.     

State of the Art in Breast Reconstruction

In patients undergoing breast reconstruction after partial and total mastectomy, selecting the appropriate timing as well as the best method of reconstruction are essential to optimize the outcome. At M.D. Anderson Cancer Center, the timing of oncoplastic repair after partial mastectomy defects and breast reconstruction after mastectomy tends to dictate the technique for reconstruction. In patients undergoing repair of a partial mastectomy defect, immediate or delayed repair before radiation therapy allows for the use of the remaining breast tissue to perform the repair. Delayed repair after radiation therapy is usually performed with autologous fat grafting or a flap. Immediate breast reconstruction after mastectomy is preferable for patients with a low risk of requiring postmastectomy radiation therapy (XRT) (stage I breast cancer, some stage II). In patients who are deemed preoperatively to be at an increased risk of requiring XRT (stage II breast cancer), delayed-immediate breast reconstruction may provide an additional option. Delayed-delayed reconstruction may be a consideration in patients known preoperatively to require XRT (stage III breast cancer), to allow for a skin-preserving delayed reconstruction after XRT. Newer techniques for breast reconstruction after mastectomy include one-stage implant, implant-based reconstruction plus acellular dermal matrix, autologous fat grafting after negative suction applied to chest wall, and perforator-based autologous tissue flaps. Often, the decision to perform a partial or total mastectomy depends upon reconstructive issues, not oncology-related considerations. Whether to repair a partial mastectomy defect or perform a total breast reconstruction after mastectomy is one of the most critical decisions in breast reconstruction.     

Sarcoma of the Breast: Outcome and Reconstructive Options

IntroductionSurgery is the mainstay of treatment for all breast sarcomas. The role of adjuvant chemotherapy and radiation therapy has not been clearly defined. The aim of this single-center retrospective study was to analyze prognostic factors, outcome, and recent advances.Materials and MethodsData from 203 patients with all breast sarcomas treated in a single center were collected from 1996 to 2010. Phyllodes tumors and metastatic disease at presentation were excluded from the population. Thirty-six women and 1 man were included in the analysis. Local recurrence, metastatic disease, survival, and reconstructive outcome were evaluated.ResultsThirty-four patients out of 37 (91.9%) had an angiosarcoma and 3 had a stromal sarcoma (8.1%). Twenty-one patients (56.8%) had previously undergone breast radiation therapy for breast carcinoma or lymphoma. Twenty-six patients (70.3%) underwent mastectomy, 14 of whom (53.8%) with breast reconstruction. Thirty-six patients (97.3%) had free margins, 1 (2.7%) had a microscopically focally involved margin after surgery. Five patients received adjuvant chemotherapy and 6 received adjuvant radiation therapy. Median follow-up was 58 months (range, 4-146 months). Twelve sarcoma-related deaths were observed with a 5-year cumulative incidence of 43.4%. Twenty-four sarcoma-related events were observed with a 5-year cumulative incidence of 70.8%. The same figure was 49.7% in patients affected by primary sarcoma and 85.7% in patients with secondary sarcoma (P = .06).ConclusionSecondary sarcomas were associated with a higher risk of events. Patients undergoing breast conservative surgery or reconstruction after mastectomy did not show a worse prognosis compared with patients undergoing mastectomy.     

Recurrence pattern and prognosis in low-risk breast cancer patients--data from the DBCG 89-A programme

The invasive disease free survival, the overall survival, and the relative risk of death compared to the Danish population as well as the risk of recurrence and new malignancies is reported for low-risk breast cancer patients of the DBCG 89-A programme. The study includes a comparison between those patients who, according to the present criteria, would be defined low-risk and those who would be defined high-risk (the retrospective lowhigh-risk group) and a comparison of treatment by mastectomy and BCS combined with radiation therapy. The DBCG 89-A programme scheduled 10 years of follow-up. Data was supplemented by record linkage to the Hospital Discharge Registry (date of event) and the Central Population Registry (date of death). The study population consisted of 8 850 patients. With 12 years of follow-up 3 811 events (43%) were recorded: loco-regional recurrence 8%, distant recurrence 11%, contralateral cancer 6%, secondary cancer 8%, and deaths 11%. The DBCG registry had an incomplete reporting of events in these low-risk patients, due to premature discontinuation of control. The incidence of recurrences was higher for the retrospective low --> high-risk group than for the low-risk group. The 10-year overall survival was 76%; lower in the retrospective low --> high-risk group (71%) than in the low-risk group (83%). The 5-year survival following local recurrence was 68% after mastectomy and 81% after BCS. The risk of mortality was higher than in the general population for all subgroups of patients. The relative risk of mortality expressed in terms of the standardized mortality ratio was 10.4 for young patients (26-39 years) and 1.2 for old patients aged 70-74 years and 1.3 for patients in the retrospective low-risk group and 1.9 for patients in the low --> high-risk group. The loco-regional treatment given did not cure all patients, in particular young patients and those of the retrospective low --> high-risk group.