Lori J. Pierce

Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials.

Summary Background After breast-conserving surgery, radiotherapy reduces recurrence and breast cancer death, but it may do so more for some groups of women than for others. We describe the absolute magnitude of these reductions according to various prognostic and other patient characteristics, and relate the absolute reduction in 15-year risk of breast cancer death to the absolute reduction in 10-year recurrence risk. Methods We undertook a meta-analysis of individual patient data for 10 801 women in 17 randomised trials of radiotherapy versus no radiotherapy after breast-conserving surgery, 8337 of whom had pathologically confirmed node-negative (pN0) or node-positive (pN+) disease. Findings Overall, radiotherapy reduced the 10-year risk of any (ie, locoregional or distant) first recurrence from 35·0% to 19·3% (absolute reduction 15·7%, 95% CI 13·7–17·7, 2p<0·00001) and reduced the 15-year risk of breast cancer death from 25·2% to 21·4% (absolute reduction 3·8%, 1·6–6·0, 2p=0·00005). In women with pN0 disease (n=7287), radiotherapy reduced these risks from 31·0% to 15·6% (absolute recurrence reduction 15·4%, 13·2–17·6, 2p<0·00001) and from 20·5% to 17·2% (absolute mortality reduction 3·3%, 0·8–5·8, 2p=0·005), respectively. In these women with pN0 disease, the absolute recurrence reduction varied according to age, grade, oestrogen-receptor status, tamoxifen use, and extent of surgery, and these characteristics were used to predict large (≥20%), intermediate (10–19%), or lower (<10%) absolute reductions in the 10-year recurrence risk. Absolute reductions in 15-year risk of breast cancer death in these three prediction categories were 7·8% (95% CI 3·1–12·5), 1·1% (–2·0 to 4·2), and 0·1% (–7·5 to 7·7) respectively (trend in absolute mortality reduction 2p=0·03). In the few women with pN+ disease (n=1050), radiotherapy reduced the 10-year recurrence risk from 63·7% to 42·5% (absolute reduction 21·2%, 95% CI 14·5–27·9, 2p<0·00001) and the 15-year risk of breast cancer death from 51·3% to 42·8% (absolute reduction 8·5%, 1·8–15·2, 2p=0·01). Overall, about one breast cancer death was avoided by year 15 for every four recurrences avoided by year 10, and the mortality reduction did not differ significantly from this overall relationship in any of the three prediction categories for pN0 disease or for pN+ disease. Interpretation After breast-conserving surgery, radiotherapy to the conserved breast halves the rate at which the disease recurs and reduces the breast cancer death rate by about a sixth. These proportional benefits vary little between different groups of women. By contrast, the absolute benefits from radiotherapy vary substantially according to the characteristics of the patient and they can be predicted at the time when treatment decisions need to be made. Funding Cancer Research UK, British Heart Foundation, and UK Medical Research Council.Breast-conserving surgery can excise all detected macroscopic tumor tissue in women with early-stage breast cancer. However, the presence of microscopic tumor foci in the conserved breast of these women, if untreated, may lead to locoregional recurrence and/or life-threatening distant recurrence. Radiotherapy in the conserved breast after surgery may reduce rates of recurrence and breast cancer death more among some groups of women than in others. This meta-analysis assessed the extent to which the absolute reduction by radiotherapy in 10-year risk of first recurrence differs among women with different prognostic and other characteristics and relates the absolute reduction in the 15-year risk of breast cancer death to the absolute reduction in the 10-year recurrence risk. 92 Obstetrical and Gynecological Survey

Ten-Year Results of a Comparison of Conservation with Mastectomy in the Treatment of Stage I and II Breast Cancer

BACKGROUND Breast-conservation therapy for early-stage breast cancer is now an accepted treatment, but there is still controversy about its comparability with mastectomy. Between 1979 and 1987, the National Cancer Institute conducted a randomized, single-institution trial comparing lumpectomy, axillary dissection, and radiation with mastectomy and axillary dissection for stage I and II breast cancer. We update the results of that trial after a median potential follow-up of 10.1 years. METHODS Two hundred forty-seven patients with clinical stage I and II breast cancer were randomly assigned to undergo either modified radical mastectomy or lumpectomy, axillary dissection, and radiation therapy. The 237 patients who actually underwent randomization have been followed for a median of 10.1 years. The primary end points were overall survival and disease-free survival. RESULTS At 10 years overall survival was 75 percent for the patients assigned to mastectomy and 77 percent for those assigned to lumpectomy plus radiation (P = 0.89). Disease-free survival at 10 years was 69 percent for the patients assigned to mastectomy and 72 percent for those assigned to lumpectomy plus radiation (P = 0.93). The rate of local regional recurrence at 10 years was 10 percent after mastectomy and 5 percent after lumpectomy plus radiation (P = 0.17) after recurrences successfully treated by mastectomy were censored from the analysis. CONCLUSIONS In the management of stage I and II breast cancer, breast conservation with lumpectomy and radiation offers results at 10 years that are equivalent to those with mastectomy.

Radiation-Related Heart Disease: Current Knowledge and Future Prospects

INTRODUCTIONIt has been recognized since the 1960s that the heart may bedamaged by substantial doses of radiation [>30 Gray (Gy)],such as used to occur during mantle radiotherapy for Hodg-kin lymphoma. During the last few years, however, evidencethat radiation-related heart disease (RRHD) can occur fol-lowing doses below 20 Gy has emerged from several inde-pendent sources. Those sources include studies of breastcancer patients who received mean cardiac doses of 3 to 17Gy when given radiotherapy following surgery and studiesof survivors of the atomic bombings of Japan who receiveddoses of up to 4 Gy.At doses above 30 Gy, an increased risk of RRHD can be-comes apparent within a year or two of exposure, and the riskincreases with higher radiotherapy dose, younger age at irra-diation, and the presence of conventional risk factors. Atlower doses, the typical latency period is much longer andis often more than a decade. The nature and magnitude ofthe risk following lower doses is not well characterized,and it is not yet clear whether there is a threshold dose belowwhich there is no risk.The evidence regarding RRHD comes from several differ-ent disciplines. The present review brings together informa-tion from pathology, radiobiology, cardiology, radiationoncology, and epidemiology; it summarizes current knowl-edge, identifies gaps in that knowledge, and outlines somepotential strategies for filling them.CURRENT KNOWLEDGEPathologyThe pathological expressions of RRHD documented fol-lowing therapeutic irradiation can be broadly reduced tofour conditions: pericarditis, pericardial fibrosis, diffusemyocardial fibrosis, and coronary artery disease (CAD)(1, 2). Radiation may also cause valvular disease, althoughtheevidence for this isnotasstrong.None of these conditionsis specific to radiation.Radiation-related pericarditis is characterized by an exu-date of a variable amount of protein-rich fluid within thepericardial sac (pericardial effusion). Rapid accumulationof this fluid can, in rare cases, cause potentially fatal cardiactamponade. Almost invariably, fibrin accumulates on the

Ten-Year Multi-Institutional Results of Breast-Conserving Surgery and Radiotherapy in BRCA1/2-Associated Stage I/II Breast Cancer

PURPOSE We compared the outcome of breast-conserving surgery and radiotherapy in BRCA1/2 mutation carriers with breast cancer versus that of matched sporadic controls. METHODS A total of 160 BRCA1/2 mutation carriers with breast cancer were matched with 445 controls with sporadic breast cancer. Primary end points were rates of in-breast tumor recurrence (IBTR) and contralateral breast cancers (CBCs). Median follow-up was 7.9 years for mutation carriers and 6.7 years for controls. RESULTS There was no significant difference in IBTR overall between carriers and controls; 10- and 15-year estimates were 12% and 24% for carriers and 9% and 17% for controls, respectively (hazard ratio [HR], 1.37; P = .19). Multivariate analyses for IBTR found BRCA1/2 mutation status to be an independent predictor of IBTR when carriers who had undergone oophorectomy were removed from analysis (HR, 1.99; P = .04); the incidence of IBTR in carriers who had undergone oophorectomy was not significantly different from that in sporadic controls (P = .37). CBCs were significantly greater in carriers versus controls, with 10- and 15-year estimates of 26% and 39% for carriers and 3% and 7% for controls, respectively (HR, 10.43; P < .0001). Tamoxifen use significantly reduced risk of CBCs in mutation carriers (HR, 0.31; P = .05). CONCLUSION IBTR risk at 10 years is similar in BRCA1/2 carriers treated with breast conservation surgery who undergo oophorectomy versus sporadic controls. As expected, CBCs are significantly increased in carriers. Although the incidence of CBCs was significantly reduced in mutation carriers who received tamoxifen, this rate remained significantly greater than in controls. Additional strategies are needed to reduce contralateral cancers in these high-risk women.

Fractionation for whole breast irradiation: An American society for radiation oncology (ASTRO) evidence-based guideline

PURPOSE In patients with early-stage breast cancer treated with breast-conserving surgery, randomized trials have found little difference in local control and survival outcomes between patients treated with conventionally fractionated (CF-) whole breast irradiation (WBI) and those receiving hypofractionated (HF)-WBI. However, it remains controversial whether these results apply to all subgroups of patients. We therefore developed an evidence-based guideline to provide direction for clinical practice. METHODS AND MATERIALS A task force authorized by the American Society for Radiation Oncology weighed evidence from a systematic literature review and produced the recommendations contained herein. RESULTS The majority of patients in randomized trials were aged 50 years or older, had disease Stage pT1-2 pN0, did not receive chemotherapy, and were treated with a radiation dose homogeneity within ±7% in the central axis plane. Such patients experienced equivalent outcomes with either HF-WBI or CF-WBI. Patients not meeting these criteria were relatively underrepresented, and few of the trials reported subgroup analyses. For patients not receiving a radiation boost, the task force favored a dose schedule of 42.5 Gy in 16 fractions when HF-WBI is planned. The task force also recommended that the heart should be excluded from the primary treatment fields (when HF-WBI is used) due to lingering uncertainty regarding late effects of HF-WBI on cardiac function. The task force could not agree on the appropriateness of a tumor bed boost in patients treated with HF-WBI. CONCLUSION Data were sufficient to support the use of HF-WBI for patients with early-stage breast cancer who met all the aforementioned criteria. For other patients, the task force could not reach agreement either for or against the use of HF-WBI, which nevertheless should not be interpreted as a contraindication to its use.

Development and Validation of a Heart Atlas to Study Cardiac Exposure to Radiation Following Treatment for Breast Cancer

PURPOSE Cardiac toxicity is an important sequela of breast radiotherapy. However, the relationship between dose to cardiac structures and subsequent toxicity has not been well defined, partially due to variations in substructure delineation, which can lead to inconsistent dose reporting and the failure to detect potential correlations. Here we have developed a heart atlas and evaluated its effect on contour accuracy and concordance. METHODS AND MATERIALS A detailed cardiac computed tomography scan atlas was developed jointly by cardiology, cardiac radiology, and radiation oncology. Seven radiation oncologists were recruited to delineate the whole heart, left main and left anterior descending interventricular branches, and right coronary arteries on four cases before and after studying the atlas. Contour accuracy was assessed by percent overlap with gold standard atlas volumes. The concordance index was also calculated. Standard radiation fields were applied. Doses to observer-contoured cardiac structures were calculated and compared with gold standard contour doses. Pre- and post-atlas values were analyzed using a paired t test. RESULTS The cardiac atlas significantly improved contour accuracy and concordance. Percent overlap and concordance index of observer-contoured cardiac and gold standard volumes were 2.3-fold improved for all structures (p < 0.002). After application of the atlas, reported mean doses to the whole heart, left main artery, left anterior descending interventricular branch, and right coronary artery were within 0.1, 0.9, 2.6, and 0.6 Gy, respectively, of gold standard doses. CONCLUSIONS This validated University of Michigan cardiac atlas may serve as a useful tool in future studies assessing cardiac toxicity and in clinical trials which include dose volume constraints to the heart.

Adjuvant bisphosphonate treatment in early breast cancer: meta-analyses of individual patient data from randomised trials

BACKGROUND Bisphosphonates have profound effects on bone physiology, and could modify the process of metastasis. We undertook collaborative meta-analyses to clarify the risks and benefits of adjuvant bisphosphonate treatment in breast cancer. METHODS We sought individual patient data from all unconfounded trials in early breast cancer that randomised between bisphosphonate and control. Primary outcomes were recurrence, distant recurrence, and breast cancer mortality. Primary subgroup investigations were site of first distant recurrence (bone or other), menopausal status (postmenopausal [combining natural and artificial] or not), and bisphosphonate class (aminobisphosphonate [eg, zoledronic acid, ibandronate, pamidronate] or other [ie, clodronate]). Intention-to-treat log-rank methods yielded bisphosphonate versus control first-event rate ratios (RRs). FINDINGS We received data on 18,766 women (18,206 [97%] in trials of 2-5 years of bisphosphonate) with median follow-up 5·6 woman-years, 3453 first recurrences, and 2106 subsequent deaths. Overall, the reductions in recurrence (RR 0·94, 95% CI 0·87-1·01; 2p=0·08), distant recurrence (0·92, 0·85-0·99; 2p=0·03), and breast cancer mortality (0·91, 0·83-0·99; 2p=0·04) were of only borderline significance, but the reduction in bone recurrence was more definite (0·83, 0·73-0·94; 2p=0·004). Among premenopausal women, treatment had no apparent effect on any outcome, but among 11 767 postmenopausal women it produced highly significant reductions in recurrence (RR 0·86, 95% CI 0·78-0·94; 2p=0·002), distant recurrence (0·82, 0·74-0·92; 2p=0·0003), bone recurrence (0·72, 0·60-0·86; 2p=0·0002), and breast cancer mortality (0·82, 0·73-0·93; 2p=0·002). Even for bone recurrence, however, the heterogeneity of benefit was barely significant by menopausal status (2p=0·06 for trend with menopausal status) or age (2p=0·03), and it was non-significant by bisphosphonate class, treatment schedule, oestrogen receptor status, nodes, tumour grade, or concomitant chemotherapy. No differences were seen in non-breast cancer mortality. Bone fractures were reduced (RR 0·85, 95% CI 0·75-0·97; 2p=0·02). INTERPRETATION Adjuvant bisphosphonates reduce the rate of breast cancer recurrence in the bone and improve breast cancer survival, but there is definite benefit only in women who were postmenopausal when treatment began. FUNDING Cancer Research UK, Medical Research Council.

Effect of Radiotherapy After Breast-Conserving Treatment in Women With Breast Cancer and Germline BRCA1/2 Mutations

PURPOSE Recent laboratory data suggest a role for BRCA1/2 in the cellular response to DNA damage. There is a paucity of clinical data, however, examining the effect of radiotherapy (RT), which causes double-strand breaks, on breast tissue from BRCA1/2 mutation carriers. Thus the goals of this study were to compare rates of radiation-associated complications, in-breast tumor recurrence, and distant relapse in women with BRCA1/2 mutations treated with breast-conserving therapy (BCT) using RT with rates observed in sporadic disease. PATIENTS AND METHODS Seventy-one women with a BRCA1/2 mutation and stage I or II breast cancer treated with BCT were matched 1:3 with 213 women with sporadic breast cancer. Conditional logistic regression models were used to compare matched cohorts for rates of complications and recurrence. RESULTS Tumors from women in the genetic cohort were associated with high histologic (P =.0004) and nuclear (P =.009) grade and negative estrogen (P=.0001) and progesterone (P=.002) receptors compared with tumors from the sporadic cohort. Using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity scoring, there were no significant differences in acute or chronic morbidity in skin, subcutaneous tissue, lung, or bone. The 5-year actuarial overall survival, relapse-free survival, and rates of tumor control in the treated breast for the patients in the genetic cohort were 86%, 78%, and 98%, respectively, compared with 91%, 80%, and 96%, respectively, for the sporadic cohort (P = not significant). CONCLUSION There was no evidence of increased radiation sensitivity or sequelae in breast tissue heterozygous for a BRCA1/2 germline mutation compared with controls, and rates of tumor control in the breast and survival were comparable between BRCA1/2 carriers and controls at 5 years. Although additional follow-up is needed, these data may help in discussing treatment options in the management of early-stage hereditary breast cancer and should provide reassurance regarding the safety of administering RT to carriers of a germline BRCA1/2 mutation.

Changes in surgical management resulting from case review at a breast cancer multidisciplinary tumor board.

The treatment of breast cancer requires a multidisciplinary approach, and patients are often referred to a multidisciplinary cancer clinic. The purpose of the current study was to evaluate the impact of this approach on the surgical management of breast cancer.

VARIABILITY OF TARGET AND NORMAL STRUCTURE DELINEATION FOR BREAST CANCER RADIOTHERAPY : AN RTOG MULTI-INSTITUTIONAL AND MULTIOBSERVER STUDY

PURPOSE To quantify the multi-institutional and multiobserver variability of target and organ-at-risk (OAR) delineation for breast-cancer radiotherapy (RT) and its dosimetric impact as the first step of a Radiation Therapy Oncology Group effort to establish a breast cancer atlas. METHODS AND MATERIALS Nine radiation oncologists specializing in breast RT from eight institutions independently delineated targets (e.g., lumpectomy cavity, boost planning target volume, breast, supraclavicular, axillary and internal mammary nodes, chest wall) and OARs (e.g., heart, lung) on the same CT images of three representative breast cancer patients. Interobserver differences in structure delineation were quantified regarding volume, distance between centers of mass, percent overlap, and average surface distance. Mean, median, and standard deviation for these quantities were calculated for all possible combinations. To assess the impact of these variations on treatment planning, representative dosimetric plans based on observer-specific contours were generated. RESULTS Variability in contouring the targets and OARs between the institutions and observers was substantial. Structure overlaps were as low as 10%, and volume variations had standard deviations up to 60%. The large variability was related both to differences in opinion regarding target and OAR boundaries and approach to incorporation of setup uncertainty and dosimetric limitations in target delineation. These interobserver differences result in substantial variations in dosimetric planning for breast RT. CONCLUSIONS Differences in target and OAR delineation for breast irradiation between institutions/observers appear to be clinically and dosimetrically significant. A systematic consensus is highly desirable, particularly in the era of intensity-modulated and image-guided RT.