Penny R. Anderson

Intensity modulated radiation therapy (IMRT) decreases acute skin toxicity for women receiving radiation for breast cancer.

Objective:To determine the clinically observed incidence and severity of acute skin toxicity with breast intensity modulated radiation therapy (IMRT), and compare the results with a matched cohort of patients treated by conventional radiation therapy. Our hypothesis is that measures to decrease dose inhomogeneity within the breast and skin with IMRT will improve acute skin toxicity. Materials and Methods:The study population consists of 73 women with early stage breast cancer treated with breast-conserving surgery and IMRT. The IMRT technique involves an iteration method for optimization to generate the IMRT plan, Monte Carlo dose calculation, and a step-and-shoot technique using multileaf collimation for beam delivery. Other aspects of the technique including the clinical definition of the clinical target volume by the physician, patient positioning, tangential beam orientation, dose and field sizes were unchanged compared conventional tangential radiation. These patients were matched one-to-one to a control group of 60 women treated with conventional photon radiation by using their bra size and chest wall separation. The study end point was acute skin toxicity. Results:There were no observed differences in the acute toxicity based upon common terminology criteria for adverse events (CTC) for acute radiation dermatitis. There was no desquamation in 42% of IMRT patients, dry desquamation in 37% and moist desquamation in 21%. The degree of desquamation was greater for conventional patients compared with IMRT patients −52% grade 0, 10% grade 1, and 38% grade 2 (P = 0.001). Subgroup analysis showed desquamation was significantly lower with IMRT for small (P = 0.038) and large breast sizes (P = 0.037), but not medium sizes (P = 0.454). For large breast sizes, the incidence of moist desquamation grade 2 was 48% with IMRT compared with 79% in controls. Significant predictors of moist desquamation on stepwise logistic regression were use of IMRT (P = 0.0011) and breast size (P < 0.0001). Conclusions:IMRT is associated with a decrease in severity of acute desquamation compared with a matched control group treated with conventional radiation therapy. As with conventional radiation, breast size remains the most important prognostic factor for acute skin toxicity. The CTC grading system for acute radiation dermatitis is not sensitive when applied to modern breast cancer treatment because of its dependence of subjective rating of erythema and inability to gauge variations in desquamation. Further study of patient symptoms, quality of life, and cosmesis is needed to evaluate the benefit of IMRT for breast cancer.

Locoregional recurrence of triple-negative breast cancer after breast-conserving surgery and radiation †‡

The results of radiation on the local control of triple receptor‐negative breast cancer (negative estrogen [ER], progesterone [PR], and HER‐2/neu receptors) was studied.

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.

Breast intensity-modulated radiation therapy reduces time spent with acute dermatitis for women of all breast sizes during radiation.

PURPOSE To study the time spent with radiation-induced dermatitis during a course of radiation therapy for breast cancer in women treated with conventional or intensity-modulated radiation therapy (IMRT). METHODS AND MATERIALS The study population consisted of 804 consecutive women with early-stage breast cancer treated with breast-conserving surgery and radiation from 2001 to 2006. All patients were treated with whole-breast radiation followed by a boost to the tumor bed. Whole-breast radiation consisted of conventional wedged photon tangents (n = 405) earlier in the study period and mostly of photon IMRT (n = 399) in later years. All patients had acute dermatitis graded each week of treatment. RESULTS The breakdown of the cases of maximum acute dermatitis by grade was as follows: 3%, Grade 0; 34%, Grade 1; 61%, Grade 2; and 2%, Grade 3. The breakdown of cases of maximum toxicity by technique was as follows: 48%, Grade 0/1, and 52%, Grade 2/3, for IMRT; and 25%, Grade 0/1, and 75%, Grade 2/3, for conventional radiation therapy (p < 0.0001). The IMRT patients spent 82% of weeks during treatment with Grade 0/1 dermatitis and 18% with Grade 2/3 dermatitis, compared with 29% and 71% of patients, respectively, treated with conventional radiation (p < 0.0001). Furthermore, the time spent with Grade 2/3 toxicity was decreased in IMRT patients with small (p = 0.0015), medium (p < 0.0001), and large (p < 0.0001) breasts. CONCLUSIONS Breast IMRT is associated with a significant decrease both in the time spent during treatment with Grade 2/3 dermatitis and in the maximum severity of dermatitis compared with that associated with conventional radiation, regardless of breast size.

Recursive Partitioning Identifies Patients at High and Low Risk for Ipsilateral Tumor Recurrence After Breast-Conserving Surgery and Radiation

PURPOSE Recursive partitioning analysis (RPA), a method of building decision trees of significant prognostic factors for outcome, was used to determine subgroups at significantly different risk for ipsilateral breast tumor recurrence (IBTR) in early-stage breast cancer. PATIENTS AND METHODS Nine hundred twelve women underwent breast-conserving surgery, axillary dissection, and radiation. Systemic therapy was chemotherapy with or without tamoxifen in 32%, tamoxifen in 27%, or none in 41%. RPA was used to create a decision tree according to predictive variables that classify patients by IBTR risk, and the Kaplan-Meier method was used to calculate 10-year risks. Median follow-up was 5.9 years. RESULTS Age was the first split in the partition tree. Patients more than 55 years old had a 4% 10-year IBTR, the only further division being use of tamoxifen or not (2% v 5%, P =.03). For patients </= 55 years old, extensive intraductal component (EIC) was the next significant split. For EIC-negative tumors, age </= 35 years and negative margins were associated with a 10-year IBTR of 3%; with close (</= 2 mm) or positive margins, 34%. Patients 36 to 55 years old with estrogen receptor-positive tumors receiving tamoxifen had a risk of IBTR of 5%, but had a 20% risk without tamoxifen. CONCLUSION This RPA showed that age </= 55 versus more than 55 years was the most significant factor for IBTR. Patients </= 35 years old had a low risk of IBTR when tumors were EIC-negative with negative margins. EIC was an independent factor for IBTR for ages </= 55 years. Use of tamoxifen was the most significant factor for patients older than 55 years, but it resulted in a greater absolute decrease in risk of IBTR for patients 36 to 55 years old.

Clinical implementation of intensity-modulated tangential beam irradiation for breast cancer.

A Monte Carlo based intensity-modulated radiation therapy (IMRT) treatment planning system has been developed and used for breast treatment. An iterative method was used for optimization to generate IMRT plans and a step-and-shoot technique was used for beam delivery. The patient setup and incident beam directions were the same as those for conventional tangential photon treatment. The weights for the opposed beamlets in the two tangential beams were determined first by the doses at the depths of the maximum dose at both sides to minimize hot spots. The intensity of an individual beamlet pair was then optimized based on the dose at the midplane. Fine tuning was made to achieve optimal target dose uniformity and to reduce the dose to the heart when necessary. The final dose calculations were performed using the Monte Carlo method and the plans were verified by phantom measurements. The dose distributions and dose-volume-histograms of IMRT plans were compared with those of conventional plans that were generated using a commercial treatment planning system and recalculated using an in-house Monte Carlo system for the first 25 patients. The dose comparisons showed that the percentage volume receiving more than 95% of the prescription dose (V95) and the percentage volume receiving more than 100% of the prescription dose (V100) for the clinical target volume (CTV) of IMRT plans were about the same as those of conventional plans. The percentage volume receiving more than 105% of the prescription dose (V105) for the CTV was reduced from 23.1% to 7.9% on average. The percentage volume of the lung receiving more than 20 Gy dose (V20 Gy) during the entire treatment was reduced by about 10%. The percentage volume of the heart receiving more than 30 Gy dose (V30 Gy) is reduced from 3.3% to 0.3%. Further studies revealed that a less than 5 degrees change in couch angle and collimator angle at patient setup had no significant effect on the dose coverage of CTV but had significant effect on the dose to the lung and heart. The study on the effect of beam spoiler showed that it increased the dose at the buildup region by 0- 13% that varies with location. The machine output linearity and stability for small monitor unit delivery of Siemens accelerators used for this study was checked and found to be suitable for breast IMRT. The total effect of variations was calculated to be less than 1% for typical breast treatments. The beam delivery time was increased by about 2 min compared with conventional tangential treatments. The whole treatment including patient setup and beam delivery can be completed in a 15 min slot. The IMRT technique has been proven practical for breast treatment clinically. The results showed that tangential IMRT improved the dose homogeneity in the breast and reduced the dose to the lung and heart.

Perineural invasion and Gleason 7-10 tumors predict increased failure in prostate cancer patients with pretreatment PSA <10 ng/ml treated with conformal external beam radiation therapy.

PURPOSE It has been well established that prostate cancer patients with pretreatment PSA <10 ng/ml enjoy excellent bNED control when treated with definitive external beam radiation therapy. This report identifies predictors of failure for patients with pretreatment PSA <10 ng/ml. These predictors are then used to define favorable and unfavorable prognostic subgroups of patients for which bNED control is compared. METHODS AND MATERIALS Between 3/87 and 11/94, 266 patients with T1-T3NXM0 prostate cancer and pretreatment PSA values <10 ng/ml were treated with definitive external beam radiation therapy. Median central axis dose and median follow-up for the entire group was 72 Gy (63-79 Gy) and 48 months (2-120 months). Predictors of bNED control were evaluated univariately using Kaplan-Meier methodology and the log-rank test and multivariately using Cox proportional hazards modeling. Covariates considered were pretreatment PSA, palpation stage, Gleason score, presence of perineual invasion (PNI) and central axis dose. Independent predictors based on multivariate results were then used to stratify the patients into two prognostic groups for which bNED control was compared. bNED failure is defined as PSA > or = 1.5 ng/ml and rising on two consecutive determinations. RESULTS Univariate analysis according to pretreatment and treatment factors for bNED control demonstrates a statistically significant improvement in 5-year bNED control for patients with Gleason score 2-6 vs. 7-10, patients without evidence of perineural invasion (PNI) vs. those with PNI, and patients with palpation stage T1/T2AB vs. T2C/T3. Multivariate analysis demonstrates that Gleason score (p = 0.0496), PNI (p = 0.0008) and palpation stage (p = 0.0153) are significant independent predictors of bNED control. Based on these factors, patients are stratified into a more favorable prognosis group (Gleason 2-6, no PNI, and stage T1/T2AB, n = 172) and a less favorable prognosis group (Gleason 7-10 or PNI or T2C/T3, n = 94). A comparison of the two groups reveals that bNED control is significantly lower in the less favorable prognosis group (74% vs. 91% at 5 years, p = 0.0024). CONCLUSIONS (1) This report identifies Gleason 7-10 and the presence of PNI as well as palpation stage T2C/T3 as factors that predict worse bNED outcome for patients with pretreatment PSA <10 ng/ml who are treated with radiation therapy alone. (2) Patients with these pretreatment prognostic factors may benefit from adjuvant therapies or altered treatment programs. (3) In order to make fair comparisons between radiation therapy and prostatectomy series, the distribution of perineual invasion and Gleason 7-10 must be taken into account.

Does Axillary Boost Increase Lymphedema Compared With Supraclavicular Radiation Alone After Breast Conservation

PURPOSE To determine independent predictors of lymphedema (LE) after breast radiotherapy and to quantify added risks of LE from regional node irradiation (RNI). MATERIALS AND METHODS A total of 2,579 women with T1-2, N 0-3, M0 breast cancer treated with breast conservation between 1970 and 2005 were studied. A total of 2,169 patients (84%) received radiation to the breast (B), 226 (8.8%) to the breast and supraclavicular LNs (B+SC), and 184 (7.1%) to the breast, supraclavicular LNs, and a posterior axillary boost (B+SC+PAB). Median follow-up was 81 months (range, 3-271). RESULTS Eighteen percent of patients developed LE. LE risks were as follows: 16% (B), 23% (B+SC), and 31% (B+SC+PAB) (p < 0.0001). LE severity was greater in patients who had RNI (p = 0.0002). On multivariate analysis, RT field (p < 0.0001), obesity index (p = 0.0157), systemic therapy (p = 0.0013), and number of LNs dissected (p < 0.0001) independently predicted for LE. In N1 patients, the addition of a SC to tangents (p < 0.0001) and the addition of a PAB to tangents (p = 0.0017) conferred greater risks of LE, but adding a PAB to B+SC RT did not (p = 0.8002). In the N2 patients, adding a PAB increased the risk of LE 4.5-fold over B+SC RT (p = 0.0011). CONCLUSIONS LE predictors included number of LNs dissected, RNI, obesity index, and systemic therapy. LE risk increased when a SC or PAB were added in the N1 subgroup. In the N2 patients, a PAB increased the risk over B+SC. The decision to boost the axilla must be weighed against the increased risk of LE that it imposes.

Postmastectomy chest wall radiation to a temporary tissue expander or permanent breast implant--is there a difference in complication rates?

PURPOSE The purpose of this study was to evaluate the likelihood of complications and cosmetic results among breast cancer patients who underwent modified radical mastectomy (MRM) and breast reconstruction followed by radiation therapy (RT) to either a temporary tissue expander (TTE) or permanent breast implant (PI). METHODS AND MATERIALS Records were reviewed of 74 patients with breast cancer who underwent MRM followed by breast reconstruction and RT. Reconstruction consisted of a TTE usually followed by exchange to a PI. RT was delivered to the TTE in 62 patients and to the PI in 12 patients. Dose to the reconstructed chest wall was 50 Gy. Median follow-up was 48 months. The primary end point was the incidence of complications involving the reconstruction. RESULTS There was no significant difference in the rate of major complications in the PI group (0%) vs. 4.8% in the TTE group. No patients lost the reconstruction in the PI group. Three patients lost the reconstruction in the TTE group. There were excellent/good cosmetic scores in 90% of the TTE group and 80% of the PI group (p = 0.22). On multivariate regression models, the type of reconstruction irradiated had no statistically significant impact on complication rates. CONCLUSIONS Patients treated with breast reconstruction and RT can experience low rates of major complications. We demonstrate no significant difference in the overall rate of major or minor complications between the TTE and PI groups. Postmastectomy RT to either the TTE or the PI should be considered as acceptable treatment options in all eligible patients.

Accuracy of the extent of axillary nodal positivity related to primary tumor size, number of involved nodes, and number of nodes examined.

PURPOSE While a number of studies have evaluated the minimum number of axillary nodes that need to be examined to accurately determine nodal positivity or negativity, there is little information on the number of nodes which must be examined to determine the extent of nodal positivity. This study attempts to determine for patients with 1-3 positive nodes the probability that the number of positive nodes reported is the true number of positive nodes as well as the probability that 4 or more nodes could be positive based on primary tumor size and number of nodes examined. MATERIALS AND METHODS From 1979 to 1998, 1652 women with Stages I-II invasive breast cancer underwent an axillary dissection as part of their breast conservation therapy and had more than 10 lymph nodes examined. The mean and median number of nodes identified in the dissection was 19 and 17 (range, 11-75). The median age was 55 years. A total of 1155 women had T1 tumors and 497 had T2 tumors. Of the 459 node-positive women, 72% had 1-3 positive nodes, 18% had 4-9 positive nodes, and 10% had 10 or more positive nodes. A mathematical model based on tumor size and number of nodes examined was created using the hypergeometric distribution and Bayes Theorem. The resulting model was used to estimate the accuracy of the reported number of positive nodes and the probability of 4 or more positive nodes based on various observed sampling combinations. RESULTS For patients with T1 tumors and 1, 2, or 3 positive nodes, the minimum number of nodes examined needed for a 90% probability of accuracy is 19, 20, and 20. For T2 tumors and 1, 2, or 3 positive nodes, a minimum of 20 nodes is required. The probability of 4 or more positive nodes increases as tumor size and the number of reported positive nodes increase and as the number of examined nodes decreases. For a 10% or less probability of 4 or more positive nodes, a patient with a T1 tumor and 1, 2, or 3 observed positive nodes would require a minimum of 8, 15, and 20 nodes removed. For a T2 tumor and 1, 2, or 3 observed positive nodes, the corresponding numbers are 10, 16, and 20. CONCLUSION The accuracy of the extent of axillary nodal positivity is influenced by the number of observed positive nodes, tumor size, and the number of nodes examined. Underestimation of the number of positive nodes will result in errors in the assessment of an individuals risk for locoregional recurrence, distant disease, and breast cancer death and will adversely impact on treatment recommendations. This model provides the clinician with a means for assessing the accuracy of the number of positive nodes reported in patients with 1-3 positive nodes.