New photobiomodulation device for prevention and cure of radiotherapy-induced oral mucositis and dermatitis: results of the prospective Safe PBM study.

PURPOSE: The study aims to assess the feasibility, safety, and tolerability of CareMin650, a new photobiomodulation device, in patients treated by radiotherapy (RT) and to collect preliminary data on efficacy for prevention and treatment of oral mucositis (OM) and radiation dermatitis (RD). METHODS: Safe PBM is a French, multicentric, prospective, non-comparative study which include patients with head and neck cancer (H&NC, cohort A) or breast cancer (BC, cohort B) treated in prophylactic (cohorts A1 and B1) or curative setting (cohort A2 and B2). Prophylactic treatment was administered from D1 to end of RT, at a dose of 3 J/cm2. Curative treatment started when a grade 1 to grade 3 lesion had occurred and was pursued until end of RT. Primary endpoint was incidence of device-related adverse events (AEs). OM and RD lesions were graded according to CTCAE V3. RESULTS: Overall, 72 patients were included (22, 9, 23, and 18 in cohorts A1, A2, B1, and B2, respectively). No device-related AE was reported after 1312 CareMin650 sessions. In cohorts A1 and B1, median time to first OM or RD lesion was 20 days. One BC patient developed G3 RD after completion of RT and discontinuation of CareMin650. Four H&NC patients developed G3 OM. In cohorts A2 and B2, lesions improved or stabilized in 71% of patients. Rates of satisfaction were high among patients and users. CONCLUSION: CareMin650 is feasible, safe, and well tolerated for preventive or curative treatment of OM and RD in cancer patients treated with RT. Preliminary efficacy results are promising.

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy.

We report our experience of bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) for breast cancer (BC) patients (pts) with inoperable brain metastases (BM) or who refused surgery. This is a retrospective study of seven metastatic BC pts treated at the Institut Curie with at least one course of BBCT before WBRT, with a delay of ≤ 12 months between the two treatments. Toxicity was scored according to the common terminology criteria for adverse events (v4. 2010). Median age was 56 years (41-65). Median follow-up was 5.9 months (0.4-24.6). The median dose of bevacizumab was 10 mg/kg. Median number of cycles BBCT was six (5-17). Different chemotherapy regimens were used, the most common combination was paclitaxel-bevacizumab. WBRT was delivered in ten fractions, five fractions/week, for two weeks, to a total of 30 Gy. One pt underwent stereotactic radio surgery (SRS) after WBRT. No pt received BBCT during RT. Most common reported side-effects were nausea (n = 4), headache (n = 3), vomiting (n = 1), and vertigo (n = 3). All pts had mild or moderate grade ≤ 2 neurologic toxicity. There were no radiological signs of necrosis or cerebral ischemia. BBCT before WBRT was not associated with severe brain toxicity. Because of the limited number of pts, the different BBCT regimens, and important delays between treatments, these results must be confirmed prospectively.

Targeting poly(ADP-ribose) polymerase activity for cancer therapy.

Poly(ADP-ribosyl)ation is a ubiquitous protein modification found in mammalian cells that modulates many cellular responses, including DNA repair. The poly(ADP-ribose) polymerase (PARP) family catalyze the formation and addition onto proteins of negatively charged ADP-ribose polymers synthesized from NAD(+). The absence of PARP-1 and PARP-2, both of which are activated by DNA damage, results in hypersensitivity to ionizing radiation and alkylating agents. PARP inhibitors that compete with NAD(+) at the enzyme's activity site are effective chemo- and radiopotentiation agents and, in BRCA-deficient tumors, can be used as single-agent therapies acting through the principle of synthetic lethality. Through extensive drug-development programs, third-generation inhibitors have now entered clinical trials and are showing great promise. However, both PARP-1 and PARP-2 are not only involved in DNA repair but also in transcription regulation, chromatin modification, and cellular homeostasis. The impact on these processes of PARP inhibition on long-term therapeutic responses needs to be investigated.

Is There a Benefit of Oxaliplatin in Combination with Neoadjuvant Chemoradiotherapy for Locally Advanced Rectal Cancer? An Updated Meta-Analysis.

BACKGROUND: Neoadjuvant fluoropyrimidine (5FU or capecitabine)-based chemoradiotherapy (CRT) has been considered the standard of care for locally advanced rectal cancer (LARC). Whether addition of oxaliplatin (OXP) will further improve clinical outcomes is still unclear. METHODS: To identify clinical trials combining oxaliplatin in preoperative CRT or perioperative chemotherapy for LARC published until March 2021, we searched PubMed and the Cochrane Library. We also searched for relevant ASCO conference abstracts. The primary endpoint was disease-free survival (DFS). Data were extracted from every study to perform a meta-analysis using Review Manager (version 5.3). RESULTS: A total of seven randomized clinical trials (ACCORD-12, CARO-AIO-04, FOWARC, JIAO, NSABP, PETACC-6, and STAR-01) with 5782 stage II or III rectal cancer patients were analyzed, including 2727 patients with OXP + 5FU regimen and 3055 patients with 5FU alone. Compared with the 5FU alone group, the OXP + 5FU regimen improved DFS (HR = 0.90, 95% CI: 0.81-0.99, p = 0.03) and pathologic complete response (pCR) (OR = 1.21, 95% CI: 1.07-1.37, p = 0.002). Patients treated with the OXP + 5FU regimen had significantly less metastatic progression (OR = 0.79; 95% CI, 0.67 to 0.94; p = 0.007). Considering adverse events (AEs), there was more grade 3-4 diarrhea with OXP + 5FU (OR = 2.41, 95% CI: 1.74-3.32, p < 0.00001). However, there were no significant differences grade 3-4 hematologic AEs (OR = 1.16, 95% CI: 0.87-1.57, p = 0.31). CONCLUSIONS: Our meta-analysis with long-term results from the randomized studies showed a benefit of the addition of OXP + 5FU regiment in terms of DFS, metastatic progression, and pCR rate that did not translate to improved OS.

Tumor aromatase expression as a prognostic factor for local control in young breast cancer patients after breast-conserving treatment.

INTRODUCTION: We sought to determine whether the levels of expression of 17 candidate genes were associated with locoregional control after breast-conserving treatments of early-stage breast cancers in young, premenopausal women. METHODS: Gene expression was measured by using RT-PCR in the breast tumors of a series of 53 young (younger than 40 years), premenopausal patients. All treatments consisted of primary breast-conserving surgery followed by whole-breast radiotherapy (+/- regional lymph nodes) with or without systemic treatments (chemotherapy +/- hormone therapy). The median follow-up was 10 years. RESULTS: The 10-year locoregional control rate was 70% (95% CI, 57% to 87%). In univariate analysis, no clinical/pathologic prognostic factors were found to be significantly associated with decreased locoregional control. Expression of three genes was found to be significantly associated with an increased locoregional recurrence rate: low estrogen-receptor beta, low aromatase, and high GATA3. Two others were associated with only a trend (P < 0.10): low HER1 and SKP2. In multivariate analysis, only the absence of aromatase was significantly associated with an increased locoregional recurrence rate (P = 0.003; relative risk = 0.49; 95% CI 0.29 to 0.82). CONCLUSIONS: Recent data give credit to the fact that breast cancer in young women is a distinct biologic entity driven by special oncogenic pathways. Our results highlight the role of estrogen-signaling pathways (mainly CYP19/aromatase, GATA3, and ER-beta) in the risk of locoregional recurrence of breast cancer in young women. Confirmation in larger prospective studies is needed.

Urokinase-type plasminogen activator and plasminogen-activator-inhibitor type 1 predict metastases in good prognosis breast cancer patients.

UNLABELLED: This retrospective analysis was designed to confirm the predictive role of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type I (PAI-1) in the outcome of early stage, node-negative breast cancer patients. PATIENTS AND METHODS: Node-negative patients having not received adjuvant chemotherapy, and for whom frozen samples were available, were selected. RESULTS: Among the 169 patients included, 56.8% presented with uPA >3 ng/mg of proteins and/or PAI-1 >14 ng/mg of proteins. The median follow-up was 73 months. Significant correlations were found between uPA and disease-free survival (p [univariate]=0.003; p [multivariate]=0.01), and between uPA, PAI-1, and uPA plus PAI-1 and distant relapses (p=0.002). No significant correlation was found between uPA/PAI-1 and the risk of locoregional recurrence. CONCLUSION: This study demonstrated that uPA and PAI-1 are useful predictors of distant metastases in a subset of early stage, node-negative breast cancer patients.

How to boost the breast tumor bed? A multidisciplinary approach in eight steps.

PURPOSE: To describe a new procedure for breast radiotherapy that will improve tumor bed localization and radiotherapy treatment using a multidisciplinary approach. PATIENTS AND METHODS: This pilot study was conducted by departments of radiation oncology, surgery, and radiology. A new procedure has been implemented, summarized as eight steps: from pre-surgery contrast CT to surgery, tumor bed planning target volume (PTV) determination, and finally breast and tumor bed irradiation. RESULTS: Twenty patients presenting with T1N0M0 tumors were enrolled in the study. All patients underwent lumpectomy with the placement of surgical clips in the tumor bed region. During surgery, 1 to 5 clips were placed in the lumpectomy cavity before the plastic procedure. All patients underwent pre- and postoperative CT scans in the treatment position. The two sets of images were registered with a match-point registration. All volumes were contoured and the results evaluated. The PTV included the clips region, the gross tumor volume, and the surgical scar, with an overall margin of 5-10 mm in all directions, corresponding to localization and setup uncertainties. For each patient the boost PTV was discussed and compared with our standard forward-planned PTV. CONCLUSIONS: We demonstrate the feasibility of a tumor bed localization and treatment procedure that seems adaptable to routine practice. Our study shows the advantages of a multidisciplinary approach for tumor bed localization and treatment. The use of more than 1 clip associated with pre- to postoperative CT image registration allows better definition of the PTV boost volume.

Postmastectomy electron beam chest wall irradiation in women with breast cancer: a clinical step toward conformal electron therapy.

PURPOSE: Electron beam radiotherapy of the chest wall with or without lymph node irradiation has been used at the Institut Curie for >20 years. The purpose of this report was to show the latest improvements of our technique developed to avoid hot spots and improve the homogeneity. METHODS AND MATERIALS: The study was split into two parts. A new electron irradiation technique was designed and compared with the standard one (dosimetric study). The dose distributions were calculated using our treatment planning software ISIS (Technologie Diffusion). The dose calculation was performed using the same calculation parameters for the new and standard techniques. Next, the early skin toxicity of our new technique was evaluated prospectively in the first 25 patients using Radiation Therapy Oncology Group criteria (clinical study). RESULTS: The maximal dose found on the five slices was 53.4 +/- 1.1 Gy for the new technique and 59.1 +/- 2.3 Gy for the standard technique. The hot spots of the standard technique plans were situated at the overlap between the internal mammary chain and chest wall fields. The use of one unique field that included both chest wall and internal mammary chain volumes solved the problem of junction. To date, 25 patients have been treated with the new technique. Of these patients, 12% developed Grade 0, 48% Grade 1, 32% Grade 2, and 8% Grade 3 toxicity. CONCLUSIONS: This report describes an improvement in the standard postmastectomy electron beam technique of the chest wall. This new technique provides improved target homogeneity and conformality compared with the standard technique. This treatment was well tolerated, with a low rate of early toxicity events.

Does concurrent radiochemotherapy affect cosmetic results in the adjuvant setting after breast-conserving surgery? Results of the ARCOSEIN multicenter, Phase III study: patients' and doctors' views.

PURPOSE: To evaluate the cosmetic results of sequential vs. concurrent adjuvant chemotherapy with radiotherapy after breast-conserving surgery for breast cancer, and to compare ratings by patients and physicians. METHODS AND MATERIALS: From 1996 to 2000, 716 patients with Stage I-II breast cancers were included in a multicenter, Phase III trial (the ARCOSEIN study) comparing, after breast-conserving surgery with axillary dissection, sequential treatment with chemotherapy first followed by radiotherapy vs. chemotherapy administered concurrently with radiotherapy. Cosmetic results with regard to both the overall aspect of the breast and specific changes (color, scar) were evaluated in a total of 214 patients (107 in each arm) by means of questionnaires to both the patient and a physician whose rating was blinded to treatment allocation. RESULTS: Patients' overall satisfaction with cosmesis was not statistically different between the two arms, with approximately 92% with at least satisfactory results (p = 0.72), although differences between the treated and untreated breasts were greater after the concurrent regimen (29% vs. 14% with more than moderate differences; p = 0.0015). Physician assessment of overall cosmesis was less favorable, with lower rates of at least satisfactory results in the concurrent arm (60% vs. 85%; p = 0.001). Consequently, the concordance for overall satisfaction with cosmesis between patients and doctors was only fair (kappa = 0.62). CONCLUSION: After breast-conserving surgery, the concurrent use of chemotherapy with radiotherapy is significantly associated with greater differences between the breasts. These differences do not translate into patients' lessened satisfaction with cosmesis.

Role of dynamic magnetic resonance imaging in the evaluation of tumor response to preoperative concurrent radiochemotherapy for large breast cancers: a prospective phase II study.

PURPOSE: To evaluate the accuracy of clinical examination and of three imaging modalities (ultrasound [US] scan, mammography, and magnetic resonance imaging [MRI]) to assess the tumor response of breast cancer to a preoperative regimen of concurrent radiochemotherapy for large breast cancers, using pathologic data as the reference. METHODS AND MATERIALS: Sixty women were accrued. Treatment consisted of 4 cycles of (5-fluorouracil-vinorelbine) chemotherapy with, starting with the second cycle of chemotherapy, locoregional radiotherapy to the breast and the internal mammary and supraclavicular and infraclavicular lymph nodes. Breast surgery and axillary lymph node dissection were subsequently performed. Breast imaging assessments were performed both before chemotherapy and preoperatively. RESULTS: The correlation coefficients between tumor dimension at imaging and pathology were statistically significant for US scan (r = 0.4; p = 0.006) and MRI (r = 0.4; p = 0.004) but not for clinical examination (r = 0.2; p = 0.16) or mammography (r = -0.15; p = 0.31). Furthermore, the area under the receiver operating characteristic curve for MRI was 0.81, compared with 0.67 for US scan. At the optimal threshold score, MRI performed with 81% sensitivity and 75% specificity. CONCLUSION: Compared with clinical examination, US scan, or mammography, MRI substantially improved the prediction of pathologic tumor response to preoperative concurrent radiochemotherapy for large breast cancers.

Age remains the first prognostic factor for loco-regional breast cancer recurrence in young (<40 years) women treated with breast conserving surgery first.

PURPOSE: To ascertain the loco-regional recurrence (LRR) rate and its major prognostic factors in patients younger than 40 and to determine the influence of age on the features of breast cancer and its treatment in two age groups: 35 years and [36-39] years. METHODS AND MATERIALS: Between 1985 and 1995, 209 premenopausal women, younger than 40, were treated for early breast cancers with primary breast conserving surgery followed by radiotherapy+/-chemotherapy. Median age was 37 years with 66 patients (32%) 35 years and 143 older (68%). Median follow-up was 12 years. Tumours' characteristics were: cT1 in 75%, pN0 in 60%. RESULTS: LRR rate was 38% at 10 years, contralateral breast cancer rate 12%. Age was the only prognostic factor for LRR. The relative risk of LRR increased by 7% for every decreasing year of age. The annual risk of local recurrence peaked between 2 and 3 years after the initial diagnosis and returned to the level of contra-lateral breast cancer at 10 years. The younger population had infiltrating carcinomas that were significantly more commonly ductal, less commonly lobular, and of higher grade - they received chemotherapy more often. CONCLUSION: Using conventional methods we could find no explanation as to why age remained the most important prognostic factor for breast cancer LRR. Known prognostic factors such as involved surgical margins seemed erased by adequate radiotherapy doses.

Responses to concurrent radiotherapy and hormone-therapy and outcome for large breast cancers in post-menopausal women.

INTRODUCTION: This study aimed to evaluate responses and outcome of hormone-therapy (HT) and radiotherapy (RT) given concurrently for large breast cancers in post-menopausal women. MATERIAL AND METHODS: Forty-two breast carcinomas in 41 women were treated with HT and concurrent RT to the breast +/- lymph node bearing areas. For 30 tumours this was followed by breast surgery (with axillary lymph node dissection when the axilla had not been irradiated). RT delivered a median dose to the tumour of 50 Gy (48-66) and 75 Gy (65-84) for, respectively, preoperative and exclusive RT-HT. Median follow-up was 64 months. RESULTS: Out of 42 clinically assessable tumours (after a mean dose of 50 Gy), 9 tumours (21%) had complete clinical responses, 24 (57%) partial responses, 9 (21%) stable disease. Breast-conserving surgery or exclusive RT-HT was possible in 74% of tumours. For 29 patients who underwent breast surgery, the rate of pathological complete responses was 17%. At 50 Gy no skin toxicity higher than grade 2 occurred. Five year OS, RFS and local control were, respectively, 85%, 84% and 97%. Lymphoedema occurred in one patient. CONCLUSION: Concurrent association of RT-HT demonstrated good efficacy, both in terms of clinical and pathological complete responses. It allowed breast conservation with acceptable tolerance and good 5-year local control.

Pathological response to preoperative concurrent chemo-radiotherapy for breast cancer: results of a phase II study.

This study evaluated, in terms of pathological complete response (pCR) and acute toxicity, preoperative concurrent (5-fluorouracil (5-FU)-vinorelbine) chemoradiotherapy for large breast cancers. A total of 60 women were included in the study. Chemotherapy consisted of 4 cycles of 5-FU, 500 mg/m2/d, continuous infusion (d1-d5) and vinorelbine, 25 mg/m2 (d1; d6). Starting with the second cycle, radiotherapy delivered 50 Gy to the breast and 46 Gy to the internal mammary and supra/infra-clavicular lymph nodes. Breast surgery and axillary lymph node dissection were then performed. Four patients did not complete their chemotherapy. Breast conservation was possible in 69% of patients. The rate of pCR was 27%. Three factors were associated with pCR: histological grade 3, absence of hormonal receptors and high mitotic index. Grade 4 haematological toxicity occurred in 22% of patients. In conclusion, chemoradiotherapy demonstrated good efficacy, both in terms of pCR and in allowing breast conservation with acceptable tolerance.

Treatment of squamous cell anal canal carcinoma (SCACC) with pulsed dose rate brachytherapy: a retrospective study.

BACKGROUND AND PURPOSE: To evaluate the results of pulsed dose rate brachytherapy (PDR) in SCACC. MATERIAL AND METHODS: From 1996 to 2002, 71 patients (pts) with SCACC were treated with PDR brachytherapy. The median age was 61.2 years (35-88), with a sex ratio of 1 M/6.5 F. The TNM classification was: 14 T1, 41 T2, 15 T3 and 1 T4, 52 N0, 13 N1, 3 N2 and 3 N3. All the pts were M0. Treatment started with external beam irradiation to the posterior pelvis (mean dose: 45.5 Gy). Forty-seven patients received chemotherapy (neoadjuvant/concomitant or both). After an interval of 2-6 weeks, PDR interstitial brachytherapy was performed. The mean dose was 17.8 Gy to the 85% reference isodose of the Paris system. RESULTS: Treatment was interrupted in only one pt. With a median follow-up of 28.5 months, 2-year actuarial overall survival was 90%. Fourteen relapses occurred (four distant, three regional, and seven local). Ten patients developed a grade III complication (Lent Soma scale) and two a grade IV complication (colostomy or abdominal perineal resection for necrosis). CONCLUSION: PDR appears to be an effective treatment for SCACC. It is capable of reproducing the results usually observed with continuous LDR.

CT-scan based localization of the internal mammary chain and supra clavicular nodes for breast cancer radiation therapy planning.

BACKGROUND AND PURPOSE: To evaluate the influence of the position and the exact localizations of supra clavicular nodes (SCN) and internal mammary chain (IMC) and their variability among patients in order to improve treatment planning in breast cancer (BC) patients. PATIENTS AND METHODS: A total of 46 CT scans of the chest were examined. All patients were female treated with breast conserving surgery and radiotherapy. The study was divided into two phases. The first consisted of measurements on 20 diagnostic CT scans, performed in the supine position with both arms over the head. All patients received contrast. This first phase was performed as a training program for radiologist and radiation oncologist to prepare for the second phase of the study: 26 CT scans in treatment position on angled board without injection. For this second group, patients had one arm raised above the head (treated side) and the other kept by the side (contralateral side). Measurements were performed on both sides to evaluate the influence of the arm position. The depths of IM- and SC vessels were measured at five points: (1) the origin of the internal mammary artery, (2) the sterno-clavicular articulation, (3-5) the first, second and third rib interspaces (RI). Measurements of the depth and of the distance between the internal mammary vessels and the middle axis of the sternum were obtained using electronic calipers on a PACS workstation. RESULTS: There were important individual variations of the depth of SCN, as follows: 20-84 mm (diagnostic) and 19-64 (treatment position). No differences in the depth of the IMC were found between treated and contralateral side at the region of the I, II, and III rib interspaces. The lateral margin of the IMC was never more than 40 mm from the middle axis of the sternum (I, II, III rib interspaces). There was no difference in the lateral limits of IMC (the distance between the IM vessels and the middle axis of the sternum) between the two sides: treated and contralateral. CONCLUSIONS: This study shows the importance of the patients' individual anatomy, their position and the large variability in the depth of SCN. It is important to visualize these regions to permit individual dosimetric optimization.

Functional outcome of patients with benign meningioma treated by 3D conformal irradiation with a combination of photons and protons.

PURPOSE: To evaluate efficacy and tolerance of external fractionated combination of photon and proton radiation therapy (RT) for intracranial benign meningiomas. METHODS AND MATERIALS: Between 1994 and 2002, 51 patients with intracranial meningiomas of the base of the skull were treated with a combination of photon and proton RT. Median total dose was 60.6 cobalt Gy equivalent (54-64). One hundred eight eye-related symptoms were collected; 80 other symptoms were noted and followed up. RESULTS: Mean follow-up was 25.4 months. Acute tolerance was excellent. Out of the 108 eye-related symptoms, 106 (96%) were evaluated. Improvements were reported for 73 (68.8%) of them. Out of the 88 other miscellaneous symptoms, 81 (92%) were evaluated. Improvements were reported in 54 cases (67%). Median time to improvement ranged from 1 to 24 months after completion of the radiotherapy, depending on the symptom. We did not observe any worsening of primary clinical signs. Radiologically, 1 patient relapsed 4 months after the end of irradiation. Pathology revealed a malignant (Grade 3) transformation of the initial Grade 1 meningioma. Four-year local control and overall survival rates were, respectively, 98% and 100%. Stabilization of the tumor was observed in 38 cases (72%), volume reduction in 10 cases (20%), and intratumor necrosis in 3 cases. Two patients complained of Grade 3 side effects: 1 unilateral hearing loss requiring aid and 1 case of complete pituitary deficiency. CONCLUSION: These results stressed the clinical efficacy of fractionated-associated photon-proton RT in the treatment of meningiomas, especially on cranial nerve palsies, without severe toxicity in almost all patients.

Linac stereotactic radiosurgery: an effective and safe treatment for elderly patients with brain metastases.

PURPOSE: To evaluate the outcomes of radiosurgery for brain metastases in patients 65 years or older. PATIENTS AND METHODS: Between January 1994 and January 2003, 117 patients (47 women, 70 men), median age 71 years (range, 65-86 years), received radiosurgery for 227 metastases. Sixty-one patients (55%) presented symptoms in relation to the brain metastases. Thirty-eight patients (32%) received whole-brain radiotherapy. Median metastasis diameter and volume were 21 mm (range, 0.5-75 mm) and 1.7 cc (range, 0.02-71 cc), respectively. RESULTS: Median follow-up was 7 months (range, 1-45 months), 9.5 months for alive patients (range, 1-45 months). Median minimum and maximum doses were 14.5 Gy (6.5 Gy, 19.5 Gy), and 20.4 Gy (13.2 Gy, 41.9 Gy), respectively. Median survival was 8 months from the date of radiosurgery. Overall survival rates at 6 and 24 months were 58% +/- 5% and 13% +/- 4%, respectively. According to multivariate analysis, a low Karnofsky performance status was an independent unfavorable prognostic factor for overall survival (p = 0.003; odds ratio [OR] = 0.28; 95% confidence interval [CI], 0.14-0.56). Median brain disease-free survival was 10 months. Brain disease-free survival rates at 6 and 24 months were 67% +/- 6% and 40% +/- 7%, respectively. According to multivariate analysis, a radiosensitive lesion was an independent favorable factor (p = 0.038; OR = 0.42; 95% CI, 0.18-0.95); more than two metastases and a low Karnofsky performance status were independent unfavorable factors for brain disease-free survival (p = 0.046; OR = 2.15; 95% CI, 1.01-4.58 and p = 0.003; OR = 30.4; 95% CI, 3.1-296, respectively). Local control rates were 98% +/- 2% and 91% +/- 8.5% at 6 and 24 months. Out of the 61 patients presenting symptoms before radiosurgery, complete symptomatic response was achieved in 12 patients (20%), partial improvement in 25 (41%), stabilization in 7 (11%), and worsening in 4 (6%) related to a progression of the irradiated metastasis. Seven cases of radionecrosis were described and were related to the margin dose (p = 0.03). CONCLUSION: Radiosurgery for elderly patients was effective and safe. Age alone should not be a criterion for denying radiosurgery to any patient with brain metastases.

Integration of a Radiosensitivity Molecular Signature Into the Assessment of Local Recurrence Risk in Breast Cancer.

PURPOSE: Recently, we developed radiosensitivity (RSI), a clinically validated molecular signature that estimates tumor radiosensitivity. In the present study, we tested whether integrating RSI with the molecular subtype refines the classification of local recurrence (LR) risk in breast cancer. METHODS AND MATERIALS: RSI and molecular subtype were evaluated in 343 patients treated with breast-conserving therapy that included whole-breast radiation therapy with or without a tumor bed boost (dose range 45-72 Gy). The follow-up period for patients without recurrence was 10 years. The clinical endpoint was LR-free survival. RESULTS: Although RSI did not uniformly predict for LR across the entire cohort, combining RSI and the molecular subtype identified a subpopulation with an increased risk of LR: triple negative (TN) and radioresistant (reference TN-radioresistant, hazard ratio [HR] 0.37, 95% confidence interval [CI] 0.15-0.92, P=.02). TN patients who were RSI-sensitive/intermediate had LR rates similar to those of luminal (LUM) patients (HR 0.86, 95% CI 0.47-1.57, P=.63). On multivariate analysis, combined RSI and molecular subtype (P=.004) and age (P=.001) were the most significant predictors of LR. In contrast, integrating RSI into the LUM subtype did not identify additional risk groups. We hypothesized that radiation dose escalation was affecting radioresistance in the LUM subtype and serving as a confounder. An increased radiation dose decreased LR only in the luminal-resistant (LUM-R) subset (HR 0.23, 95% CI 0.05-0.98, P=.03). On multivariate analysis, the radiation dose was an independent variable only in the LUMA/B-RR subset (HR 0.025, 95% CI 0.001-0.946, P=.046), along with age (P=.008), T stage (P=.004), and chemotherapy (P=.008). CONCLUSIONS: The combined molecular subtype-RSI identified a novel molecular subpopulation (TN and radioresistant) with an increased risk of LR after breast-conserving therapy. We propose that the combination of RSI and molecular subtype could be useful in guiding radiation therapy-based decisions in breast cancer.

Can digitally reconstructed radiographs (DRRS) replace simulation films in prostate cancer conformal radiotherapy?

PURPOSE: To evaluate the precision of using digitally reconstructed radiographs (DRRs) of either 3 mm or 6 mm slice separation vs. using simulator images for the setup verification of patients receiving CT planned conformal radiotherapy to the prostate. To calculate the transfer error between CT and simulator. METHODS AND MATERIALS: Twenty patients were CT scanned (3 mm slice spacing/width). DRRs were generated for both 3 mm (DRR 3) and 6 mm (DRR 6) separations. DRRs and a simulator image of an anterior and a lateral field were used as reference images. Five observers matched each of the reference images to treatment images using the Theraview "Target check" facility. It was assumed that poorer images would lead to a loss of precision of field placement estimations (FPE) between observers. The study was designed to detect a difference greater than 1.5 mm(2) in the precision of image placement. The transfer error was the mean difference in the setup error derived from the DRRs and the simulation films. RESULTS: The precision of evaluations for simulator films and 3 mm DRRs were similar. There was a trend for the DRR 6 mm to achieve less precise results which was greatest for craniocaudal examinations (variance: simulator 1.5 mm(2), DRR6 2.8 mm(2), p = 0.17), but this did not reach statistical significance. A range of transfer errors was identified, with standard deviations ranging from 1.7 to 4.2 mm. There was evidence of a significant systematic bias in anterior craniocaudal (1.3-1.9 mm, p < 0.004) and anterior posterior (-1.9 mm, p = 0.027). CONCLUSION: The precision of setup evaluations using DRRs is similar to that achieved by using simulator fields when planning conformal prostate radiotherapy. The use of DRRs could reduce systematic errors introduced in the planning process.

Efficacy and morbidity of arc-therapy radiosurgery for cerebral arteriovenous malformations: a comparison with the natural history.

PURPOSE: To report the results of arc-therapy radiosurgery for cerebral arteriovenous malformation (AVM) and to compare the adverse event rate with the rate expected from the natural history. METHODS AND MATERIALS: We performed a retrospective study of our 118 first patients with a mean follow-up of 46 months (range, 5-105 months). The AVMs had features indicating a poor prognosis at initial presentation and had already been treated by previous embolizations in 88% of patients. The mean volume of the targets was 7.4 cm3 (range, 0.3-28.3 cm3). The mean minimal and maximal dose was 17.7 Gy (range, 10-25 Gy) and 24.5 Gy (range, 17-36 Gy), respectively. RESULTS: The crude and 5-year actuarial rate of cure (total obstruction of the AVM shunt at angiography) was 54% (60 of 112) and 77%, respectively. The only independent prognostic factor of cure was the AVM volume (crude cure rate 67% for <7 cm3 vs. 35% for > or =7 cm3; p = 0.001). No patient died. Transient and permanent complications and hemorrhage occurred in 5%, 1.7%, and 6% of patients, respectively. The annual risk of an adverse event (hemorrhage or complication) was 3.9%. CONCLUSION: The results of our series showed that radiosurgery, performed alone or after prior shrinkage of the AVM by embolization, is both effective and well tolerated, with a rate of adverse events comparable to that expected from the natural history.