Luigia Nardone

Diffusion-weighted Imaging in Evaluating the Response to Neoadjuvant Breast Cancer Treatment

Abstract:  The aim of this study was to investigate the role of diffusion imaging in the evaluation of response to neoadjuvant breast cancer treatment by correlating apparent diffusion coefficient (ADC) value changes with pathological response. From June 2007 to June 2009, all consecutive patients with histopathologically confirmed breast cancer undergoing neoadjuvant chemotherapy were enrolled. All patients underwent magnetic resonance imaging (MRI) (including diffusion sequence) before and after neoadjuvant treatment. The ADC values obtained using two different methods of region of interest (ROI) placement before and after treatment were compared with MRI response (assessed using RECIST 1.1 criteria) and pathological response (assessed using Mandard’s classification).

Role of the Apparent Diffusion Coefficient in the Prediction of Response to Neoadjuvant Chemotherapy in Patients With Locally Advanced Breast Cancer

BACKGROUND We evaluated the diagnostic performance of the baseline diffusion weighted imaging (DWI) and the apparent diffusion coefficient (ADC) in the prediction of a complete pathologic response (pCR) to neoadjuvant chemotherapy (NAC) in patients with breast cancer stratified according to the tumor phenotype. PATIENTS AND METHODS We retrospectively studied 225 patients with stage II, III, and IV breast cancer who had undergone contrast-enhanced magnetic resonance imaging (MRI) and DWI before and after NAC, followed by breast surgery. RESULTS The tumor phenotypes were luminal (n = 143; 63.6%), triple-negative (TN) (n = 37; 16.4%), human epidermal growth factor receptor 2 (HER2)-enriched (n = 17; 7.6%), and hybrid (hormone receptor-positive/HER2(+); n = 28; 12.4%). After NAC, a pCR was observed in 39 patients (17.3%). No statistically significant difference was observed in the mean ADC value between a pCR and no pCR in the general population (1.132 ± 0.191 × 10(-3) mm(2)/s vs. 1.092 ± 0.189 × 10(-3) mm(2)/s, respectively; P = .23). The optimal ADC cutoff value in the general population was 0.975 × 10(-3) mm(2)/s (receiver operating characteristic [ROC] area under the curve [AUC], 0.587 for the prediction of a pCR). After splitting the population into subgroups according to tumor phenotype, we observed a significant or nearly significant difference in the mean ADC value among the responders versus the nonresponders in the TN (P = .06) and HER2(+) subgroups (P = .05). No meaningful difference was seen in the luminal and hybrid subgroups (P = .59 and P = .53, respectively). In contrast, in the TN and HER2(+) subgroups (cutoff value, 0.995 × 10(-3) mm(2)/s and 0.971 × 10(-3) mm(2)/s, respectively), we observed adequate ROC AUCs (0.766 and 0.813, respectively). CONCLUSION The pretreatment ADC value is not capable of predicting the pCR in the overall population of patients with locally advanced breast cancer. Nonetheless, an ameliorated diagnostic performance was observed in specific phenotype subgroups (ie, TN and HER2(+) tumors).

Effect of breast cancer phenotype on diagnostic performance of MRI in the prediction to response to neoadjuvant treatment.

AIM The estimation of response to neoadjuvant chemotherapy (NAC) is useful in the surgical decision in breast cancer. We addressed the diagnostic reliability of conventional MRI, of diffusion weighted imaging (DWI) and of a merged criterion coupling morphological MRI and DWI. Diagnostic performance was analysed separately in different tumor subtypes, including HER2+ (human epidermal growth factor receptor 2)/HR+ (hormone receptor) (hybrid phenotype). MATERIALS AND METHODS Two-hundred and twenty-five patients underwent MRI before and after NAC. The response to treatment was defined according to the RECIST classification and the evaluation of DWI with apparent diffusion coefficient (ADC). The complete pathological response - pCR was assessed (Mandard classification). RESULTS Tumor phenotypes were Luminal (63.6%), Triple Negative (16.4%), HER2+ (7.6%) or Hybrid (12.4%). After NAC, pCR was observed in 17.3% of cases. Average ADC was statistically higher after NAC (p<0.001) among patients showing pCR vs. those who had not pCR. The RECIST classification showed adequate performance in predicting the pCR in Triple Negative (area under the receiver operating characteristic curve, ROC AUC=0.9) and in the HER2+ subgroup (AUC=0.826). Lower performance was found in the Luminal and Hybrid subgroups (AUC 0.693 and 0.611, respectively), where the ADC criterion yielded an improved performance (AUC=0.787 and 0.722). The coupling of morphological and DWI criteria yielded maximally improved performance in the Luminal and Hybrid subgroups (AUC=0.797 and 0.761). CONCLUSION The diagnostic reliability of MRI in predicting the pCR to NAC depends on the tumor phenotype, particularly in the Luminal and Hybrid subgroups. In these cases, the coupling of morphological MRI evaluation and DWI assessment may facilitate the diagnosis.

Low-Dose Hyperradiosensitivity: Is There a Place for Future Investigation in Clinical Settings?

BACKGROUND AND PURPOSE In vitro radiation doses of below 0.5 Gy have been shown to be more effective than higher doses per unit dose in killing clonogenic cells of many epithelial tumor cell lines. This phenomenon is known as low-dose hyperradiosensitivity. Preclinical studies have now suggested that there is synergism between chemotherapy and low-dose fractionated radiotherapy (LD-FRT). To test the clinical efficacy of this approach, we prospectively evaluated concurrent palliative chemotherapy and LD-FRT in patients with various types of epithelial tumors. METHODS AND MATERIALS Patients suffering from relapses or metastases of epithelial tumors were scheduled to receive concurrent LD-FRT (two fractions of 0.4 Gy per day) and chemotherapy. Radiologic assessments were performed after three cycles of chemotherapy plus LD-FRT. RESULTS Between June 2006 and October 2007, 12 patients with lung cancer, 7 patients with head-and-neck tumors, 2 patients with breast cancer, and 1 patient with esophageal carcinoma, for a total patient population of 22, underwent concomitant LD-FRT and chemotherapy. All patients but 3 (86%) had received previous treatments for their cancer. The median total dose of LD-FRT delivered was 800 cGy (range, 320-1280 cGy). The overall response rate was 45% (42% in previously treated patients). Grade 3-4 hematologic toxicities (Radiation Therapy Oncology Group ratings) were observed in 2 patients. At a median follow-up of 6.5 months, however, no local toxicity was observed. CONCLUSION In our experience, concurrent LD-FRT and chemotherapy was well tolerated. Because the response rate seems promising, prospective Phase II studies of the strategy are now under way.

Pain in osseous metastases: results of radiotherapy

Abstract Seventy‐nine patients with osseous metastases were prospectively evaluated for bone pain. The evaluation of pain has been accomplished using the Keele Scale system. All cases have been treated with radiotherapy. The therapeutic response for analgesic effect has been evaluated in complete response (CR) when total disappearance of pain was present; in partial response (PR) with the reduction of at least 1 point on the Keele Scale; in non‐responsive (NR) when patients showed worsening or no change in pain symptomatology during or following therapy. 51.8% have presented complete response, 36.8% partial response and 11.3% no response. The global response (CR + PR) has been 88.6%. This response was evaluated in relation to fractionating daily dose of radiotherapy and minimum dose necessary for analgesia.

A feasibility study of neo-adjuvant low-dose fractionated radiotherapy with two different concurrent anthracycline-docetaxel schedules in stage IIA/B-IIIA breast cancer

AIMS AND BACKGROUND The aim of the study was to evaluate the feasibility of neoadjuvant low-dose fractionated radiotherapy, in combination with two anthracycline-docetaxel regimens, in breast cancer treatment. MATERIALS AND METHODS Women with stage IIA/B-IIIA breast cancer were assigned to receive the treatment of low-dose fractionated radiotherapy (0.4 Gy/per fraction, 2 fractions per day, for 2 days, every 21 days for 8-6 cycles) with concomitant neoadjuvant chemotherapy with non-pegylated liposomal doxorubicin and docetaxel. Two chemotherapy schedules were planned to be combined with low-dose fractionated radiotherapy. The first schedule consisted of four cycles of non-pegylated liposomal doxorubicin sequentially followed by four cycles of docetaxel, and the second schedule consisted of six cycles of non-pegylated liposomal doxorubicin plus concomitant docetaxel. Acute toxicity was evaluated according to the Radiation Therapy Oncology Group score system. Pathological response was evaluated by the Mandard score and expressed as tumor regression grade. RESULTS Between March 2008 and February 2009, 10 patients underwent low-dose fractionated radiotherapy and concomitant chemotherapy. No grade 3-4 breast toxicity was observed. Five patients had a clinical complete response. Seven patients underwent conservative surgery. Overall, tumor regression grade 1 (absence of residual cancer) was achieved in one patient (10%) and grade 2 (residual isolated cells scattered through the fibrosis) in 4 patients (40%). The pathologic major response rate (tumor regression grade 1 + 2) was 20% in patients receiving low-dose fractionated radiotherapy and sequential non-pegylated liposomal doxorubicin and docetaxel and 80% in the group receiving low-dose fractionated radiotherapy and concurrent non-pegylated liposomal doxorubicin and docetaxel treatment. CONCLUSIONS Concomitant low-dose fractionated radiotherapy combined with anthracycline and docetaxel is feasible. The toxicity profile of radio-chemotherapy was similar to that of chemotherapy alone: there was no acute skin or cardiac toxicity. The concurrent application of liposomal doxorubicin and docetaxel with low-dose fractionated radiation led to higher histological response rates compared to the sequential application of the same two drugs.

Radiotherapy in Italy after conservative treatment of early breast cancer. A survey by the Italian Society of Radiation Oncology (AIRO).

Aims and Background The aim of surveys on clinical practice is to stimulate discussion and optimize practice. In this paper the current Italian radiotherapy practice after breast-conserving surgery for early breast cancer is described and adherence to national and international guidelines is assessed. Furthermore, results are compared with an earlier survey in northern Italy and international reports. Study Design A multiple-choice questionnaire sent to all 138 Italian radiation oncology centers. Results 48% of centers responded. Most performed breast-conserving surgery when tumor size was ≤3 cm. All centers routinely performed axillary dissection; 45 carried out sentinel node biopsy followed by axillary dissection when the sentinel node was positive. Most centers re-excised when resection margins were positive. The median interval between surgery and radiotherapy, when chemotherapy was not administered, was 60 days. Adjuvant chemotherapy was preferably administered before radiotherapy. Regional lymph nodes were never irradiated in 10 centers; in all others irradiation depended on the number of positive lymph nodes and/or involvement of axillary fat and/or tumor location in medial quadrants. All centers used standard fractionation; hypofractionated schemes were available in 6. Most centers used 4–6 MV photons. In 59 centers the boost dose of 10 Gy could be increased if margins were not negative. All centers ensured patient setup reproducibility. Treatment planning was computerized in 59 centers. The irradiation dose was prescribed at the ICRU point in 56 centers and portal films were made in 54 centers. Intraoperative radiotherapy was used in 4 centers: for partial breast irradiation in 1 and for boost administration in 3 centers. Conclusions Although the quality of radiotherapy delivery has improved in Italy in recent years, approaches that do not conform to international standards persist.

SPIDER: Managing Clinical Data of Cancer Patients Treated through a Multidisciplinary Approach by a Palm Based System

Background: The complexity of modern oncology, based on multi-disciplinary management of cancer patients, results in critical amounts of data, leading to problems in managing and sharing information. Methods: Spider is a multi-user system, based on integrated palm technology, created to facilitate data recording, managing and sharing, through Intra-Internet connection. By palms or PCs, data are collected directly at the place where information is generated. Every health professional can edit, modify and display all of the patients data according to his/her operational level. A powerful engine enables Spider’s users to create series of cancer patients’ appointments linked to one another by specified time intervals and save them as “Protocols”. Applying a protocol to the patient, the system schedules a wave of appointments and alerts keeping the correlation with time intervals previously specified by specialists. XML technology is integrated with traditional RDBMS technology to build the Electronic Patient File (EPF) updated during each patient’s admission or consultation, including any new diagnostic/therapeutic events and collective decisions. The system automatically produces all clinical documents routinely in use (discharge letters, exams’ requests, etc.). Results: Spider’s different archives include 4387 patients (Prostate, n=849; Lung, n=1596; Rectum, n=1541; Head & Neck, n=291; Cervix, n=110). The EPF includes specific modules: staging, surgery, chemotherapy, hormonotherapy, radiotherapy, toxicity, pathology, follow-up and clinical summary. Spider Hospitalization displays the ward map and important details of patients occupying each single bed. Conclusions: Spider makes data capture easier and accurate. The availability of large amounts of information accelerates outcome analysis and improves cancer research.

Prolonged continuous infusion of carboplatin and concomitant radiotherapy in advanced head and neck cancer. A phase I study.

A Phase I study on conventional radiotherapy and concomitant infusional chemotherapy with carboplatin (CBDCA) was initiated in order to evaluate the toxicity and feasibility of this combined treatment. Twenty-one patients with advanced head and neck carcinoma entered the study: 9 patients (Group A) received a 14-day infusion of 30 mg/m2 of CBDCA daily and 12 (Group B), a 21 -day infusion beginning from the first day of radiotherapy. Total doses of 420 and 630 mg/m2 were given to group A and B, respectively. RT total dose ranged from 65 to 70 Gy with standard fractionation (180 cGy/5d/w). Major side effects observed were hematologic and mucosal. In group A grade 3 leukopenia was observed in five patients, grade 3 thrombocytopenia in one, and grade 3 mucositis in 2. In group B hematologic toxicity was severe: grade 3 and 4 leukopenia was seen in 4 and 3 patients, respectively, 3 patients had grade 3 and 2 patients grade 4 thrombocytopenia with a late appearance of nadir. Severe grade 3 mucositis was observed in 6 patients. Nineteen patients were evaluable for tumor response: 7/17 patients with stage II1-IV disease achieved a CR and 8 a PR. According to our experience, prolonged infusion with CBDCA during conventional RT courses is feasible, though a certain level of toxicity remains. A 30 mg/m2 daily dose for 21 -day infusion is associated with severe hematologic toxicity, while 14-day infusion can be considered the maximum tolerable dose. Whether CBDCA infusion has any advantage over bolus is yet to be confirmed.

Primary systemic treatment and concomitant low dose radiotherapy for breast cancer: final results of a prospective phase II study.

BACKGROUND To evaluate the efficacy of preoperative low dose fractionated radiotherapy (LD-FRT) and chemotherapy in breast cancer. MATERIALS AND METHODS Patients with stage IIA-IIIA breast cancer, received LD-FRT (0.40 Gy bid, on day 1 and 2, for 6 cycles) to primary tumor volume and concurrent chemotherapy with non-pegylated liposomal anthracycline and docetaxel. Pathological response was assessed by Mandard Tumor Regression Grade (TRG). We evaluated the pathological major response rate (PMRR) as TRG1 and TRG2. The expected outcome was a PMRR of 60%. The accrual was determined by the single proportion powered analysis (α = 0.05, power = 0.8). RESULTS Twentyone patients were enrolled. No grade 2-4 acute skin and hematological toxicity was observed. TRG1 was obtained in 3 patients (14.3%), TRG2 in 4 patients (19%). The PMRR was 33.3%; it does not concur with the expected result, but is similar to that of chemotherapy alone. According to molecular subtype, 2/11 luminal A patients and 4/6 luminal B patients obtained a PMRR to preoperative treatment (35.3%); 1/4 basal like patients reported TRG1 (25%). CONCLUSIONS LD-FRT concomitant with primary systemic treatment has a good toxicity profile. The response rate is consistent with that of chemotherapy alone, and suggests different interactions between low dose radiotherapy and molecular subtypes. Additional investigations are planned.