AIRO Breast Cancer Group Best Clinical Practice 2022 Update.

INTRODUCTION: Breast cancer is the most common tumor in women and represents the leading cause of cancer death. Radiation therapy plays a key-role in the treatment of all breast cancer stages. Therefore, the adoption of evidence-based treatments is warranted, to ensure equity of access and standardization of care in clinical practice. METHOD: This national document on the highest evidence-based available data was developed and endorsed by the Italian Association of Radiation and Clinical Oncology (AIRO) Breast Cancer Group.We analyzed literature data regarding breast radiation therapy, using the SIGN (Scottish Intercollegiate Guidelines Network) methodology (www.sign.ac.uk). Updated findings from the literature were examined, including the highest levels of evidence (meta-analyses, randomized trials, and international guidelines) with a significant impact on clinical practice. The document deals with the role of radiation therapy in the treatment of primary breast cancer, local relapse, and metastatic disease, with focus on diagnosis, staging, local and systemic therapies, and follow up. Information is given on indications, techniques, total doses, and fractionations. RESULTS: An extensive literature review from 2013 to 2021 was performed. The work was organized according to a general index of different topics and most chapters included individual questions and, when possible, synoptic and summary tables. Indications for radiation therapy in breast cancer were examined and integrated with other oncological treatments. A total of 50 questions were analyzed and answered.Four large areas of interest were investigated: (1) general strategy (multidisciplinary approach, contraindications, preliminary assessments, staging and management of patients with electronic devices); (2) systemic therapy (primary, adjuvant, in metastatic setting); (3) clinical aspects (invasive, non-invasive and micro-invasive carcinoma; particular situations such as young and elderly patients, breast cancer in males and cancer during pregnancy; follow up with possible acute and late toxicities; loco-regional relapse and metastatic disease); (4) technical aspects (radiation after conservative surgery or mastectomy, indications for boost, lymph node radiotherapy and partial breast irradiation).Appendixes about tumor bed boost and breast and lymph nodes contouring were implemented, including a dedicated web application. The scientific work was reviewed and validated by an expert group of breast cancer key-opinion leaders. CONCLUSIONS: Optimal breast cancer management requires a multidisciplinary approach sharing therapeutic strategies with the other involved specialists and the patient, within a coordinated and dedicated clinical path. In recent years, the high-level quality radiation therapy has shown a significant impact on local control and survival of breast cancer patients. Therefore, it is necessary to offer and guarantee accurate treatments according to the best standards of evidence-based medicine.

Diffusion-weighted imaging in evaluating the response to neoadjuvant breast cancer treatment.

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). Fifty-one women (mean age 48.41 years) were included in this study. Morphological MRI (RECIST classification) well evaluated the responder status after chemotherapy (TRG class; area-under-the-curve 0.865). Mean pretreatment ADC values obtained with the two different methods of ROI placement were 1.11 and 1.02 × 10(-3) mm(2) /seconds. Mean post-treatment ADC values were 1.40 and 1.35 × 10(-3) mm(2) /seconds, respectively. A significant inverse correlation between mean ADC increase and Mandard's classifications was observed for both the methods of ADC measurements. Diagnostic performance analysis revealed that the single ROI method has a superior diagnostic accuracy compared with the multiple ROIs method (accuracy: 82% versus 74%). The coupling of the diffusion imaging with the established morphological MRI provides superior evaluation of response to neoadjuvant chemotherapy treatment in breast cancer patients compared with morphological MRI alone. There is a potential in the future to optimize patient therapy on the basis of ADC value changes. Additional works are needed to determine whether these preliminary observed changes in tumor diffusion are a universal response to tumor cell death, and to more fully delineate the ability of ADC value changes in early recognizing responder from nonresponder patients.

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 < or =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.

Comparison of two radiation techniques for the breast boost in patients undergoing neoadjuvant treatment for breast cancer.

OBJECTIVE: After breast conservative surgery (BCS) and whole-breast radiotherapy (WBRT), the use of boost irradiation is recommended especially in patients at high risk. However, the standard technique and the definition of the boost volume have not been well defined. METHODS: We retrospectively compared an anticipated pre-operative photon boost on the tumour, administered with low-dose fractionated radiotherapy, and neoadjuvant chemotherapy with two different sequential boost techniques, administered after BCS and standard adjuvant WBRT: (1) a standard photon beam (2) and an electron beam technique on the tumour bed of the same patients. The plans were analyzed for the dosimetric coverage of the CT-delineated irradiated volume. The minimal dose received by 95% of the target volume (D95), the minimal dose received by 90% of the target volume (D90) and geographic misses were evaluated. RESULTS: 15 patients were evaluated. The sequential photon and electron boost techniques resulted in inferior target volume coverage compared with the anticipated boost technique, with a median D95 of 96.3% (range 94.7-99.6%) and 0.8% (range 0-30%) and a median D90 of 99.1% (range 90.2-100%) and 54.7% (range 0-84.8%), respectively. We observed a geographic miss in 26.6% of sequential electron plans. The results of the anticipated boost technique were better: 99.4% (range 96.5-100%) and 97.1% (range 86.2-99%) for median D90 and median D95, respectively, and no geographic miss was observed. We observed a dose reduction to the heart, with left-sided breast irradiation, using the anticipated pre-operative boost technique, when analyzed for all dose-volume parameters. When compared with the sequential electron plans, the pre-operative photon technique showed a higher median ipsilateral lung Dmax. CONCLUSION: Our data show that an anticipated pre-operative photon boost results in a better coverage with respect to the standard sequential boost while also saving the organs at risk and consequently fewer side effects. ADVANCES IN KNOWLEDGE: This is the first dosimetric study that evaluated the association between an anticipated boost and neoadjuvant chemotherapy treatment.

Hypervascularity Predicts Complete Pathologic Response to Chemotherapy and Late Outcomes in Breast Cancer.

BACKGROUND: Our objective was to investigate the relationship between asymmetric increase in breast vascularity (AIBV) and pathologic profiles of breast cancer. We also addressed the prognostic performance of AIBV and of vascular maps reduction after neoadjuvant chemotherapy (NAC) in predicting pathologic complete response (pCR) at surgery and outcome at follow-up. MATERIALS AND METHODS: Two hundred nineteen patients with unilateral locally advanced breast cancer (LABC) underwent magnetic resonance imaging before and after NAC. Axial, sagittal, and coronal maximum intensity projections were obtained in a subjective comparative evaluation. Asymmetrical versus symmetrical breast vascularity was defined through number of vessels, diameter, and signal intensity. Kaplan-Meier methodology was employed for late survival (31.4 ± 18 months follow-up). RESULTS: AIBV ipsilateral to LABC occurred in 62.5% (P < .001). AIBV was significantly associated with invasive ductal carcinoma, G3, triple-negative, HER2+, and hybrid phenotypes (P < .001). pCR was more frequent among patients with AIBV (24%) (P = .001). After NAC, the vascular map was significantly reduced, particularly in patients with pCR (P < .001). At follow-up, the recurrence rate was 22% (6.1% mortality). AIBV after NAC was associated with worse late survival (P = .036). A trend towards worse late survival existed among patients with AIBV before NAC. We did not observe statistically different survival according to the variation of vascularity after NAC. CONCLUSION: LABC with ipsilateral AIBV before NAC is associated with more aggressive pathologic profiles. Nonetheless, it is more sensitive to NAC and shows a higher frequency of pCR. The persistence of AIBV after NAC entails a worse late prognosis and should prompt more aggressive therapeutic strategies.

Reducing heart dose during left breast cancer radiotherapy: comparison among 3 radiation techniques.

PURPOSE: Breast cancer survivors have a high risk of cardiac death as a consequence of heart irradiation during left breast tangential radiotherapy (RT). This study compares the cardiac dose delivered by standard 3D conformal tangential RT (CRT) to that delivered by prospective-gating RT (PGRT) or 5-field intensity-modulated RT (IMRT). METHODS: Patients with early left breast cancer, referred for adjuvant RT to our institution, were enrolled in this study. For each patient, 2 simulation computed tomography scans were acquired: the first during free breathing, and the second on prospective gating during deep inspiration breath-hold. The scans were monitored by the Varian RPM™ respiratory gating system. For each patient, 3 treatment plans were performed: a 3D-CRT and an IMRT plan, each based on the free-breathing scan, and a PGRT plan, based on the deep inspiration breath-hold scan. Dose-volume histograms were compared by means of the Friedman test. RESULTS: The median mean heart dose was 3 Gy (range 0.9-7.3 Gy) in the CRT plans, 1.9 Gy (range 0.5-3.6 Gy) in the PGRT plans, and 4.5 Gy (range 1.1-10.5 Gy) in the IMRT plans (p = 0.001). The mean heart V25 was 1.2% (range 0%-9.7%), 0% (range 0%-2.0%), and 0.2% (range 0%-7.3%) for CRT, PGRT, and IMRT plans, respectively (p<0.001). CONCLUSIONS: Prospective-gating RT to the left breast offered the best protection of heart and lung, as well as a lower irradiation of the contralateral breast, compared to CRT or IMRT.

Impact of dose and volume on lymphedema.

Lymphedema represents one of the major problem of morbidity in breast cancer therapy. Approximately 15-30% of patients show more or less severe lymphedema of the arm, following cancer therapy. Main pathogenetic mechanisms, risk factors, main grading criteria and scales as LENT-SOMA, CTCv2, CTCAE v3 are presented. A close correlation has been documented between the extent of axillary dissection and the association with radiotherapy in determining an increased risk of lymphedema. Details of surgery and radiotherapy are relevant in the definition of the risk of edema of the arm. Because the axillary area does not correspond to an organ, evaluable parameters as V20 and Dmean available for other organs are not applicable. There is some evidence of a correlation between the irradiation volume and the development of lymphedema. Data of the impact of the dose and its fractionation on the development of lymphedema are contrasting. The monitoring system of late toxicity used by the authors is presented.

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).

Pain in osseous metastases: results of radiotherapy.

Seventy-nine patients with osseous metastases were prospectively evaluated 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.

Biological factors and therapeutic modulation in breast cancer radiotherapy.

The natural history and survival of breast cancer are extremely variable although the advances and improvement in treatment in recent years led to a lower mortality. In fact, in spite of the administration of systemic adjuvant therapy, women with metastatic lymph nodes at diagnosis have a risk of disease progression at 5 years of 40-50%. The disease heterogeneity and the intrinsic tumor cell resistance to therapies are determining factors of the problem. The role of parameters as tumor size, grading, vascular spread, axillary lymph node status, are well defined. However the increasingly early diagnosis and changes in clinical practice have led to the need for non morphologic parameters as estrogen and progesteron receptors, cell proliferation index, labelling index, growth factors tumor-dependent genes (p53, HER2), cell cycle regulators (cyclins). Specific cellular and molecular alterations are studied to identify diagnosticoinstrumental images (MRI) of tumor angiogenesis, the cause of the different tumor aggressiveness. In the surgical and consequently clinico-oncologic approach there is the problem of the interpretation and prognostic role of sentinel lymph node when it is positive for micrometastasis only, if diagnosed by immunohistochemistry.

Prognostic role of sentinel lymph node biopsy in breast cancer.

Sentinel lymph node biopsy was shown to be an accurate procedure in the study of axillary lymph nodes; it allowed a marked decrease in surgery-related morbidity of breast cancer and axillary dissection could be avoided. Other parameters as molecular markers, nuclear grading, patient age, tumor size, are not able to predict the axillary lymph node status and consequent local therapeutic approach similar to those provided by sentinel lymph node biopsy. The extent of sentinel lymph node metastatic involvement, the extracapsular spread, the size of primary tumor and peritumoral lymphatic/vascular infiltration are the four characteristics shown to be significant, if considered in association and not separately as predictors of the extent of axillary involvement in presence of a positive sentinel lymph node. However, so far, specific studies did not confirm concordant and reproducible results. Therefore, apart from controlled studies, axillary dissection is always required in presence of a metastatic sentinel lymph node.

Lymphatic drainage and CTV in breast cancer.

Conformal radiotherapy has improved the technique and favored the solution of the problem of limiting cardiac and pulmonary irradiation. However new uncertainties have arisen especially with regard to treatment reproducibility. Passing from the clinical concept of CTV to the geometric concept of PTV, the anatomic identification of the different structure becomes of major importance together with the knowledge of the clinical evolution of breast cancer. The irradiation of breast lymph nodes now requires, if possible, 3D conformal processing of the treatment. Treatment parameters should be selected as to ensure adequate irradiation of target volumes while sparing healthy tissues as much as possible. In a near future, IMRT should be able to markedly improve the dose homogeneity to target with consequent lower cardiopulmonary toxicity.

Dose fractionation and biological optimization in breast cancer.

Standard radiotherapy in breast cancer is performed at the dose of 1.8-2 Gy daily 5 fractions a week for a total dose between 45 and 60 Gy. However research is addressed to different fractionations. For total time reduction, the interest was focused on conventional brachytherapy which radiobiologically represents "continuous" accelerated hyperfractionation, as well as on conventional external beam radiotherapy with accelerated hyperfractionation. A phase I study was conducted to define and validate a radiotherapy schedule with non conventional fractionation. Nine patients with metastatic breast cancer were enrolled in the study. None of them had undergone breast surgery or lymph node dissection. They were sequentially divided into three different, progressively increasing dose levels administered with double daily fractionation. Each schedule of accelerated fractionation (AF) included the administration of 1.8 Gy in two daily fractions, at least six hours apart for 10, 11 and 12 days and a total dose of 36, 39.6 and 43.2 Gy, respectively. Results of dose escalation, acute toxicity and mathematical calculation of radiobiological equivalence led to consider the dose of 36 Gy in 20 fractions during 10 days the most suitable for cost/benefit ratio within a non conventional fractionation.

Diagnostic imaging in the clinical management of patients at high risk for breast cancer.

Although being predominantly anecdotal, breast carcinoma shows a considerable component of multifactorial genetic transmission, referable to dominant autosomal inheritance. Among the genes responsible for hereditary breast cancer two main genes (BRCA1 and BRCA2) have already been identified. At present, genetic tests to identify known inherited mutations associated with breast tumor predisposition, are available. Asymptomatic subjects with genetic BRCA1/2 mutations represent a group at high risk; therefore it is now indispensable to work out adequate strategies of prevention and/or of early diagnosis. Besides education (information) and genetic counselling, there are three perspectives of intervention for these subjects: bilateral prophylactic surgery, pharmacologic prophylaxis and periodical diagnostic monitoring; unfortunately all of them are still burdened by limitations.

Role of magnetic resonance imaging in the pre and postchemotherapy evaluation in locally advanced breast carcinoma.

The study was carried out to evaluate the response to preoperative chemotherapy of locally advanced breast cancer with MRI. The series included 45 women with locally advanced breast cancer who underwent MRI before and after neoadjuvant chemotherapy. Based on the volume of residual disease, the response to chemotherapy was classified as: complete response, partial response, minor response, no change and disease progression. Responses to neoadjuvant chemotherapy were compared to MRI findings and to prognostic factors. Based on MRI findings 8 patients were assigned to the complete response group, 16 to the partial response group, 11 to the minor response group, 9 to the no change group and 1 patient to the disease progression group. MRI showed 90.2% sensitivity, 100% specificity and 91.1% accuracy. The correlation between MRI findings and prognostic factors may be useful to predict cancer aggressiveness and to understand the natural history of different breast carcinomas.

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.

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.

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.

Low-dose radiotherapy as a chemo-potentiator of a chemotherapy regimen with pemetrexed for recurrent non-small-cell lung cancer: a prospective phase II study.

PURPOSE: Low-dose radiotherapy (LDR) (<50 cGy) induces enhanced cell killing in vitro via the hyper-radiation sensitivity phenomenon. Aim of this study was to evaluate the safety and efficacy of a palliative regimen combining pemetrexed and LDR (as a chemopotentiator) on patients affected by recurrent non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: Eligible patients had an ECOG performance status ≤2, one prior chemotherapy regimen for advanced NSCLC, adequate organ function, measurable lesions. Patients received pemetrexed (500 mg/m(2) IV) and concurrent LDR (40 cGy bid on days 1 and 2) delivered to target pulmonary or metastatic disease. This cycle was repeated fourfold every 21 days. The accrual was determined by the single proportion powered analysis (α=0.05, power=0.8) with H0 ("bad" response probability, 9% according to literature) and H1 ("good" response probability, 35% ongoing study); 19 is the number required. RESULTS: Nineteen patients with stage III and IV disease were enrolled. Only one patient experienced neutropenia grade 4. All patients are evaluable for clinical response of irradiated lesion: overall response rate was 42%. CONCLUSIONS: Low-dose radiotherapy combined with pemetrexed has a similar toxicity profile to chemotherapy alone. The response rate of this novel approach is encouraging, since it was higher than what was reported for pemetrexed alone (42% versus 9.1%). Additional scientific investigation of this new treatment paradigm is warranted.

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.