DNA Methyltransferase Gene Polymorphisms for Prediction of Radiation-Induced Skin Fibrosis after Treatment of Breast Cancer: A Multifactorial Genetic Approach.

PURPOSE: This study was conducted to investigate the role of four polymorphic variants of DNA methyltransferase genes as risk factors for radiation-induced fibrosis in breast cancer patients. We also assessed their ability to improve prediction accuracy when combined with mitochondrial haplogroup H, which we previously found to be independently associated with a lower hazard of radiation-induced fibrosis. MATERIALS AND METHODS: DNMT1 rs2228611,DNMT3A rs1550117,DNMT3A rs7581217, and DNMT3B rs2424908 were genotyped by real-time polymerase chain reaction in 286 Italian breast cancer patients who received radiotherapy after breast conserving surgery. Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue-Subjective Objective Management Analytical (LENT-SOMA) scale. The discriminative accuracy of genetic models was assessed by the area under the receiver operating characteristic curves (AUC). RESULTS: Kaplan-Meier curves showed significant differences among DNMT1 rs2228611 genotypes in the cumulative incidence of grade ≥ 2 subcutaneous fibrosis (log-rank test p-value= 0.018). Multivariate Cox regression analysis revealed DNMT1 rs2228611 as an independent protective factor for moderate to severe radiation-induced fibrosis (GG vs. AA; hazard ratio, 0.26; 95% confidence interval [CI], 0.10 to 0.71; p=0.009). Adding DNMT1 rs2228611 to haplogroup H increased the discrimination accuracy (AUC) of the model from 0.595 (95% CI, 0.536 to 0.653) to 0.655 (95% CI, 0.597 to 0.710). CONCLUSION: DNMT1 rs2228611 may represent a determinant of radiation-induced fibrosis in breast cancer patients with promise for clinical usefulness in genetic-based predictive models.

Hypofractionated radiation therapy for breast cancer: long-term results in a series of 85 patients.

PURPOSE: Whole-breast irradiation after conservative surgery is the standard treatment for early breast cancer. The purpose of this study is to report the late toxicity, cosmetic result, and disease control in a group of patients treated with hypofractionated radiotherapy (RT) comparing results with retrospective data of a control group who underwent conventional RT. METHODS: From 2006 to 2008, 85 patients were treated with hypofractionated schedule to dose of 45 Gy, 2.25 Gy/fr, followed by a boost. We evaluated late toxicity, cosmetic result, and disease control. The data were compared to a control group of 70 patients who underwent conventional RT before 2006. RESULTS: At 8 years of follow-up, the cumulative incidence of late skin toxicity was 6.2 in the hypofractionated RT group and 7.5 in the standard RT group (p = 0.94). The cumulative incidence of late subcutaneous tissue toxicity was 11.6 in the hypofractionated RT group and 18.7 in the standard RT group (p = 0.23). Cosmetic outcome was rated as excellent or good in 84/85 patients of the hypofractionated RT group and in 68/70 patients of the conventional RT group (p = 0.7). No statistically significant differences were found in terms of local control (p = 0.05), disease-free survival (p = 0.06), or overall survival (p = 0.17) between the 2 groups. CONCLUSIONS: The present analysis, focused on long-term effects, disease control, and survival, confirms, in a daily practice setting, the low incidence of skin atrophy and fibrosis, the satisfactory cosmetic outcome, and the high grade of local and distant disease control with hypofractionated schedule.

Technical guidelines for head and neck cancer IMRT on behalf of the Italian association of radiation oncology - head and neck working group.

Performing intensity-modulated radiotherapy (IMRT) on head and neck cancer patients (HNCPs) requires robust training and experience. Thus, in 2011, the Head and Neck Cancer Working Group (HNCWG) of the Italian Association of Radiation Oncology (AIRO) organized a study group with the aim to run a literature review to outline clinical practice recommendations, to suggest technical solutions and to advise target volumes and doses selection for head and neck cancer IMRT. The main purpose was therefore to standardize the technical approach of radiation oncologists in this context. The following paper describes the results of this working group. Volumes, techniques/strategies and dosage were summarized for each head-and-neck site and subsite according to international guidelines or after reaching a consensus in case of weak literature evidence.

Prone versus supine position for adjuvant breast radiotherapy: a prospective study in patients with pendulous breasts.

PURPOSE: To analyze dosimetric parameters of patients receiving adjuvant breast radiotherapy (RT) in the prone versus supine position. METHODS AND MATERIALS: Forty-one out of 55 patients with pendulous breasts and candidates for adjuvant RT were enrolled in the study after informed consent. They underwent computed tomography (CT)-simulation in both prone and supine position. Target and non target volumes were outlined on CT images. Prescribed dose was 50 Gy delivered by two tangential photon fields followed by 10 Gy electron boost. Target coverage and dose homogeneity to clinical target volume (CTV) and planning target volume (PTV) were assessed by V95, V105 and V107 and dose to lung, heart and left anterior descending coronary artery (LAD) by V5, V10, V20, and mean and maximum dose. Data were analyzed by Student's t-test. RESULTS: CTV and PTV coverage was significantly better in supine than in prone position. Lung V5, V10, and V20 were significantly lower in prone than in supine position. Heart V5, V10, V20, and LAD mean and maximum dose, in the 17 patients with left breast tumor, were lower in prone than in supine position, but without statistical significance. Based on treatment planning data and on treatment feasibility, 29/41 patients (70.7%) were treated in prone position. Acute and late toxicities of patients treated in prone and in supine position were not statistically different. CONCLUSION: Prone position is a favorable alternative for irradiation of mammary gland in patients with pendulous breasts and in our series was adopted in 71% of the cases.

Common variants of eNOS and XRCC1 genes may predict acute skin toxicity in breast cancer patients receiving radiotherapy after breast conserving surgery.

PURPOSE: To evaluate the impact of functional polymorphisms in genes related to DNA repair mechanisms (XRCC1, TP53, MSH2, MSH3, XPD), oxidative stress response (GSTP1, GSTA1, eNOS, SOD2) and fibroblast proliferation (TGFß1) on the risk of acute skin toxicity in breast cancer patients receiving radiotherapy. MATERIAL AND METHODS: Skin toxicity was scored according to the Radiation Therapy Oncology Group criteria in 286 breast cancer patients who received radiotherapy after breast conserving surgery. Genotyping was conducted by PCR-RFLP analysis and real-time PCR allelic discrimination assay on genomic DNA extracted from peripheral blood. RESULTS: In the multivariate analysis, nominally significant associations, before multiple testing corrections, were found between XRCC1 T-77C (T carriers vs. CC, OR: 2.240, 95% CI: 1.015-4.941, P=0.046), eNOS G894T polymorphisms (TT vs. G carriers, OR: 2.473, 95% CI: 1.220-5.012, P=0.012), breast diameter (OR: 1.138, 95% CI: 1.001-1.293, P=0.048), boost dose-fractionation (3 Gy vs. no boost, OR: 4.902, 95% CI: 1.458-16.483, P=0.010) and ≥ grade 2 acute radiation skin toxicity in breast cancer patients. CONCLUSIONS: As our exploratory study suggests that XRCC1 T-77C and eNOS G874T may confer an increased risk of acute skin reactions to radiotherapy in breast cancer patients, further confirmatory studies are warranted to determine the clinical significance.

Common variants of GSTP1, GSTA1, and TGFß1 are associated with the risk of radiation-induced fibrosis in breast cancer patients.

PURPOSE: To provide new insights into the genetic basis of normal tissue radiosensitivity, we evaluated the association between eight polymorphic variants located in six genes related to DNA repair mechanisms, oxidative stress, and fibroblast proliferation (XRCC1 Arg399Gln, XRCC1 Arg194Trp, TP53 Arg72Pro, GSTP1 Ile105Val, GSTA1 C-69T, eNOS G894T, TGFß1 C-509T, and TGFß1 T869C) and the risk of subcutaneous fibrosis in a retrospective series of patients who received radiotherapy after breast-conserving surgery. METHODS AND MATERIALS: Subcutaneous fibrosis was scored according to the Late Effects of Normal Tissue--Subjective Objective Management Analytical scale in 257 breast cancer patients who underwent surgery plus adjuvant radiotherapy. Genotyping was conducted by polymerase chain reaction--restriction fragment length polymorphism analysis on genomic DNA extracted from peripheral blood. The association between genetic variants and the risk of moderate to severe fibrosis was evaluated by binary logistic regression analysis. RESULTS: Two hundred thirty-seven patients were available for the analysis. Among them, 41 patients (17.3%) developed moderate to severe fibrosis (Grade 2-3), and 196 (82.7%) patients displayed no or minimal fibrotic reactions (Grade 0-1). After adjustment of confounding factors, GSTP1 Ile105Val (odds ratio [OR] 2.756; 95% CI, 1.188-6.393; p = 0.018), GSTA1 C-69T (OR 3.223; 95% CI, 1.176-8.826; p = 0.022), and TGFß1 T869C (OR 0.295; 95% CI, 0.090-0.964; p = 0.043) polymorphisms were found to be significantly associated with the risk of Grade 2-3 radiation-induced fibrosis. In the combined analysis, carriers of three risk genotypes were found to be at higher odds for the development of Grade 2-3 fibrosis than were patients with two risk genotypes (OR 4.415; 95% CI, 1.553-12.551, p = 0.005) or with no or one risk genotype (OR 8.563; 95% CI, 2.671-27.447; p = 0.0003). CONCLUSIONS: These results suggest that functional variations in genes involved in oxidative stress response and fibroblast proliferation may modulate the development of radiation-induced fibrosis in breast cancer patients. The results of the combined analysis support the notion that approaches based on the combination of different genetic markers have the potential to predict normal tissue responses.

Concomitant chemo-radiotherapy for unresectable oesophageal cancer: A mono-institutional study on 40 patients.

BACKGROUND/AIM: To analyse clinical response, overall (OS) and disease free survival (DFS) and toxicity in patients with unresectable oesophageal cancer treated by concomitant chemo-radiotherapy (CRT). MATERIALS AND METHODS: Forty patients with stage IIa-IVa biopsy proven oesophageal carcinoma were treated with CRT. All patients were studied with endoscopy and CT and judged unresectable after multidisciplinary discussion. CRT consisted of 3 cycles of cisplatin 100 mg/m(2) or carboplatin 300 mg/m(2) on day 1 and 5-fluorouracil 1000 mg/m(2) as a continuous infusion of 96 h associated with concurrent 3D-conformal RT. By using 15 MeV X-rays, a total dose of 60-66 Gy was delivered with daily fractions of 1.8-2.0 Gy. RESULTS: Complete response (CR), partial response (PR) and no response (NR) were observed in 50%, 20% and 20% of cases, respectively. Of the 20 patients with CR, 15 developed loco-regional recurrent disease. OS and DFS rates at 3 and 5 years were 38%, 8%, 49% and 10%, respectively. Total radiation dose ≥60 Gy improved loco-regional control and complete response (CR vs. PR + NR; p = 0.004) influenced both DFS and loco-regional control. Grade 3 gastrointestinal and haematological acute toxicity occurred in 3/40 patients (7.5%). One patient developed grade 4 renal failure. Late toxicity was reported in 2/40 patients (5.0%), consisting of grade 3 radiation pneumonitis. CONCLUSIONS: Concomitant CRT for unresectable oesophageal cancer can result in an acceptable loco-regional control with limited toxicity. Response after treatment and total radiation dose influenced the outcome.

Variation in gynecological oncology follow-up practice: attributable to cancer centers or to patient characteristics? A Piedmont Regional Oncology Network Study.

AIMS AND BACKGROUND: Although guidelines recommend minimalist follow-up, there is wide variability in gynecological oncology practice. The aims of this study were to describe between-center differences in the follow-up of endometrial, ovarian, and uterine cervical cancer; to identify the determinants of test prescription; to estimate the related costs; and to assess the weight of center habits and patient characteristics as sources of unexplained variability. METHODS AND STUDY DESIGN: The medical records of patients treated between August 2004 and July 2005 for gynecological malignancies and followed up for the detection of recurrent disease were retrospectively collected from 29 centers of the Piedmont Oncology Network. Multivariate multilevel analyses were performed to study the determinants of test prescription and costs. RESULTS: Analyses were performed on 351 patients (median follow-up: 578 days). The unexplained variability in computed tomography prescriptions (26%), ultrasound prescriptions (17%), and total cost of follow-up (15%) can be attributed to center habits, independenty of the clinical characteristics of the patients. CONCLUSIONS: Much of the unexplained variability in the follow-up for gynecological malignancies is attributable to different habits of centers belonging to a cancer network. These results prompted us to design a multicenter randomized controlled trial to compare minimalist versus intensive follow-up programs in endometrial cancer.

Detection of setup uncertainties with 3D surface registration system for conformal radiotherapy of breast cancer.

AIM: To investigate the clinical application of a technique for patient set-up verification in breast cancer radiotherapy based on a 3D surface image registration system. BACKGROUND: Accurate and reproducible patient set-up is a prerequisite to correctly deliver fractionated radiotherapy. Various approaches are available to verify and correct patient setup for 3D image acquisition in a radiation treatment room. MATERIALS AND METHODS: The study analyzed the setup reproducibility of 15 patients affected by breast cancer and candidates for conformal radiotherapy by using the AlignRT system (VisionRT, London, UK). At the initial setup, electronic portal imaging device (EPID) images were compared with Digitally Reconstructed Radiographs (DRRs) and a reference three-dimensional (3D) surface image was obtained by AlignRT. Surface images were acquired prior to every subsequent setup procedure. The systematic and random errors along longitudinal and vertical directions were measured and compared for the two systems. RESULTS: The procedure for surface registration, image acquisition and comparison with the reference image took less than 1 min on average. The T test for systematic error showed no significant difference between the 2 verification systems along the longitudinal (p = 0.69) and vertical (p = 0.67) axes. The T-test for random error showed a significant difference between the 2 systems along the vertical axis (p = 0.05). CONCLUSION: AlignRT is fast, simple, non-invasive and seems to be reliable in detecting patient setup errors. Our results suggest that it could be used to assess the setup reproducibility for breast cancer patients.

Hypofractionated radiotherapy after conservative surgery for breast cancer: analysis of acute and late toxicity.

BACKGROUND: A variety of hypofractionated radiotherapy schedules has been proposed after breast conserving surgery in the attempt to shorten the overall treatment time. The aim of the present study is to assess acute and late toxicity of using daily fractionation of 2.25 Gy to a total dose of 45 Gy to the whole breast in a mono-institutional series. METHODS: Eighty-five women with early breast cancer were assigned to receive 45 Gy followed by a boost to the tumour bed. Early and late toxicity were scored according to the Radiation Therapy Oncology Group criteria. For comparison, a group of 70 patients with similar characteristics and treated with conventional fractionation of 2 Gy to a total dose of 50 Gy in 25 fractions followed by a boost, was retrospectively selected. RESULTS: Overall median treatment duration was 29 days for hypofractionated radiotherapy and 37 days for conventional radiotherapy. Early reactions were observed in 72/85 (85%) patients treated with hypofractionation and in 67/70 (96%) patients treated with conventional fractionation (p = 0.01). Late toxicity was observed in 8 patients (10%) in the hypofractionation group and in 10 patients (15%) in the conventional fractionation group, respectively (p = 0.4). CONCLUSIONS: The hypofractionated schedule delivering 45 Gy in 20 fractions shortened the overall treatment time by 1 week with a reduction of skin acute toxicity and no increase of late effects compared to the conventional fractionation. Our results support the implementation of hypofractionated schedules in clinical practice.

FDG-PET/CT imaging for staging and radiotherapy treatment planning of head and neck carcinoma.

BACKGROUND: Positron emission tomography (PET) has a potential improvement for staging and radiation treatment planning of various tumor sites. We analyzed the use of 18F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) images for staging and target volume delineation of patients with head and neck carcinoma candidates for radiotherapy. METHODS: Twenty-two patients candidates for primary radiotherapy, who did not receive any curative surgery, underwent both CT and PET/CT simulation. Gross Tumor Volume (GTV) was contoured on CT (CT-GTV), PET (PET-GTV), and PET/CT images (PET/CT-GTV). The resulting volumes were analyzed and compared. RESULTS: Based on PET/CT, changes in TNM categories and clinical stage occurred in 5/22 cases (22%). The difference between CT-GTV and PET-GTV was not statistically significant (p = 0.2) whereas the difference between the composite volume (PET/CT-GTV) and CT-GTV was statistically significant (p < 0.0001). CONCLUSION: PET/CT fusion images could have a potential impact on both tumor staging and treatment planning.

Prevention of malignant seeding at drain sites after invasive procedures (surgery and/or thoracoscopy) by hypofractionated radiotherapy in patients with pleural mesothelioma.

INTRODUCTION: Literature data show that mesothelioma cells can implant along the surgical pathway of invasive procedures such as thoracotomy and thoracoscopy. We investigated the use of hypofractionated radiotherapy for preventing such malignant seeding. MATERIAL AND METHODS: Thirty-two consecutive patients diagnosed with pleural mesothelioma were included in the present retrospective study. All patients underwent surgery and/or thoracoscopy for diagnosis, staging or talc pleurodesis. They were treated with electron external beam radiation therapy (21 Gy in 3 fractions over 1 week), directed to the surgical pathway after the invasive procedure. After completion of radiation treatment, 20 of 32 patients (63%) underwent chemotherapy. RESULTS: After a mean follow-up of 13.6 months (range 3-41) from the end of radiation therapy, no patient had tumour progression in the treated area. The treatment was well tolerated, as only erythema grade I (Radiation Therapy Oncology Group, RTOG, scale) was noted in 11 patients. Seventeen patients died of disease with local progression after a mean survival time of 12.6 months (range 3-27); thirteen patients are alive with disease after a mean follow-up of 13.9 months (range 4-41); two patients are alive without evidence of disease after a mean follow-up of 16.50 months (range 6-27). DISCUSSION: The present study shows the efficacy and safety of local radiotherapy in preventing malignant seeding after thoracoscopy in patients with pleural mesothelioma although larger prospective trials are probably still needed to validate this treatment approach.

Pulmonary changes after radiotherapy for conservative treatment of breast cancer: a prospective study.

PURPOSE: Radiotherapy (RT) after conservative surgery for breast cancer involves part of the pulmonary parenchyma with a potential detrimental effect of reducing the normal functional reserve. Such an effect deserves to be studied in depth, considering the given long life expectancy of these women. We prospectively analyzed high-resolution computed tomography (HRCT) and pulmonary function tests (PFTs) with correlation with dosimetric data from RT. METHODS AND MATERIALS: Lung HRCT and PFTs were performed in 41 women who had undergone conservative surgery for breast cancer before and 3 and 9 months after postoperative RT. The PFTs included forced vital capacity, forced expiratory volume in 1 s, total lung capacity, maximal expiratory flow at 50% and 25% of vital capacity, and the diffusion capacity of carbon monoxide. HRCT was matched with the RT treatment plan images to analyze the dosimetric correlation. RESULTS: At 3 months after RT, the lung alterations were classified at HRCT as follows: 46.3% were Grade 1, 24.4% Grade 2, and 7.3% Grade 3, and at 9 months, 58.5% were Grade 1, 19.5% Grade 2, and 0% Grade 3. The PFTs showed a significant decrease at 3 months, with only partial recovery at 9 months. Chemotherapy, but not hormonal therapy, was associated with PFT changes. The grade of fibrosis increased with increasing lung volume treated to a dose > or = 25 Gy. CONCLUSION: Lung changes, mainly related to damage to the alveolar-capillary barrier and smallest airway ramifications, were observed at 3 months, with only partial recovery at 9 months after RT. Minimizing the lung volume receiving > or = 25 Gy could reduce pulmonary toxicity.

Delineation of target volume for radiotherapy of high-grade gliomas by 99m Tc-MIBI SPECT and MRI fusion.

BACKGROUND AND PURPOSE: Computed tomography (CT) and magnetic resonance imaging (MRI) are traditionally used for treatment planning of high-grade glioma. 99m Tc-methoxy-isobutyl-isonitrile (MIBI) single-photon emission computed tomography (SPECT) showed high sensitivity and specificity in literature series. In the present study, it was investigated how the information provided by 99m Tc-MIBI SPECT and MRI fusion could affect target delineation for radiotherapy of high-grade glioma. PATIENTS AND METHODS: 21 patients with high-grade glioma were studied by MRI and 99m Tc-MIBI SPECT imaging. The gross tumor volume (GTV) was outlined on MRI (MRI-GTV) and SPECT images (SPECT-GTV). Three additional volumes were analyzed: the (MRI+SPECT)-GTV representing the whole amount of MRI-GTV plus SPECT-GTV, the (MRI&SPECT)-GTV identified by the overlapping region of MRI-GTV and SPECT-GTV, and the (SPECT/MRI)-GTV identified by the extension of SPECT-GTV outside MRI-GTV. RESULTS: MRI contrast-enhanced and 99m Tc-MIBI SPECT-positive lesions were found in all 21 patients. The average SPECT-GTV was slightly larger than the average MRI-GTV, with greater difference for resected than for unresected cases. The average increment of (MRI+SPECT)-GTV compared to MRI-GTV was 33%, being significantly higher for resected than for unresected cases (p = 0.006). CONCLUSION: The fusion of 99m Tc-MIBI SPECT and MRI significantly affected the delineation of the target volume identified by MRI alone.

Role of radiotherapy in the treatment of cervical lymph node metastases from an unknown primary site: retrospective analysis of 113 patients.

PURPOSE: The management of patients with cervical lymph-node metastases from unknown primary site (UPS) remains a matter of discussion. This study aimed to analyze the results and prognostic factors in a series of patients treated with radiotherapy. METHODS AND MATERIALS: Data from 113 patients who presented with cervical lymph nodes metastases from UPS treated from 1980 to 2004 were reviewed. Eighty-seven patients (77.0%) were squamous cell carcinoma (SCC). Ninety-one patients were treated with curative and 22 with palliative intent. Fifty-nine of 113 patients (52.2%) received surgery followed by radiotherapy and 54 of 113 (47.8%) received radiotherapy alone. Radiotherapy was delivered to the neck and pharyngeal mucosa in 67 patients and to the ipsilateral or bilateral neck in 45 patients. Twenty-one patients (18.5%) also received chemotherapy. RESULTS: The 5-year overall survival rates were 40.7% for the entire group and 46.6% for the SCC subgroup. The occurrence of the occult primary was observed in 23 of 113 patients (20.3%), 19 (82.6%) within the head and neck region. At multivariate analysis, treatment with curative intent and extensive irradiation of bilateral neck and pharyngeal mucosa were favorable prognostic factors for the whole series, and treatment with curative intent, extensive irradiation of bilateral neck and pharyngeal mucosa, and absence of extracapsular spread were favorable prognostic factors for the SCC subgroup. CONCLUSIONS: Patients with cervical lymph node metastases from UPS have a similar prognosis to those affected by other head and neck malignancies. Curative treatment strategies including neck dissection and extensive irradiation by three-dimensional conformal radiation therapy resulted in significantly better outcomes.

Voice quality after treatment for T1a glottic carcinoma--radiotherapy versus laser cordectomy.

The purpose of this study was to assess the anatomic and functional outcomes and compare the voice quality in patients affected by T1a glottic carcinoma treated with curative intent with radiotherapy or laser cordectomy. Fifty-seven cases were analysed: 27 after curative radiotherapy and 30 after laser cordectomy. All patients were studied with videolaryngostroboscopy, voice analysis by narrow spectrogram, and vocal parameters (Jitter, Shimmer, noise/harmonic ratio, and diplophonia). Videolaryngostroboscopy showed severe glottic inadequacy in 25% of cases treated with radiation and insufficient compensation 'ventricular band' or 'with arytenoid hyperadduction' in 65% of cases after surgery. Severe dysphonia on the electro-acoustic analysis of voice was observed in 25% of cases after radiation and 70% after laser (p < 0.001). Fundamental frequency and vocal parameters showed more favourable results in the radiation group (p < 0.001). Voice assessment showed better results after radiotherapy compared with laser cordectomy. Voice outcome should be carefully considered in the treatment decision for T1 glottic carcinoma.