Stefano Bracci

Image Guided Hypofractionated 3-Dimensional Radiation Therapy in Patients With Inoperable Advanced Stage Non-Small Cell Lung Cancer

PURPOSE Hypofractionated radiation therapy (HypoRT) can potentially improve local control with a higher biological effect and shorter overall treatment time. Response, local control, toxicity rates, and survival rates were evaluated in patients affected by inoperable advanced stage non-small cell lung cancer (NSCLC) who received HypoRT. METHODS AND MATERIALS Thirty patients with advanced NSCLC were enrolled; 27% had stage IIIA, 50% had stage IIIB, and 23% had stage IV disease. All patients underwent HypoRT with a prescribed total dose of 60 Gy in 20 fractions of 3 Gy each. Radiation treatment was delivered using an image guided radiation therapy technique to verify correct position. Toxicities were graded according to Radiation Therapy Oncology Group morbidity score. Survival rates were estimated using the Kaplan-Meier method. RESULTS The median follow-up was 13 months (range, 4-56 months). All patients completed radiation therapy and received the total dose of 60 Gy to the primary tumor and positive lymph nodes. The overall response rate after radiation therapy was 83% (3 patients with complete response and 22 patients with partial response). The 2-year overall survival and progression-free survival rates were 38.1% and 36%, respectively. Locoregional recurrence/persistence occurred in 11 (37%) patients. Distant metastasis occurred in 17 (57%) patients. Acute toxicities occurred consisting of grade 1 to 2 hematological toxicity in 5 patients (17%) and grade 3 in 1 patient; grade 1 to 2 esophagitis in 12 patients (40%) and grade 3 in 1 patient; and grade 1 to 2 pneumonitis in 6 patients (20%) and grade 3 in 2 patients (7%). Thirty-three percent of patients developed grade 1 to 2 late toxicities. Only 3 patients developed grade 3 late adverse effects: esophagitis in 1 patient and pneumonitis in 2 patients. CONCLUSIONS Hypofractionated curative radiation therapy is a feasible and well-tolerated treatment for patients with locally advanced NSCLC. Randomized studies are needed to compare HypoRT to conventional treatment.

Efficacy and Safety of Adjuvant Proton Therapy Combined With Surgery for Chondrosarcoma of the Skull Base: A Retrospective, Population-Based Study

PURPOSE Chondrosarcoma is a rare malignant tumor of the cartilage affecting young adults. Surgery, followed by charged-particle irradiation, is considered the reference standard for the treatment of patients with grade I to II skull base chondrosarcoma. The present study was conducted to assess the effect of the quality of surgery and radiation therapy parameters on local control (LC) and overall survival (OS). METHODS AND MATERIALS From 1996 to 2013, 159 patients (median age 40 years, range 12-83) were treated with either protons alone or a combination of protons and photons. The median total dose delivered was 70.2 Gy (relative biologic effectiveness [RBE]; range 67-71). Debulking and biopsy were performed in 133 and 13 patients, respectively. RESULTS With a median follow-up of 77 months (range 2-214), 5 tumors relapsed based on the initial gross tumor volume. The 5- and 10-year LC rates were 96.4% and 93.5%, respectively, and the 5- and 10-year OS rates were 94.9% and 87%, respectively. A total of 16 patients died (13 of intercurrent disease, 3 of disease progression). On multivariate analysis, age <40 years and primary disease status were independent favorable prognostic factors for progression-free survival and OS, and local tumor control was an independent favorable predictor of OS. In contrast, the extent of surgery, dosimetric parameters, and adjacent organs at risk were not prognostic factors for LC or OS. CONCLUSIONS Systematic high-dose postoperative proton therapy for skull base chondrosarcoma can achieve a high LC rate with a low toxicity profile. Maximal safe surgery, followed by high-dose conformal proton therapy, is therefore recommended.

Intensity modulated radiotherapy in early stage Hodgkin lymphoma patients: Is it better than three dimensional conformal radiotherapy?

BackgroundCure rate of early Hodgkin Lymphoma are high and avoidance of late toxicities is of paramount importance. This comparative study aims to assess the normal tissue sparing capability of intensity-modulated radiation therapy (IMRT) versus standard three-dimensional conformal radiotherapy (3D-CRT) in terms of dose-volume parameters and normal tissue complication probability (NTCP) for different organs at risk in supradiaphragmatic Hodgkin Lymphoma (HL) patients.MethodsTen HL patients were actually treated with 3D-CRT and all treatments were then re-planned with IMRT. Dose-volume parameters for thyroid, oesophagus, heart, coronary arteries, lung, spinal cord and breast were evaluated. Dose-volume histograms generated by TPS were analyzed to predict the NTCP for the considered organs at risk, according to different endpoints.ResultsRegarding dose-volume parameters no statistically significant differences were recorded for heart and origin of coronary arteries. We recorded statistically significant lower V30 with IMRT for oesophagus (6.42 vs 0.33, p = 0.02) and lungs (4.7 vs 0.1 p = 0.014 for the left lung and 2.59 vs 0.1 p = 0.017 for the right lung) and lower V20 for spinal cord (17.8 vs 7.2 p = 0.02). Moreover the maximum dose to the spinal cord was lower with IMRT (30.2 vs 19.9, p <0.001). Higher V10 with IMRT for thyroid (64.8 vs 95, p = 0.0019) and V5 for lungs (30.3 vs 44.8, p = 0.03, for right lung and 28.9 vs 48.1, p = 0.001 for left lung) were found, respectively. Higher V5 and V10 for breasts were found with IMRT (V5: 4.14 vs 20.6, p = 0.018 for left breast and 3.3 vs 17, p = 0.059 for right breast; V10: 2.5 vs 13.6 p = 0.035 for left breast and 1.7 vs 11, p = 0.07 for the right breast.) As for the NTCP, our data point out that IMRT is not always likely to significantly increase the NTCP to OARs.ConclusionsIn HL male patients IMRT seems feasible and accurate while for women HL patients IMRT should be used with caution.

Lung Metastases Treated With Stereotactic Ablative Radiation Therapy in Oligometastatic Colorectal Cancer Patients: Outcomes and Prognostic Factors After Long-Term Follow-Up

Background We evaluated a series of oligometastatic colorectal cancer (CRC) patients treated with stereotactic ablative body radiotherapy (SABR) delivered in all active lung metastases. Patients and Methods Forty‐four patients with 69 lung metastases were treated with SABR. Eleven patients presented with other sites of metastases before stereotactic body radiotherapy (SBRT), even though they had controlled/cured systemic disease. Results The median follow‐up was 36 months. The median overall survival (OS) was 38 months and 2 years, 3‐year OS rates were 67.7% and 50.8%, respectively. The median progression‐free survival (PFS) was 10 months and 2 years, 3‐year PFS rates were 20.3% and 16.2%, respectively. Local recurrence occurred in 16 patients (36%).The first site of failure was local only in 22%, distant only in 35%, and local and distant in 14% of the patients. The 1‐year, 2‐year, and 3‐year local PFS (LPFS) were 68.8%, 60.2%, and 54.2%, respectively. No Grade ≥ 3 toxicities were recorded in the univariate analysis; multiple lung metastases and synchronous oligometastatic disease were significantly associated with worse PFS (P = .04, and P < .001, respectively) and worse metastases‐free survival (MFS; P = .04, and P < .001, respectively). The type of response was identified as a significant prognostic factor for OS (P = .014), PFS (P = .006), and LPFS (P < .001). In multivariate analysis single lung metastases treated with SBRT was associated with better MFS (P = .015). Metachronous oligometastatic disease and type of response were associated with significantly better PFS. Conclusion Stereotactic body radiotherapy is a valid therapy in the treatment of lung metastases for oligometastatic CRC patients presenting long survival. The rate of local control remains lower compared with other primaries. Further prospective cohorts would better evaluate effective fractionation for patients with oligometastatic CRC. Micro‐Abstract We evaluated outcomes and prognostic factors of a series of patients with oligometastatic colorectal cancer treated with stereotactic ablative body radiotherapy delivered in all active lung metastases. Local control of lung metastases is high after stereotactic body radiotherapy but still lower compared with other primaries. No standard exists regarding the most appropriate dose and fractionation.

Role of radiation therapy in mycosis fungoides refractory to systemic therapy

The long natural history of early stage mycosis fungoides (MF) makes its management a difficult problem. Skin lesions are sensitive to different therapies and a variety of treatment modalities have been used, such as topical nitrogen mustard, puvatherapy, UV-B, retinoids, radiation therapy, extracorporal photopheresis and systemic chemotherapy. For patients with refractory early stage MF, treatment selection is made by clinical parameters such as the age, sex and performance status of the patients, as well as the institutional expertise and the toxicity profiles of the different therapeutic approaches. We report radiation therapy in a relapsed/resistant stage IB patient with mycosis fungoides treated with local radiation therapy for symptomatic progression unresponsive to bexarotene therapy. Total skin electron beam therapy has been employed in early stage and for limited skin failure MF, while the role of local radiation therapy in MF is less defined. In our experience local radiotherapy has proved to be a very efficient, tolerable and cost effective approach in patients with MF unresponsive to systemic approaches.

Potential Role of Single Nucleotide Polymorphisms of xrcc1 , xrcc3 , and rad51 in Predicting Acute Toxicity in Rectal Cancer Patients Treated With Preoperative Radiochemotherapy

Objectives: To investigate the association between polymorphisms of DNA repair genes and xenobiotic with acute adverse effects in locally advanced rectal cancer patients treated with neoadjuvant radiochemotherapy. Methods: Sixty-seven patients were analyzed for the current study. Genotypes in DNA repair genes XRCC1 (G28152A), XRCC3 (A4541G), XRCC3 (C18067T), RAD51 (G315C), and GSTP1 (A313G) were determined by pyrosequencing technology. Results: The observed grade ≥3 acute toxicity rates were 23.8%. Chemotherapy and radiotherapy were interrupted for 46 and 14 days, respectively, due to critical complications. Four patients were hospitalized, 6 patients had been admitted to the ER, and 5 patients received invasive procedures (2 bladder catheters, 2 blood transfusions, and 1 growth factor therapy). RAD51 correlated with acute severe gastrointestinal toxicity in heterozygosity (Aa) and homozygosity (AA) (P=0.036). Grade ≥3 abdominal/pelvis pain toxicity was higher in the Aa group (P=0.017) and in the Aa+AA group (P=0.027) compared with homozygous (aa) patients. Acute skin toxicity of any grade occurred in 55.6% of the mutated patients versus 22.8% in the wild-type group (P=0.04) for RAD51. XRCC1 correlated with skin toxicity of any grade in the Aa+AA group (P=0.03) and in the Aa group alone (P=0.044). Grade ≥3 urinary frequency/urgency was significantly higher in patients with AA (P=0.01), Aa (P=0.022), and Aa+AA (P=0.031) for XRCC3 compared with aa group. Conclusions: Our study suggested that RAD51, XRCC1, and XRCC3 polymorphisms may be predictive factors for radiation-induced acute toxicity in rectal cancer patients treated with preoperative combined therapy.

Manipulation of radiation-induced bystander effect in prostate adenocarcinoma by dose and tumor differentiation grade: in vitro study.

Abstract Purpose: This in vitro study evaluated the ability of prostate adenocarcinoma (ADC) cells to induce radiation-induced bystander effect (RIBE) exploring the factors that may be responsible and affect its intensity. The idea was to mimic a strong, clinically applicable RIBE that could lead to the development of innovative approaches in modern radiotherapy of prostate cancer, especially for those patients with hormone-refractory ADC in which radiotherapy might have a limited role. Materials and methods: Two human prostate cancer cell lines of different differentiation, PC-3 and DU-145, have been irradiated using wide range of doses to obtain radiation-conditioned medium (RCM), which was used to treat the unirradiated cells and to evaluate the cytokines level. Using a trypan blue dye exclusion method, cell growth was assessed. Results: Prostate ADC cells were able to induce RIBE; intensity depended on dose and cell differentiation. RIBE intensity of DU-145 was not correlated with the cytokines level, while for PC-3 Interleukin-6 (IL-6) correlates with strongest RIBE induced by 20 Gy. Conclusions: RIBE can be manipulated by modifying radiation dose and depends on cell differentiation status. IL-6 correlates with RIBE after exposure of PC-3 to a very high dose of radiation, thus indicates its possible involvement in bystander signaling.

Hypofractionated intensity-modulated simultaneous integrated boost and image-guided radiotherapy in the treatment of high-risk prostate cancer patients: a preliminary report on acute toxicity

AIMS AND BACKGROUND To evaluate acute toxicity of hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost and image-guided radiotherapy in the treatment of high-risk prostate cancer patients. METHODS Between November 2009 and March 2012, 59 patients with high-risk prostate cancer were enrolled. The eclipse inverse planning system (Varian) was used to calculate an IMRT plan with simultaneous integrated boost, delivering 68.75 Gy (2.75 Gy per fraction) to the prostate, 55 Gy (2.2 Gy per fraction) to the seminal vesicles and positive nodes, and 45 Gy (1.8 Gy per fraction) to the pelvis, 4 fractions per week, 25 fractions. Prior to each treatment, patients underwent a kilo-voltage cone-beam CT performing an image-guided radiation therapy (IGRT). All patients were submitted to neoadjuvant, concomitant and adjuvant hormone therapy. RESULTS The median follow-up for all patients was 13 months (range, 3-28). At the last follow-up, no grade 3 or 4 side effect was observed. Toxicity occurred as follows during the treatment: grade 1 and 2 gastrointestinal toxicity 5.2% and 6.9%, respectively; grade 1 and 2 genitourinary toxicity 24.1% and 1.7%, respectively. Only 1.7% of the patients developed grade 3 genitourinary toxicity. No grade 3 gastrointestinal toxicity was observed. CONCLUSIONS The present study demonstrated that 4/w hypofractionated intensity-modulated radiotherapy with simultaneous integrated boost and image-guided radiotherapy in patients with high-risk prostate cancer is feasible and safe. Low acute toxicity rates were verified. Longer follow-up is needed to evaluate the outcomes in terms of late toxicity and survival.

Multifraction radiotherapy for palliation of painful bone metastases: 20 Gy versus 30 Gy

Aims and Background To compare 2 multifraction radiotherapy schedules in the palliation of painful bone metastases. Methods and Study Design We retrospectively analyzed clinical data of 105 patients with a total of 140 painful bone metastases who were treated with 20 Gy in 5 fractions or 30 Gy in 10 fractions. The primary tumors were breast (30%), lung (28%), and prostate (14%). The main sites of irradiation were spine (n = 79) and sacrum or pelvis (n = 39). Pain was graded by patients according to the pain numeric rating scale just before and 1 month after radiotherapy. Pain progression was defined as an increase ≥2 on pain scale after an initial response. Results The overall response rate at 1 month was 88.6%. Overall response rate was 89.6% in the 20-Gy arm and 87.3% in the 30-Gy arm (p = 0.669). The rate of complete response was statistically better in patients treated with 30 Gy (p = 0.019). The mean reduction in pain was 3.2 in the 20-Gy group and 3.6 in the 30-Gy group. Pain progression was 6.5% and 1.6%, respectively. The incidence of acute toxicity was statistically significantly higher in the 30-Gy arm (23.8%) than in the 20-Gy arm (2.6%) (p = 0.001). One pathologic fracture of the irradiated bone was observed in the 30-Gy arm. Two lesions, one in each group, were re-irradiated for pain recurrence. Pain progression was found in 6.5% of the irradiated lesions in the 20-Gy arm and in 1.6% in the 30-Gy arm. Conclusions In our series, both regimens achieved high rate of pain relief, although the group treated with higher total dose reported better complete response rate. The 30-Gy arm had a significantly higher rate of acute toxicity.

Curative radiotherapy in patients with anal cancer: clinical outcomes and prognostic factors in a single-institution experience

PurposeOur aim was to retrospectively analyse a series of patients with anal cancer treated with curative intent at a single institute in terms of survival and local disease control.Materials and methodsForty-two patients with anal cancer were treated with primary radiotherapy with or without concurrent chemotherapy. The influence of the prognostic factors on overall (OS), disease-free (DFS), disease-specific (DSS), colostomy-free (CFS) and metastasis-free (MFS) survival was evaluated.ResultsNine patients had stage I, 15 stage II, four stage IIIA and 14 stage IIIB disease. Tumour progression/ persistence occurred in five patients (12%). The 5-year OS, DSS, DFS, CFS and MFS were 72.7%, 84.2%, 85.7%, 81.1% and 87.1%, respectively. On univariate analysis, T stage emerged as highly significant for OS, DSS, CFS and DFS, whereas N status was a significant prognostic factor for DSS. On multivariate analysis, T stage was a significant prognostic factor for OS and CFS.ConclusionsOur data support the view that combined chemoradiation treatment of anal cancer is feasible and may provide survival benefits with an acceptable rate of adverse effects. We should consider T and N stages as important prognostic factors for survival.RiassuntoObiettivoIl nostro obiettivo era quello di analizzare retrospettivamente una serie di pazienti con cancro anale trattati con intento curativo, in termini di sopravvivenza e controllo locale.Materiali e metodiQuarantadue pazienti con cancro anale sono stati trattati con radioterapia +/− chemioterapia concomitante. è stato valutato l’impatto dei fattori prognostici su sopravvivenza globale (OS), sopravvivenza libera da malattia (DFS), sopravvivenza specifica di malattia (DSS), sopravvivenza libera da colostomia (CFS) e sopravvivenza libera da metastasi (MFS).RisultatiLo stadio di malattia era: 9 pazienti stadio I, 15 pazienti stadio II, 4 pazienti stadio IIIA, e 14 stadio IIIB. La progressione/persistenza di malattia si è verificata in 5 pazienti (12%). I valori di OS, DSS, DFS, CFS, MFS a 5 anni sono stati 72,7%, 84,2%, 85,7% 81,1% e 87,1%, rispettivamente. All’analisi univariata, il T è emerso come fattore prognostico significativo per l’OS, DSS, CFS e DFS, mentre l’N è risultato significativo per la DSS. All’analisi multivariata, il T è risultato un fattore significativo per l’OS e la CFS.ConclusioniI nostri dati confermano che la radiochemioterapia nel cancro anale è fattibile e può fornire un beneficio di sopravvivenza con tossicità accettabili. Dovremmo considerare il T e l’N come importanti fattori prognostici per la sopravvivenza.