Special stereotactic radiotherapy techniques: procedures and equipment for treatment simulation and dose delivery.

Stereotactic radiotherapy (SRT ) is a multi-step procedure with each step requiring extreme accuracy. Physician-dependent accuracy includes appropriate disease staging, multi-disciplinary discussion with shared decision-making, choice of morphological and functional imaging methods to identify and delineate the tumor target and organs at risk, an image-guided patient set-up, active or passive management of intra-fraction movement, clinical and instrumental follow-up. Medical physicist-dependent accuracy includes use of advanced software for treatment planning and more advanced Quality Assurance procedures than required for conventional radiotherapy. Consequently, all the professionals require appropriate training in skills for high-quality SRT. Thanks to the technological advances, SRT has moved from a "frame-based" technique, i.e. the use of stereotactic coordinates which are identified by means of rigid localization frames, to the modern "frame-less" SRT which localizes the target volume directly, or by means of anatomical surrogates or fiducial markers that have previously been placed within or near the target. This review describes all the SRT steps in depth, from target simulation and delineation procedures to treatment delivery and image-guided radiation therapy. Target movement assessment and management are also described.

Clinical implementation of 3D in vivo dosimetry for abdominal and pelvic stereotactic treatments.

PURPOSE: To analyze results from three years of in vivo transit EPID dosimetry of abdominal and pelvic stereotactic radiotherapy and to establish tolerance levels for routine clinical use. MATERIAL: 80 stereotactic VMAT treatments (152 fractions) targeting the abdomen or pelvis were analyzed. In vivo 3D doses were reconstructed with an EPID commercial algorithm. Gamma Agreement Index (GAI) and DVH differences in Planning Target Volume (PTV) and Clinical Target Volume (CTV) were evaluated. Initial tolerance level was set to GAI > 85% in PTV. Fractions Over Tolerance Level (OTL) were deemed to be due to set-up errors, incorrect use of immobilization devices, 4D errors, transit EPID algorithm errors and unknown/unidentified errors. Statistical Process Control (SPC) was applied to determine local tolerance levels. RESULTS: Average GAI were (82.7 ± 20.9) % in PTV and (72.9 ± 29.7) % in CTV. 37.8% of fractions resulted OTL and were classified as: set-up errors (3.3%), incorrect use of immobilization devices (2.1%), 4D errors (2.1%), EPID transit algorithm errors (17.1%). OTL causes for the remaining 13.2% of fractions were not identified. The differences between PTV and CTV measured in vivo and calculated mean dose (average difference ± standard deviation) were (-3.3% ± 3.2%) and (-2.3% ± 3.0%). When tolerance levels based on SPC to PTV mean dose differences were applied, the percentage of OTL decreased to 7% and no EPID algorithm error occurred. One error was not identified. CONCLUSIONS: The application of local tolerance levels to EPID in vivo dosimetry proved to be useful for detecting extra-lung SBRT treatment errors.

Does deep inspiration breath hold reduce plan complexity? Multicentric experience of left breast cancer radiotherapy with volumetric modulated arc therapy.

PURPOSE: Volumetric modulated arc therapy (VMAT) for left breast treatments allows heart sparing without compromising PTV coverage. However, this technique may require highly complex plans. Deep Inspiration Breath Hold (DIBH) procedure increases the heart-to-breast distance, facilitating the dose sparing of the heart. The aim of the present work was to investigate if the cardiac-sparing benefits of the DIBH technique were achieved with lower plan modulation and complexity than Free Breathing (FB) treatments. METHODS AND MATERIALS: Ten left side breast cases were considered by two centers with different treatment planning systems (TPS) and Linacs. VMAT plans were elaborated in FB and DIBH according to the same protocol. Plan complexity was evaluated by scoring several complexity indices. A new global score index accounting for both plan quality and dosimetric parameters was defined. Pre-treatment QA was performed for all VMAT plans using EPID and Epiqa software. RESULTS: DIBH-VMAT plans were associated with significant PTV coverage improvement and mean heart dose reduction (p < 0.003), increasing the resulting global score index. All the evaluated complexity indices showed lower plan complexity for DIBH plans than FB ones, but only in few cases the results were statistically significant. All plans passed the gamma analysis with the selected criteria. CONCLUSIONS: The DIBH technique is superior to the FB technique when the heart needs further sparing, allowing a reduction of the doses to OARs with a slightly lower degree of plan complexity and without compromising plan deliverability. These benefits were achieved regardless of the technological scenarios adopted.

A national multicenter study on 1072 DCIS patients treated with breast-conserving surgery and whole breast radiotherapy (COBCG-01 study).

BACKGROUND AND PURPOSE: Breast-conserving surgery (BCS) and whole breast radiation (RT) with or without endocrine therapy (ET) represent the standard of care for ductal carcinoma in situ (DCIS). The use of adjuvant treatments after surgery is still controversial in this setting. We performed a retrospective multicenter analysis on a series of DCIS patients treated with BCS and adjuvant RT. MATERIALS AND METHODS: We collected clinical data from nine Italian centers on 1072 women having a diagnosis of DCIS and treated between 1997 and 2012. We reported on the 5- and 10-year local recurrence (LR) rates, overall survival, and breast cancer specific survival (BCSS) employing the Kaplan-Meier method. RESULTS: At a median follow-up of 8.4 years, 67 LR (6.3%) and 47 deaths (4.4%) were observed. LR rates at 5 and 10 years were 3.4% and 7.6%, respectively. BCSS rates at 5 and 10 years were 99.7% and 99.1%, respectively. At univariate regression analysis, postmenopausal state (p = 0.009), estrogen receptor (ER) (p = 0.0001) and progesterone receptor (p = 0.018) positivity and ET (p = 0.006) were inversely correlated with LR. Final surgical margins (FSM) status <1 mm was significantly correlated with higher LR (p = 0.003). At multivariate regression analysis postmenopausal state (p = 0.03), and ER positive (p = 0.045) maintained the significant favorable feature, while FSM <1 mm (p = 0.024) confirmed its negative impact on LR. CONCLUSIONS: Our real-life study pointed out the significant favorable prognostic role of postmenopausal state and ER positive status on LR occurrence. FSM <1 mm was significantly correlated to a higher chance to experience LR.

Characterization of EPID software for VMAT transit dosimetry.

Dosimetry check (DC) is a commercial software that allows reconstruction of 3D dose distributions using transit electronic portal imaging device (EPID) images. In this work, we evaluated the suitability of DC software for volumetric modulated arc therapy (VMAT) transit dosimetry. The volumetric gamma agreement index 3%/3 mm between twenty VMAT dose distributions reconstructed by DC and calculated with treatment planning system (TPS) were compared to those obtained using PTW OCTAVIUS®4D to assess DC accuracy in VMAT quality assurance (QA). The sensitivity of DC in detecting VMAT delivery and set-up errors and anatomical variations has been investigated by measuring the variation of the gamma agreement index before and after the introduction of specific errors in four VMAT plans related to different anatomical sites. The influence of dose computation algorithm in presence of density inhomogeneity was also assessed. The assessment of VMAT QA shows agreements with TPS maps comparable to OCTAVIUS® 4D (OCT) in homogeneous phantom (p < 0.001). DC mean gamma agreement index was 94.2% ± 3.4, versus 95.6% ± 2.5 of OCT, lower dose threshold was set to 10%. Introduction of deliberate errors resulted in lower gamma agreement index and in 38/56 cases the gamma agreement index was over the detection threshold. The dose computation algorithm of DC is accurate in all anatomical sites except lung. However in lung cases, the aqua vivo approach used in this work reduced the algorithm dependence of DC results. DC accurately reproduced VMAT 3D dose distributions in phantom and is sensitive to detect errors caused by delivery inaccuracy and anatomical variations of patients.

Impact of hormonal status on outcome of ductal carcinoma in situ treated with breast-conserving surgery plus radiotherapy: Long-term experience from two large-institutional series.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a heterogeneous disease, for which the best adjuvant treatment is still uncertain. Many attempts of risk-groups stratification have been made over time, developing prognostic scores to predict risk of local recurrence (LR) on the basis of features such as age, final surgical margins (FSM) status, grade, and tumor size. The aim of our analysis was to evaluate the patterns of recurrence from a two large-institutional retrospective series. PATIENTS AND METHODS: We collected data on 457 patients treated with BCS and adjuvant RT between 1990 and 2012. Final analysis was performed on 278 patients, due to missing data about hormonal status (HS). Patients were treated at the Radiation Oncology Unit of the University of Florence (n = 195), and S. Maria Annunziata Hospital (n = 83) (Florence, Italy). RESULTS: At a median follow up time of 10.8 years (range 3-25), we observed 20 LR (7.2%). The 5-year and 10-year LR rates were 4.9% and 10.2%, respectively. At Cox regression univariate analysis, estrogen receptor (ER) positive status (p = 0.001), HS positive (p = 0.003), and FSM <1 mm (p = 0.0001) significantly impacted on LR. At Cox regression multivariate analysis positive ER status maintained a protective role (p = 0.003), and FSM status <1 mm its negative impact (p = 0.0001) on LR rate. CONCLUSIONS: Our experience confirmed the wide heterogeneity of DCIS. Inadequate FSM and negative ER status negatively influenced LR rates. Tumor biology should be integrated in adjuvant treatment decision-making process.

Accelerated partial breast irradiation using intensity-modulated radiotherapy versus whole breast irradiation: 5-year survival analysis of a phase 3 randomised controlled trial.

BACKGROUND: Accelerated partial breast irradiation (APBI) has been introduced as an alternative treatment method for selected patients with early stage breast cancer (BC). Intensity-modulated radiotherapy (IMRT) has the theoretical advantage of a further increase in dose conformity compared with three-dimensional techniques, with more normal tissue sparing. The aim of this randomised trial is to compare the local recurrence and survival of APBI using the IMRT technique after breast-conserving surgery to conventional whole-breast irradiation (WBI) in early stage BC. METHODS: This study was performed at the University of Florence (Florence, Italy). Women aged more than 40years affected by early BC, with a maximum pathological tumour size of 25mm, were randomly assigned in a 1:1 ratio to receive either WBI or APBI using IMRT. Patients in the APBI arm received a total dose of 30 Gy to the tumour bed in five daily fractions. The WBI arm received 50Gy in 25 fractions, followed by a boost on the tumour bed of 10Gy in five fractions. The primary end-point was occurrence of ipsilateral breast tumour recurrences (IBTRs); the main analysis was by intention-to-treat. This trial is registered with ClinicalTrials.gov, number NCT02104895. FINDINGS: A total of 520 patients were randomised (260 to external WBI and 260 to APBI with IMRT) between March 2005 and June 2013. At a median follow-up of 5.0 years (Interquartile Range (IQR) 3.4-7.0), the IBTR rate was 1.5% (three cases) in the APBI group (95% confidence interval (CI) 0.1-3.0) and in the WBI group (three cases; 95% CI 0.0-2.8). No significant difference emerged between the two groups (log rank test p=0.86). We identified seven deaths in the WBI group and only one in the APBI group (p=0.057). The 5-year overall survival was 96.6% for the WBI group and 99.4% for the APBI group. The APBI group presented significantly better results considering acute (p=0.0001), late (p=0.004), and cosmetic outcome (p=0.045). INTERPRETATION: To our knowledge, this is the first randomised study using the IMRT technique for APBI delivery. No significant difference in terms of IBTR and overall survival was observed between the two arms. APBI displayed a significantly better toxicity profile.

Radiotherapy timing in the treatment of limited-stage small cell lung cancer: the impact of thoracic and brain irradiation on survival.

AIMS AND BACKGROUND: Small cell lung cancer is an aggressive histologic subtype of lung cancer in which the role of chemotherapy and radiotherapy has been well established in limited-stage disease. We retrospectively reviewed a series of limited-stage small cell lung cancers treated with chemotherapy and thoracic and brain radiotherapy. METHODS AND STUDY DESIGN: A total of 124 patients affected by limited-stage small cell lung cancer has been treated over 10 years in our Institute. Fifty-three patients (42.8%) had concomitant radio-chemotherapy treatment and 71 patients (57.2%) a sequential treatment. Eighty-eight patients (70.9%) underwent an association of a platinum-derived drug (cisplatinum or carboplatinum) and etoposide. Prophylactic cranial irradiation was planned in all patients with histologically proven complete response to primary radio-chemotherapy. RESULTS: With a mean follow-up of 2.2 years, complete response was obtained in 50.8% of cases. We found a significant difference between different radio-chemotherapy association approaches (P = 0.007): percentages of overall survival were respectively 10.0%, 12.9% and 5.6% in early, late concomitant and sequential radio-chemotherapy timing. Cranial prophylaxis did not seem to influence overall survival (P = 0.21) or disease-free survival for local relapse (P = 0.34). CONCLUSIONS: Concomitant radio-chemotherapy is the best approach according to our experience. Our results show a benefit of prophylactic cranial irradiation in distant metastasis-free survival.

Vinorelbine-based chemo-radiotherapy in non-small cell lung cancer.

AIMS AND BACKGROUND: Concomitant radio-chemotherapy improves survival of patients with locally advanced non-small cell lung cancer, with a better local-regional control. METHODS AND STUDY DESIGN: We report our experience with vinorelbine-based chemotherapy in neoadjuvant and radical settings in 43 patients. Regimens consisted of cisplatin plus vinorelbine in 74.4% patients and carboplatin plus vinorelbine in 14.0%; 11.6% underwent mono-chemotherapy with oral vinorelbine. We estimated the crude probability of death or local recurrence by the Kaplan-Meier method. Cox regression models were used to identify the main significant predictors of death or local recurrence. RESULTS: A significant effect of the response to treatment was shown on both local disease free-survival (P = 0.004) and overall survival (P <0.0001). Patients with progressive disease after primary treatment had a significantly higher risk of further relapse at both univariate (P = 0.046) and multivariate regression analysis (P = 0.014) than patients with a complete response. They also showed a significantly higher risk of death at both univariate (P = 0.0005) and multivariate regression analysis (P <0.0001) than patients with a complete response. The most common toxicity was hematologic and gastroenteric. We recorded grade III/IV leukopenia in 11%, anemia in 6%, and esophagitis in 14% of the patients. CONCLUSIONS: Our experience showed that vinorelbine-based chemotherapy is an effective and safe regimen, in association with a platinum compound and thoracic radiotherapy.

Limited-stage small-cell lung cancer treated with early chemo-radiotherapy: the impact of effective chemotherapy.

AIMS AND BACKGROUND: Small cell lung cancer is characterized by an aggressive clinical course and a high sensitivity to both chemotherapy and radiotherapy. We present the Florence University experience in concurrent early radio-chemotherapy in patients affected by limited-stage small cell lung cancer, with particular emphasis on treatment safety, disease outcome and prognostic factors. METHODS AND STUDY DESIGN: Fifty-seven patients were treated between June 2000 and February 2005. All patients underwent platinum-based chemotherapy, administered intravenously following two different regimens, for at least three cycles. Eighteen patients (31.6%) received epirubicin and ifosfamide in 3-week cycles alternating with etoposide and cisplatin, administered on day 1 to 3; 39 patients (68.4%) received etoposide and cisplatin. A total of 6 cycles were planned. Radiotherapy was administered concurrently to the first cycle of etoposide and cisplatin. RESULTS: Clinical stage (P = 0.036) and number of chemotherapy courses (P = 0.009) emerged as the only significant death predictors at univariate analysis. Number of chemotherapy courses persisted as a significant death predictor also at multivariate regression analysis, with a reduced death risk for 5-6 chemotherapy cycles in comparison to 3-4 cycles (hazard ratio, 0.44). At a mean follow up of 38.5 months (standard deviation, 3.24 years; range, 6-164 months), considering the best overall tumor response achieved at any time during the whole treatment period, we obtained 32 complete responses (56.1%), 23 partial responses (40.3%) and 2 stable diseases. CONCLUSIONS: Our analysis showed that concurrent early radio-chemotherapy in limited-stage small cell lung cancer treatment represents a safe and effective approach in patients. We confirmed the relevant impact on overall survival of effective chemotherapy delivery.

Adjuvant radiotherapy after extrapleural pneumonectomy for mesothelioma. Prospective analysis of a multi-institutional series.

BACKGROUND AND PURPOSE: To evaluate survival, locoregional control and toxicity in a series of 56 mesothelioma patients treated from May 2005 to May 2010 with post-operative radiotherapy after extrapleural pneumonectomy (EPP) in three Italian Institutions (Brescia, Florence, and Modena). MATERIAL AND METHODS: Fifty-six patients treated with adjuvant radiotherapy (RT) after EPP were analyzed. Four patients were treated with 3DCRT, 50 with IMRT and two with helical tomotherapy. Forty-five to 50 Gy in 25 fractions were given to the affected hemithorax and to ipsilateral mediastinum, with a simultaneous integrated boost to the sites of microscopically involved margins up to 60 Gy in 20/56 cases. RESULTS: Three year locoregional control (LRC), distant metastasis free (DMF), disease free (DF), disease specific (DSS) and overall survival (OS) rates are 90%, 66%, 57%, 62%, and 60%, respectively. CONCLUSION: Postoperative RT with modern techniques is an effective method to obtain excellent local control and cure rates in mesothelioma patients submitted to EPP.

Post-operative radiotherapy in N2 non-small cell lung cancer: a retrospective analysis of 175 patients.

BACKGROUND AND PURPOSE: Post-operative radiotherapy (PORT) in radically resected non-small cell lung cancer (NSCLC) has the aim to reduce loco regional recurrence and to improve overall survival. PORT has been evaluated in several trials but indication to post-operative treatment in N2 patients is still debated. MATERIAL AND METHODS: We retrospectively analyzed 175 patients treated at University of Florence between 1988 and 2004 with completely resected NSCLC stages IIIA-IIIB, N2 disease. Surgery consisted in a lobectomy in 58.9% and in a bi-lobectomy or in a pneumonectomy in 41.1% of patients. One hundred and nineteen patients underwent PORT and 56 patients did not receive PORT (no-PORT). RESULTS: At a median follow-up of 27.6 months (range 4-233 months), we found a significant reduction in local recurrence (LR) in PORT group (log-rank test p=0.015; HR: 0.45; 95%CI: 0.24-0.87). No statistical difference were found in terms of overall survival (OS) (log-rank test p=0.92). Concerning other prognostic factors, male sex emerged as statistically significant (HR:4.33;1.04-18.02) on local progression free survival (LPFS) at univariate analysis. Acute and long-term toxicity was mild. CONCLUSION: Our retrospective analysis showed that PORT may improve local disease control in N2 NSCLC patients with an acceptable treatment-related toxicity.

Localized prostate cancer treated with intensity-modulated radiotherapy.

AIMS AND BACKGROUND: The development and use of new radiotherapy techniques, especially 3D conformal radiotherapy or intensity-modulated radiotherapy, has allowed the safe application of high doses of external beam radiotherapy without increasing toxicity. The aim of this analysis was to describe the acute and when possible late toxicity and the feasibility on using intensity-modulated radiotherapy into our routine work. PATIENTS AND METHODS: From June 2003 to December 2004, 60 patients with prostate cancer underwent high dose (80 Gy) radiotherapy treatment with intensity-modulated radiotherapy at the University of Florence. In the current analysis, we included patients without clinical or radiographic evidence of distant disease at the time of the first evaluation in the radiotherapy unit. RESULTS: Intensity-modulated radiotherapy treatments were delivered successfully without any interruption or technical problem. High-dose intensity-modulated radiotherapy was well tolerated acutely. Four patients (10%) developed grade 1 late rectal toxicity after completion of intensity-modulated radiotherapy and 8 patients (20%) developed grade 1 late urinary symptoms. CONCLUSIONS: Intensity-modulated radiotherapy is the approach of choice for high-dose radiotherapy delivery. No patient had severe toxicity (grade 3) despite the high dose delivered. From a cost-benefit point of view, our experience shows that delivery of intensity-modulated radiotherapy requires only minor corrections to the ordinary activity schedule.

Loco regional failure pattern after lumpectomy and breast irradiation in 4,185 patients with T1 and T2 breast cancer. Implications for nodal irradiation.

The aim of this study is to determinate incidence and risk factors for loco regional failure (LRR) (breast, supraclavicular, axillary and internal mammary nodes) and indications for nodal irradiation. From January 1980 to December 2001, 4,185 patients with T1-T2 breast cancer were treated with conservative surgery and whole breast radiotherapy without nodal irradiation at the University of Florence. The median age was 55 years (range 19-86). All patients were followed for a median of eight years (range 3 months to 20 years). Multivariate analysis showed as independent prognostic factors for isolated nodal relapse (NR) the presence of more than three positive lymph nodes (PAN) (p = 0.001), angiolymphatic invasion (p = 0.002) and pT2 (p = 0.02). However, only 4.8% of patients with more than three PAN developed NR as the only site of recurrence. Having one to three PAN was not associated with an increased risk of NR. We believe that it is not necessary to prescribe nodal irradiation to patients with negative or one to three PAN. Regarding patients with more than three PAN, the number of isolated NR is also small to routinely justify a node irradiation.

Late treatment-related complications in 214 patients with extremity soft-tissue sarcoma treated by surgery and postoperative radiation therapy.

BACKGROUND: We assessed the occurrence of long-bone fracture and other side effects in a group of 214 consecutive patients who underwent radical excision for soft-tissue sarcoma of the limb followed by postoperative irradiation. METHODS: Two hundred fourteen patients underwent postoperative irradiation after radical excision of soft-tissue sarcoma of the limb; 156 (73%) received postoperative brachytherapy (BRT) plus external-beam radiation therapy (EBRT), and 58 (27%) underwent postoperative EBRT only. All patients were followed-up for a median time of 4.5 years (range 3 months to 10 years). RESULTS: Seven patients developed bone fracture, which is considered severe morbidity; time between surgery and occurrence of fracture ranged between 10 and 72 months (average 31). Severe sclerosis with impairment of limb function was diagnosed in 5 and peripheral nerve damage in 3 patients. Wound complications were detected in 8 patients. CONCLUSIONS: In our series, no statistically significant correlation between bone fracture and clinical features or "technical" parameters was found, but all of the patients who experienced bone fracture (7 of 7) were postmenopausal women >55 years old.

Accelerated intensity-modulated external radiotherapy as a new technical approach to treat the index quadrant after conserving surgery in early breast cancer: a preliminary study.

PURPOSE: We present a novel technical approach to treat the index quadrant after conserving surgery in patients with early breast cancer and study its clinical feasibility. METHODS AND MATERIAL: Patients selected for the study, after breast conserving surgery with histologically verified breast carcinoma, signed a full informed consent to intensity-modulated external radiotherapy of the partial breast. Treatment was performed with the 6 MV beam from one of the Elekta Precise LINAC units installed in our Department. The prescribed dose was 30 Gy in 5 fractions in 10 days. RESULTS: Acute toxicity was minimal. No skin changes were noted during treatment or during the first 6 months after radiotherapy treatment. CONCLUSIONS: Accelerated partial breast irradiation using intensity-modulated external radiotherapy is technically feasible. We think the approach will give good results in terms of local control, toxicity and quality of life, at the same time sparing resources for the patient and health care system.