Filippo Alongi

Is Stereotactic Body Radiation Therapy an Attractive Option for Unresectable Liver Metastases? A Preliminary Report From a Phase 2 Trial

PURPOSE To evaluate the feasibility of high-dose stereotactic body radiation therapy (SBRT) in the treatment of unresectable liver metastases. METHODS AND MATERIALS Patients with 1 to 3 liver metastases, with maximum individual tumor diameters less than 6 cm and a Karnofsky Performance Status of at least 70, were enrolled and treated by SBRT on a phase 2 clinical trial. Dose prescription was 75 Gy on 3 consecutive days. SBRT was delivered using the volumetric modulated arc therapy by RapidArc (Varian, Palo Alto, CA) technique. The primary end-point was in-field local control. Secondary end-points were toxicity and survival. RESULTS Between February 2010 and September 2011, a total of 61 patients with 76 lesions were treated. Among the patients, 21 (34.3%) had stable extrahepatic disease at study entry. The most frequent primary sites were colorectal (45.9%) and breast (18%). Of the patients, 78.7% had 1 lesion, 18.0% had 2 lesions, and 3.3% had 3 lesions. After a median of 12 months (range, 2-26 months), the in-field local response rate was 94%. The median overall survival rate was 19 months, and actuarial survival at 12 months was 83.5%. None of the patients experienced grade 3 or higher acute toxicity. No radiation-induced liver disease was detected. One patient experienced G3 late toxicity at 6 months, resulting from chest wall pain. CONCLUSIONS SBRT for unresectable liver metastases can be considered an effective, safe, and noninvasive therapeutic option, with excellent rates of local control and a low treatment-related toxicity.

Feasibility and early clinical assessment of flattening filter free (FFF) based stereotactic body radiotherapy (SBRT) treatments

PurposeTo test feasibility and safety of clinical usage of Flattening Filter Free (FFF) beams for delivering ablative stereotactic body radiation therapy (SBRT) doses to various tumor sites, by means of Varian TrueBeam™ (Varian Medical Systems).Methods and MaterialsSeventy patients were treated with SBRT and FFF: 51 lesions were in the thorax (48 patients),10 in the liver, 9 in isolated abdominal lymph node, adrenal gland or pancreas. Doses ranged from 32 to 75 Gy, depending on the anatomical site and the volume of the lesion to irradiate. Lung lesions were treated with cumulative doses of 32 or 48 Gy, delivered in 4 consecutive fractions. The liver patients were treated in 3 fractions with total dose of 75 Gy. The isolated lymph nodes were irradiated in 6 fractions with doses of 45 Gy. The inclusion criteria were the presence of isolated node, or few lymph nodes in the same lymph node region, in absence of other active sites of cancer disease before the SBRT treatment.ResultsAll 70 patients completed the treatment. The minimum follow-up was 3 months. Six cases of acute toxicities were recorded (2 Grade2 and 2 Grade3 in lung and 2 Grade2 in abdomen). No patient experienced acute toxicity greater than Grade3. No other types or grades of toxicities were observed at clinical evaluation visits.ConclusionsThis study showed that, with respect to acute toxicity, SBRT with FFF beams showed to be a feasible technique in 70 consecutive patients with various primary and metastatic lesions in the body.

Radiation Dose-Response Relationship for Risk of Coronary Heart Disease in Survivors of Hodgkin Lymphoma

TO THE EDITOR: In their recent article in Journal of Clinical Oncology, van Nimwegen et al described a case-control study in a cohort of Hodgkin lymphoma (HL) survivors treated between 1965 and 1995 who had an increased risk of coronary heart disease (CHD) that was linearly related to mean heart radiation dose. The authors noted that “the linear radiation dose-response relationship identified can be used to predict CHD risk for future HL patients and survivors.” These findings are relevant in the management of long-termHL survivors, but in themodern era of combinedmodality treatment of HL, the role of radiation therapy (RT) has been significantly modified, leading to personalized RT in terms of clinical and technical aspects. In several settings, RT in combination with systemic therapies influences the natural history and management of malignancies, irrespective of adverse effects. A consequence of this therapeutic process is that prolongation of the survival of these patients inevitably exposes them to a greater risk of chronic diseases over the years. The issue of late cardiac toxicity is not new in the setting of irradiation for thoracic malignancies such as breast cancer. This aspect remains well recognized in the modern RT era, although there is a warning derived from retrospective evaluations in the era of old RT. The combination of RT and chemotherapy is considered the standard approach in HL. The use of limited radiation field (involved-field and involved-site RT) allows control of known tumor sites, whereas the use of limited cycles of chemotherapy can eradicate HL cells outside the radiation field. This approach, when compared with chemotherapy alone, has an advantage in diseasefree survival. The impact of reduced volumes and doses has been addressed, especially with the integration of modern imaging and advanced techniques for delivery of treatment. In this regard, the concept of extended-field irradiation has now been replaced by the use of detectable nodal irradiation that uses [F]fluorodeoxyglucose positron emission tomography, with results similar to those achieved with large volumes but fewer adverse events. The rationale for this therapeutic change is that recurrences in patients treated for HL occur in sites of previous involvement. Conversely, technological advances in RT, such as image-guided RT by means of on-board imaging, allow clinicians to improve the accuracy of delivery and thus minimize irradiation of healthy tissues. Apart from the adoption of intensitymodulated RT techniques (eg, volumetric-modulated arc therapy) that are potentially able to better reduce high doses tothe heart, other approaches could minimize heart radiation exposure in these patients. For example, in other thoracic diseases, breathing-adapted RT delivery could reduce the dose to the heart and left coronary artery. Using these techniques could improve the toxicity profile of RT in the near future. In regard to this scenario of new RT techniques and technologies, the study by van Nimwegen et al deserves critical evaluation. Most of patients analyzed in the study were treated with two-dimensional RT from 1965, which had a large impact on cardiac outcomes. Moreover, radiation charts and simulation radiographs were used to estimate in-field heart volume and mean heart dose without considering patient anatomy. In our opinion, the method seems rather crude. In the modern era of RT, it would be unthinkable to avoid accurate dosimetry using modern algorithms that adjust for tissue inhomogeneities. Thus, although RT allows radiation oncologists to improve the safety profile in their patients, the role of systemic therapy in treating cardiovascular damage is crucial. Anthracycline-based chemotherapy, a mainstay in HL as well as in other neoplastic diseases, has had a significant impact on cardiovascular morbidity. In conclusion, the issue of RT-induced cardiac risk needs to be revisited, especially considering the data emerging from the use of new RT techniques and reduced treatment volumes and doses. In the absence of these data, it seems that we are watching a black and white silent movie in the digital movie era.

Need for High Radiation Dose (≥70 Gy) in Early Postoperative Irradiation After Radical Prostatectomy: A Single-Institution Analysis of 334 High-Risk, Node-Negative Patients

PURPOSE To determine the clinical benefit of high-dose early adjuvant radiotherapy (EART) in high-risk prostate cancer (hrCaP) patients submitted to radical retropubic prostatectomy plus pelvic lymphadenectomy. PATIENTS AND METHODS The clinical outcome of 334 hrCaP (pT3-4 and/or positive resection margins) node-negative patients submitted to radical retropubic prostatectomy plus pelvic lymphadenectomy before 2004 was analyzed according to the EART dose delivered to the prostatic bed, <70.2 Gy (lower dose, median 66.6 Gy, n = 153) or >or=70.2 Gy (median 70.2 Gy, n = 181). RESULTS The two groups were comparable except for a significant difference in terms of median follow-up (10 vs. 7 years, respectively) owing to the gradual increase of EART doses over time. Nevertheless, median time to prostate-specific antigen (PSA) failure was almost identical, 38 and 36 months, respectively. At univariate analysis, both 5-year biochemical relapse-free survival (bRFS) and disease-free survival (DFS) were significantly higher (83% vs. 71% [p = 0.001] and 94% vs. 88% [p = 0.005], respectively) in the HD group. Multivariate analysis confirmed EART dose >or=70 Gy to be independently related to both bRFS (hazard ratio 2.5, p = 0.04) and DFS (hazard ratio 3.6, p = 0.004). Similar results were obtained after the exclusion of patients receiving any androgen deprivation. After grouping the hormone-naïve patients by postoperative PSA level the statistically significant impact of high-dose EART on both 5-year bRFS and DFS was maintained only for those with undetectable values, possibly owing to micrometastatic disease outside the irradiated area in case of detectable postoperative PSA values. CONCLUSION This series provides strong support for the use of EART doses >or=70 Gy after radical retropubic prostatectomy in hrCaP patients with undetectable postoperative PSA levels.

Volumetric modulated arc therapy with flattening filter free (FFF) beams for stereotactic body radiation therapy (SBRT) in patients with medically inoperable early stage non small cell lung cancer (NSCLC)

PURPOSE To assess the impact of volumetric modulated arc therapy (VMAT) with flattening filter free (FFF) beams for stereotactic body radiotherapy (SBRT) in inoperable stage I NSCLC. Current data were compared against a cohort of patients previously treated with advanced conformal techniques (3DCRT) based on conformal arcs. METHODS AND MATERIALS From July 2006 to December 2011 132 patients underwent SBRT, 86 by 3DCRT with flattened beams (FF), while the last 46 with VMAT RapidArc and unflattened beams (FFF). All patients were treated with 48 Gy in four fractions of 12 Gy each. Patients underwent follow-up. Clinical outcome was evaluated with thoracic and abdominal CT scan and 18FDG-CTPET before and after treatment. RESULTS Both techniques achieved adequate dose conformity to the target but with a statistically significant reduction of ipsilateral lung doses in RapidArc plans and also of Beam-on-Time (BOT) with FFF mode. The median follow up was 16 months (range 2-24 months). At 1 year, local control rate was 100% with FFF beams compared with 92.5% with FF beams (p=0.03). CONCLUSIONS SBRT with FFF beams permitted us a safe delivery of high dose per fraction in a short treatment time and resulted in an earlier radiological response compared with FF beams.

Evidence of Limited Motion of the Prostate by Carefully Emptying the Rectum as Assessed by Daily MVCT Image Guidance with Helical Tomotherapy

PURPOSE To assess setup and organ motion error by means of analysis of daily megavoltage computed tomography (MVCT) of patients treated with hypofractionated helical tomotherapy (71.4-74.2 Gy in 28 fractions). METHODS AND MATERIALS Data from 21 patients were analyzed. Patients were instructed to empty the rectum carefully before planning CT and every morning before therapy by means of a self-applied rectal enema. The position of the prostate was assessed by means of automatic bone matching (BM) with the planning kilovoltage CT (BM, setup error) followed by a direct visualization (DV) match on the prostate. Deviations between planning and therapy positions referred to BM and BM + DV were registered for the three main axes. In case of a full rectum at MVCT with evident shift of the prostate, treatment was postponed until after additional rectal emptying procedures; in this case, additional MVCT was performed before delivering the treatment. Data for 522 fractions were available; the impact of post-MVCT procedure was investigated for 17 of 21 patients (410 fractions). RESULTS Prostate motion relative to bony anatomy was limited. Concerning posterior-anterior shifts, only 4.9% and 2.7% of fractions showed deviation of 3 mm or greater of the prostate relative to BM without and with consideration of post-MVCT procedures, respectively. Interobserver variability for BM + DV match was within 0.8 mm (1 SD). CONCLUSIONS Daily MVCT-based correction is feasible. The BM + DV matching was found to be consistent between operators. Rectal emptying using a daily enema is an efficient tool to minimize prostate motion, even for centers that have not yet implemented image-guided radiotherapy.

Clinical factors predicting late severe urinary toxicity after postoperative radiotherapy for prostate carcinoma: a single-institute analysis of 742 patients.

PURPOSE To investigate the clinical factors independently predictive of long-term severe urinary sequelae after postprostatectomy radiotherapy. PATIENTS AND METHODS Between 1993 and 2005, 742 consecutive patients underwent postoperative radiotherapy with either adjuvant (n = 556; median radiation dose, 70.2 Gy) or salvage (n = 186; median radiation dose, 72 Gy) intent. RESULTS After a median follow-up of 99 months, the 8-year risk of Grade 2 or greater and Grade 3 late urinary toxicity was almost identical (23.9% vs. 23.7% and 12% vs. 10%) in the adjuvant and salvage cohorts, respectively. On univariate analysis, acute toxicity was significantly predictive of late Grade 2 or greater sequelae in both subgroups (p <.0001 in both cases), and hypertension (p = .02) and whole-pelvis radiotherapy (p = .02) correlated significantly in the adjuvant cohort only. The variables predictive of late Grade 3 sequelae were acute Grade 2 or greater toxicity in both groups and whole-pelvis radiotherapy (8-year risk of Grade 3 events, 21% vs. 11%, p = .007), hypertension (8-year risk, 18% vs. 10%, p = .005), age ≤ 62 years at RT (8-year risk, 16% vs. 11%, p = .04) in the adjuvant subset, and radiation dose >72 Gy (8-year risk, 19% vs. 6%, p = .007) and age >71 years (8-year risk, 16% vs. 6%, p = .006) in the salvage subgroup. Multivariate analysis confirmed the independent predictive role of all the covariates indicated as statistically significant on univariate analysis. CONCLUSIONS The risk of late Grade 2 or greater and Grade 3 urinary toxicity was almost identical, regardless of the RT intent. In the salvage cohort, older age and greater radiation doses resulted in a worse toxicity profile, and younger, hypertensive patients experienced a greater rate of severe late sequelae in the adjuvant setting. The causes of this latter correlation and apparently different etiopathogenesis of chronic damage in the two subgroups were unclear and deserve additional investigation.

PHASE I-II STUDY OF HYPOFRACTIONATED SIMULTANEOUS INTEGRATED BOOST WITH TOMOTHERAPY FOR PROSTATE CANCER

PURPOSE To report planning and acute toxicity data of the first 60 patients treated within a Phase I-II study with moderate hypofractionation by image-guided helical tomotherapy. METHODS AND MATERIALS Various clinical target volumes (CTVs) were defined: CTV1-pelvic nodes; CTV2-upper portion of seminal vesicles; CTV3-lower portion of SV; CTV4-prostate; overlap between planning target volume (PTV) 4 and rectum. Different doses to each PTV were simultaneously delivered in 28 fractions. For 31 low-risk patients: 56.0, 61.6, and 71.4 Gy for PTV2-4, respectively; for 20 intermediate-risk patients: 51.8, 61.6, 65.5, and 74.2 Gy for PTV1-4, respectively; for 9 high-risk patients: 51.8 and 65.5 Gy for PTV1-2 and 74.2 Gy for PTV3-4. For all patients, the dose to overlap was 65.5 Gy. RESULTS The mean fraction of rectum receiving more than 65 Gy (V65) and rectal Dmax were 10% and 70.8 Gy respectively. In cases of pelvic node irradiation, the intestinal cavity (outside PTV) receiving > 45 and 50 Gy was 86 and 12 cc, respectively. A homogeneous dose distribution within each PTV was guaranteed. Acute genitourinary toxicity according to RTOG scoring system was as follows: 21/60 (35%) Grade 1, 12/60 (20%) Grade 2, 2/60 (3%) Grade 3. Acute rectal toxicities were: 18/60 (30%) Grade 1. Twelve (20%) patients showed Grade 1 upper intestinal toxicity (uGI). No patients experienced > or = Grade 2 acute rectal or uGI side effects. CONCLUSIONS This study shows excellent results with regard to acute toxicity. Further research is necessary to assess definitive late toxicity and tumor control outcome.

Phase I-II study of hypofractionated simultaneous integrated boost using volumetric modulated arc therapy for adjuvant radiation therapy in breast cancer patients: a report of feasibility and early toxicity results in the first 50 treatments

BackgroundTo report results in terms of feasibility and early toxicity of hypofractionated simultaneous integrated boost (SIB) approach with Volumetric Modulated Arc Therapy (VMAT) as adjuvant treatment after breast-conserving surgery.MethodsBetween September 2010 and May 2011, 50 consecutive patients presenting early-stage breast cancer were submitted to adjuvant radiotherapy with SIB-VMAT approach using RapidArc in our Institution (Istituto Clinico Humanitas ICH). Three out of 50 patients were irradiated bilaterally (53 tumours in 50 patients). All patients were enrolled in a phase I-II trial approved by the ICH ethical committee. All 50 patients enrolled in the study underwent VMAT-SIB technique to irradiate the whole breast with concomitant boost irradiation of the tumor bed. Doses to whole breast and surgical bed were 40.5 Gy and 48 Gy respectively, delivered in 15 fractions over 3 weeks. Skin toxicities were recorded during and after treatment according to RTOG acute radiation morbidity scoring criteria with a median follow-up of 12 months (range 8–16). Cosmetic outcomes were assessed as excellent/good or fair/poor.ResultsThe median age of the population was 68 years (range 36–88). According to AJCC staging system, 38 breast lesions were classified as pT1, and 15 as pT2; 49 cases were assessed as N0 and 4 as N1. The maximum acute skin toxicity by the end of treatment was Grade 0 in 20/50 patients, Grade 1 in 32/50, Grade 2 in 0 and Grade 3 in 1/50 (one of the 3 cases of bilateral breast irradiation). No Grade 4 toxicities were observed. All Grade 1 toxicities had resolved within 3 weeks. No significant differences in cosmetic scores on baseline assessment vs. 3 months and 6 months after the treatment were observed: all patients were scored as excellent/good (50/50) compared with baseline; no fair/poor judgment was recorded. No other toxicities or local failures were recorded during follow-up.ConclusionsThe 3-week course of postoperative radiation using VMAT with SIB showed to be feasible and was associated with acceptable acute skin toxicity profile. Long-term follow-up data are needed to assess late toxicity and clinical outcomes.

Dose-volume relationships for acute bowel toxicity in patients treated with pelvic nodal irradiation for prostate cancer.

PURPOSE To find correlation between dose-volume histograms (DVHs) of the intestinal cavity (IC) and moderate-severe acute bowel toxicity in men with prostate cancer treated with pelvic nodal irradiation. METHODS AND MATERIALS The study group consisted of 191 patients with localized prostate cancer who underwent whole-pelvis radiotherapy with radical or adjuvant/salvage intent during January 2004 to November 2007. Complete planning/clinical data were available in 175 of these men, 91 of whom were treated with a conventional four-field technique (50.4 Gy, 1.8 Gy/fraction) and 84 of whom were treated with IMRT using conventional Linac (n = 26, 50.4 Gy, 1.8 Gy/fraction) or Helical TomoTherapy (n = 58, 50-54 Gy, 1.8-2 Gy/fraction). The IC outside the planning target volume (PTV) was contoured and the DVH for the first 6 weeks of treatment was recovered in all patients. The correlation between a number of clinical and DVH (V10-V55) variables and toxicity was investigated in univariate and multivariate analyses. The correlation between DVHs for the IC outside the PTV and DVHs for the whole IC was also assessed. RESULTS Twenty-two patients experienced toxicity (3/22 in the IMRT/tomotherapy group). Univariate analyses showed a significant correlation between V20-V50 and toxicity (p = 0.0002-0.001), with a higher predictive value observed for V40-V50. Previous prostatectomy (p = 0.066) and abdominal/pelvic surgery (p = 0.12) also correlated with toxicity. Multivariate analysis that included V45, abdominal/pelvic surgery, and prostatectomy showed that the most predictive parameters were V45 (p = 0.002) and abdominal/pelvic surgery (p = 0.05, HR = 2.4) CONCLUSIONS Our avoidance IMRT approach drastically reduces the incidence of acute bowel toxicity. V40-V50 of IC and, secondarily, previous abdominal/pelvic surgery were the main predictors of acute bowel toxicity.