Lucia Perna

IMRT significantly reduces acute toxicity of whole-pelvis irradiation in patients treated with post-operative adjuvant or salvage radiotherapy after radical prostatectomy

PURPOSEnTo investigate the role of IMRT in reducing the risk of acute genito-urinary (GU), upper gastrointestinal (uGI) and lower gastrointestinal (lGI) toxicity following whole-pelvis irradiation (WPRT) after radical prostatectomy.nnnPATIENTS AND METHODSn172 consecutive patients with prostate cancer were post-operatively irradiated to the prostatic bed (PB) and pelvic lymph-nodal area with adjuvant (n=100) or salvage (n=72) intent. Eighty-one patients underwent three-dimensional conformal (3DCRT) WPRT, while the remaining 91 underwent IMRT (54/91 with helical tomotherapy (HTT); 37/91 with Linac intensity-modulated RT (LinacIMRT)).nnnRESULTSnPatients treated with IMRT experienced a decreased risk of acute toxicity. The crude incidence of grade > or =2 toxicity was GU 12.3% vs. 6.6% (p=0.19); lGI 8.6% vs. 3.2% (p=0.14); uGI 22.2% vs. 6.6% (p=0.004), for 3DCRT and IMRT, respectively. With respect to uGI and lGI, the acute toxicity profile of the HTT patients was even better when compared to that of 3DCRT patients (crude incidence:1.8% and 0.0%, respectively). Treatment interruptions due to uGI toxicity were 11/81 in the 3DCRT group vs. 2/91 in the IMRT group (p=0.006).nnnCONCLUSIONSnThe risk of acute toxicity following post-operative WPRT delivered by means of IMRT was reduced compared to that of 3DCRT. The most significant reduction concerned uGI, mainly owing to better bowel sparing with IMRT.

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

PURPOSEnTo investigate the clinical factors independently predictive of long-term severe urinary sequelae after postprostatectomy radiotherapy.nnnPATIENTS AND METHODSnBetween 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.nnnRESULTSnAfter 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.nnnCONCLUSIONSnThe 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.

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

PURPOSEnTo 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.nnnMETHODS AND MATERIALSnThe 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.nnnRESULTSnTwenty-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)nnnCONCLUSIONSnOur 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.

Treatment planning comparison between conformal radiotherapy and helical tomotherapy in the case of locally advanced-stage NSCLC

BACKGROUND AND PURPOSEnTo investigate the impact of Helical Tomotherapy (HT) upon the dose distribution when compared to our routinely delivered 3D conformal radiotherapy (CRT) in the case of patients affected by stage III non-small-cell lung cancer (NSCLC).nnnMATERIAL AND METHODSnThirteen stage III inoperable NSCLC patients were scheduled to receive 61.2-70.2Gy, 1.8Gy/fraction. Two treatment techniques (HT and CRT) were considered, and in the case of CRT the dose calculation was performed using both the pencil beam (PB) and Anisotropic Analytical Algorithm (AAA) available on the Varian Eclipse planning system. Dose volume constraints for PTV coverage and OAR sparing were assessed for the HT inverse planning with the highest priority upon PTV coverage and spinal cord sparing. The three plans were compared in terms of dose-volume histograms (DVHs) and normal tissue complication probability (NTCP). A statistical analysis was performed using non-parametric Wilcoxon matched pairs tests.nnnRESULTSnIn CRT the use of a less accurate algorithm (PB) decreased the monitor unit number by 2.4%. HT significantly improved dose homogeneity within PTV compared with CRT_AAA. For lung parenchyma V20-V40 were lower with HT, corresponding to a decrease of 7% in the risk of radiation pneumonitis. The volume of the heart and esophagus irradiated to >45-60Gy were reduced using HT plans. For eight PTs with an esophagus-PTV overlap >5%, HT significantly reduced both late and acute esophageal complication probability.nnnCONCLUSIONSnOur findings obtained in stage III NSCLC patients underline that HT guarantees an important sparing of lungs and esophagus, thus HT has the potential to improve therapeutic ratio, when compared with CRT, by means of dose escalation and/or combined treatment strategy. In CRT of locally advanced lung cancers, the use of a more advanced algorithm would give significantly better modeling of target dose and coverage.

Sparing the penile bulb in the radical irradiation of clinically localised prostate carcinoma: A comparison between MRI and CT prostatic apex definition in 3DCRT, Linac-IMRT and Helical Tomotherapy

BACKGROUND AND PURPOSEnTo assess the impact of using MRI and Helical Tomotherapy (HT) compared to 3DCRT and dynamic IMRT on the dose to the penile bulb (PB).nnnMATERIALS AND METHODSnEight patients diagnosed with prostate cancer entered a treatment protocol including CT and MRI simulation. The prostate apex was defined on both MRI and CT. Treatment plans (HT, Linac-IMRT, 3DCRT and conventional technique), were elaborated on both MRI and CT images. A dose of 71.4Gy (2.55Gy/fraction) was prescribed; it was requested that PTVs be covered by 95% isodose line. The mean dose and V50 of PB were evaluated.nnnRESULTSnPTV-MRI plans reduced PB mean dose and V50 compared to PTV-CT plans. This improvement, deriving also from the treatment modality, was 89% for 3DCRT, 99% for Linac-IMRT and 97% for HT (p<0.01), considering V50. Conventional plans resulted in a significantly higher mean PB dose/V50 compared to 3DCRT-PTV-CT (+27%/+38%), Linac-IMRT-PTV-CT (+42%/+57%) and HT-PTV-CT (+32%/+48%) (p<0.01). The comparison between conventional and PTV-MRI techniques showed a still larger increase: +73%/+93% 3DCRT; +86%/+99% Linac-IMRT; +56%/+99% HT (p<0.01). The PB mean dose reduction with Linac-IMRT compared to 3DCRT was 24% (p=0.034) and 40% (p=0.027) for PTV-CT and PTV-MRI, respectively. This gain remained significant even when comparing Linac-IMRT to HT: 21% (p=0.07) PTV-CT and 68% (p=0.00002) PTV-MRI. HT was superior to 3DCRT with respect to PTV-CT (average gain 4%, p=0.044), whereas it resulted to be detrimental considering PTV-MRI (26Gy vs 16.5Gy), possibly due to the helical delivery of HT; however, in a patient where the distance bulb-PTV <1cm, HT provided better PB sparing than 3DCRT (29.5Gy vs 45.2Gy).nnnCONCLUSIONSnMRI allowed efficient sparing of PB irrespective of the treatment modality. Linac-IMRT was shown to further reduce the dose to the bulb compared to 3DCRT and HT.

Physics aspects of prostate tomotherapy : Planning optimization and image-guidance issues

Purpose. To review planning and image-guidance aspects of more than 3 years experience in the treatment of prostate cancer with Helical Tomotherapy (HT). Methods and materials. Planning issues concerning two Phase I-II clinical studies were addressed: in the first one, 58 Gy in 20 fractions were delivered to the prostatic bed for post-prostatectomy patients: in the second one, a simultaneous integrated boost (SIB) approach was applied for radical treatment, delivering 71.4–74.2 Gy to the prostate in 28 fractions. On-line daily MVCT image guidance was applied: bone match was used for post-operative patients while prostate match was applied for radically treated patients. MVCT data of a large sample of both categories of patients were reviewed. Results. At now, more than 250 patients were treated. Planning data show the ability of HT in creating highly homogeneous dose distributions within PTVs. Organs at risk (OAR) sparing also showed to be excellent. HT was also found to favorably compare to inversely-optimized IMAT in terms of PTVs coverage and dose distribution homogeneity. In the case of pelvic nodes irradiation, a large sparing of bowel was evident compared to 3DCRT and conventional 5-fields IMRT. The analysis of MVCT data showed a limited motion of the prostate (about 5% of the fractions show a deviation ≥3 mm in posterior-anterior direction), due to the careful application of rectal emptying procedures. Based on phantom measurements and on the comparison with intra-prostatic calcification-based match, direct visualization prostate match seems to be sufficiently reliable in assessing shifts ≥3 mm. Conclusions. HT offers excellent planning solutions for prostate cancer, showing to be highly efficient in a SIB scenario. Daily MVCT information showed evidence of a limited motion of the prostate in the context of rectal filling control obtained by instructing patients in self-administrating a rectal enema.

Contouring Variability of the Penile Bulb on CT Images: Quantitative Assessment Using a Generalized Concordance Index

PURPOSEnWithin a multicenter study (DUE-01) focused on the search of predictors of erectile dysfunction and urinary toxicity after radiotherapy for prostate cancer, a dummy run exercise on penile bulb (PB) contouring on computed tomography (CT) images was carried out. The aim of this study was to quantitatively assess interobserver contouring variability by the application of the generalized DICE index.nnnMETHODS AND MATERIALSnFifteen physicians from different Institutes drew the PB on CT images of 10 patients. The spread of DICE values was used to objectively select those observers who significantly disagreed with the others. The analyses were performed with a dedicated module in the VODCA software package.nnnRESULTSnDICE values were found to significantly change among observers and patients. The mean DICE value was 0.67, ranging between 0.43 and 0.80. The statistics of DICE coefficients identified 4 of 15 observers who systematically showed a value below the average (p value range, 0.013 - 0.059): Mean DICE values were 0.62 for the 4 bad observers compared to 0.69 of the 11 good observers. For all bad observers, the main cause of the disagreement was identified. Average DICE values were significantly worse from the average in 2 of 10 patients (0.60 vs. 0.70, p < 0.05) because of the limited visibility of the PB. Excluding the bad observers and the bad patients, the mean DICE value increased from 0.67 to 0.70; interobserver variability, expressed in terms of standard deviation of DICE spread, was also reduced.nnnCONCLUSIONSnThe obtained values of DICE around 0.7 shows an acceptable agreement, considered the small dimension of the PB. Additional strategies to improve this agreement are under consideration and include an additional tutorial of the so-called bad observers with a recontouring procedure, or the recontouring by a single observer of the PB for all patients included in the DUE-01 study.

Static and rotational intensity modulated techniques for head-neck cancer radiotherapy: A planning comparison

PURPOSEnTo compare helical Tomotherapy (HT), two volumetric-modulated arc techniques and conventional fixed-field intensity modulated techniques (S-IMRT) for head-neck (HN) cancers.nnnMETHODS AND MATERIALSnEighteen HN patients were considered. Four treatment plans were generated for each patient: HT, S-IMRT optimised with Eclipse treatment planning system and two volumetric techniques using Elekta-Oncentra approach (VMAT) and Varian-RapidArc (RA), using two full arcs. All techniques were optimised to simultaneously deliver 66Gy to PTV1 (GTV and enlarged nodes) and 54Gy to PTV2 (subclinical and electively treated nodes). Comparisons were assessed on several dosimetric parameters and, secondarily, on planned MUs and delivery time.nnnRESULTSnConcerning PTV coverage, significantly better results were found for HT and RA. HT significantly improved the target coverage both compared to S-IMRT and VMAT. No significant differences were found between S-IMRT and volumetric techniques in terms of dose homogeneity. For OARs, all the techniques were able to satisfy all hard constraints; significantly better results were found for HT, especially in the intermediate dose range (15-30xa0Gy). S-IMRT reached a significantly better OARs sparing with respect to VMAT and RA. No significant differences were found for body mean dose, excepting higher values of V5-V10 for HT. A reduction of planned MUs and delivery treatment time was found with volumetric techniques.nnnCONCLUSIONSnThe objectives of satisfying target coverage and sparing of critical structures were reached with all techniques. S-IMRT techniques were found more advantageous compared to RA and VMAT for OARs sparing. HT reached the best overall treatment plan quality.

Inter-observer variability in contouring the penile bulb on CT images for prostate cancer treatment planning

Several investigations have recently suggested the existence of a correlation between the dose received by the penile bulb (PB) and the risk of erectile dysfunction (ED) after radical radiotherapy for clinically localized prostate carcinoma.A prospective multi-Institute study (DUE-01) was implemented with the aim to assess the predictive parameters of ED. Previously, an evaluation of inter-observer variations of PB contouring was mandatory in order to quantify its impact on PB dose-volume parameters by means of a dummy run exercise.Fifteen observers, from different Institutes, drew the PB on the planning CT images of ten patients; inter-observer variations were analysed in terms of PB volume variation and cranial/caudal limits. 3DCRT treatment plans were simulated to evaluate the impact of PB contouring inter-variability on dose-volume statistics parameters. For DVH analysis the values of PB mean dose and the volume of PB receiving more than 50 Gy and 70 Gy (V50 and V70, respectively) were considered. Systematic differences from the average values were assessed by the Wilcoxon test.Seven observers systematically overestimated or underestimated the PB volume with deviations from the average volumes ranging between -48% and +34% (p < 0.05). The analysis of the cranial and caudal borders showed a prevalence of random over systematic deviations.Inter-observer contouring variability strongly impacts on DVH parameters, although standard deviations of inter-patient differences were larger than inter-observer variations: 14.5 Gy versus 6.8 Gy for mean PB dose, 23.0% versus 11.0% and 16.8% versus 9.3% for V50 and V70 respectively.In conclusion, despite the large inter-observer variation in contouring PB, a large multi-centric study may have the possibility to detect a possible correlation between PB % dose-volume parameters and ED. The impact of contouring uncertainty could be reduced by a posteriori contouring from a single observer or by introducing Magnetic Resonance Imaging (MRI) in the planning procedures and/or in improving the skill of observers through post-dummy run tutoring of those observers showing large systematic deviations from the mean.

Predictors of acute bowel toxicity in patients treated with IMRT whole pelvis irradiation after prostatectomy

PURPOSE/OBJECTIVEnWhole pelvis irradiation with IMRT (WPRT-IMRT) after prostatectomy is efficient in reducing acute toxicity: however, a number of patients still experience moderate acute bowel toxicity.nnnMATERIALS AND METHODSnNinety-six patients treated with WPRT-IMRT after prostatectomy with adjuvant or salvage intent were analysed. A number of parameters were individually recovered, including the DVHs of the intestinal cavity outside PTV and of the loops referred to both the WPRT phase and the whole treatment. Correlation between clinical-dosimetric parameters and acute bowel toxicity was investigated by logistic analyses. Best predictive cut-off values for continuous variables were assessed by ROC curves.nnnRESULTSn15/96 (15.6%) Patients experienced grade 2 toxicity (no grade 3). Best dose-volume predictors were the fraction of loops receiving more than 45, 50 and 55 Gy (respectively, V45TL ≥ 50cc, V50TL ≥ 13cc, V55TL ≥ 3cc; p-values ranging from 0.005 to 0.027). Age, GU acute toxicity, rectal acute toxicity and time between prostatectomy and IMRT were also predictors of acute bowel toxicity. Multivariate analysis showed that the most predictive independent parameters were age (OR: 1.13; 95%CI: 1.02-1.25; p=0.021) and V50TL (≥ 13cc, OR: 8.2; 95%CI: 1.7-40; p=0.009).nnnCONCLUSIONSnThe risk of moderate acute uGI toxicity during WPRT-IMRT for post-operatively treated patients increases with age; the risk is substantially reduced in patients with small overlap between PTV and loops.