Emanuele Pignoli

Hyperfractionated Accelerated Radiotherapy in the Milan Strategy for Metastatic Medulloblastoma

PURPOSE With a view to improving the prognosis for patients with metastatic medulloblastoma, we tested the efficacy and toxicity of a hyperfractionated accelerated radiotherapy (HART) regimen delivered after intensive sequential chemotherapy. PATIENTS AND METHODS Between 1998 and 2007, 33 consecutive patients received postoperative methotrexate (8 g/m(2)), etoposide (2.4 g/m(2)), cyclophosphamide (4 g/m(2)), and carboplatin (0.8 g/m(2)) in a 2-month schedule, then HART with a maximal dose to the neuraxis of 39 Gy (1.3 Gy/fraction, 2 fractions/d) and a posterior fossa boost up to 60 Gy (1.5 Gy/fraction,2 fractions/d). Patients with persistent disseminated disease before HART were consolidated with two myeloablative courses and circulating progenitor cell rescue. RESULTS Patients were classified as having M1 (n = 9), M2 (n = 6), M3 (n = 17), and M4 (n = 1) disease. Seven patients younger than 10 years old who achieved complete response after chemotherapy received a lower dose to the neuraxis (31.2 Gy). Twenty-two of the 32 assessable patients responded to chemotherapy; disease was stable in five patients and progressed in five patients. One septic death occurred before radiotherapy. Eight patients experienced relapse after a median of 12 months. Fourteen of the 33 patients underwent consolidation therapy after HART. With a median 82-month survivor follow-up, the 5-year event-free, progression-free, and overall survival rates were 70%, 72%, and 73%, respectively. No severe clinical complications of HART have emerged so far. CONCLUSION HART after intensive postoperative chemotherapy, followed by myeloablative chemotherapy in selected cases, proved feasible in children with metastatic medulloblastoma. The results of our treatment compare favorably with other series treated using conventional therapies.

Light-induced fluorescence spectroscopy of adenomas, adenocarcinomas and non-neoplastic mucosa in human colon I. In vitro measurements

In an attempt to evaluate whether induced fluorescence could be exploited to discriminate neoplastic from non-neoplastic tissue, fluorescence spectroscopy was performed at 450-800 nm on 83 biopsy specimens of colonic mucosa. Measurements showed that fluorescence spectra of adenoma, adenocarcinoma and non-neoplastic mucosa manifest dissimilar patterns. Nine variables, whose photophysical and/or biological bases need further investigation, were derived from the spectra. Discriminant functions between the groups of lesions were determined by using a stepwise discriminant analysis. The diagnostic test had a sensitivity of 80.6% and 88.2%, and a specificity of 90.5% and 95.2% in discriminating neoplastic from non-neoplastic mucosa and adenoma from non-neoplastic mucosa respectively. These results suggest that fluorescence spectroscopy has the potential to improve endoscopic diagnosis of premalignant and malignant lesions of colonic mucosa.

Radiobiological basis and clinical results of the simultaneous integrated boost (SIB) in intensity modulated radiotherapy (IMRT) for head and neck cancer: A review

The simultaneous integrated boost (SIB)-IMRT technique allows the simultaneous delivery of different dose levels to different target volumes within a single treatment fraction. The most significant aspect associated with SIB-IMRT is related to the fractionation strategy, concerning two time-dose parameters: (1) the shortening of the overall treatment time (OTT); (2) the increase of fraction size (FS) to the boost volume. The SIB-IMRT technique represents, therefore, a new way to investigate the accelerated fractionation in definitive treatment of head and neck (H&N) cancers. The aims of this paper are the following: (1) to briefly review the influence of OTT and FS on H&N tumors and on acutely and late responding normal tissues; (2) to review the results of clinical studies of accelerated radiotherapy not employing IMRT in H&N cancer; (3) to review the clinical experiences of the SIB-IMRT technique and to compare the different SIB regimes in terms of radiobiological efficacy.

Accuracy evaluation of fusion of CT, MR, and SPECT images using commercially available software packages (SRS PLATO and IFS)

PURPOSE A problem for clinicians is to mentally integrate information from multiple diagnostic sources, such as computed tomography (CT), magnetic resonance (MR), and single photon emission computed tomography (SPECT), whose images give anatomic and metabolic information. METHODS AND MATERIALS To combine this different imaging procedure information, and to overlay correspondent slices, we used commercially available software packages (SRS PLATO and IFS). The algorithms utilize a fiducial-based coordinate system (or frame) with 3 N-shaped markers, which allows coordinate transformation of a clinical examination data set (9 spots for each transaxial section) to a stereotactic coordinate system. The N-shaped markers were filled with fluids visible in each modality (gadolinium for MR, calcium chloride for CT, and 99mTc for SPECT). The frame is relocatable, in the different acquisition modalities, by means of a head holder to which a face mask is fixed so as to immobilize the patient. Position errors due to the algorithms were obtained by evaluating the stereotactic coordinates of five sources detectable in each modality. RESULTS SPECT and MR position errors due to the algorithms were evaluated with respect to CT: deltax was < or = 0.9 mm for MR and < or = 1.4 mm for SPECT, deltay was < or = 1 mm and < or = 3 mm for MR and SPECT, respectively. Maximal differences in distance between estimated and actual fiducial centers (geometric mismatch) were in the order of the pixel size (0.8 mm for CT, 1.4 mm for MR, and 1.8 mm for SPECT). In an attempt to distinguish necrosis from residual disease, the image fusion protocol was studied in 35 primary or metastatic brain tumor patients. CONCLUSIONS The image fusion technique has a good degree of accuracy as well as the potential to improve the specificity of tissue identification and the precision of the subsequent treatment planning.

No Salvage Using High-Dose Chemotherapy Plus/Minus Reirradiation for Relapsing Previously Irradiated Medulloblastoma

PURPOSE Myeloablative regimens were frequently used for medulloblastoma relapsing after craniospinal irradiation (CSI): in 1997-2002, we used repeated surgery, standard-dose and myeloablative chemotherapy, and reirradiation. METHODS AND MATERIALS In 10 patients, reinduction included sequential high-dose etoposide, high-dose cyclophosphamide/vincristine, and high-dose carboplatin/vincristine, then two myeloablative courses with high-dose thiotepa (+/- carboplatin); 6 other patients received two of four courses of cisplatin/etoposide. Hematopoietic precursor mobilization followed high-dose etoposide or high-dose cyclophosphamide or cisplatin/etoposide therapy. After the overall chemotherapy program, reirradiation was prescribed when possible. RESULTS Seventeen patients were treated: previous treatment included CSI of 19.5-36 Gy with posterior fossa/tumor boost and chemotherapy in 16 patients. Fifteen patients were in their first and 2 in their second and third relapses, respectively. First progression-free survival had lasted a median of 26 months. Relapse sites included leptomeninges in 9 patients, spine in 4 patients, posterior fossa in 3 patients, and brain in 1 patient. Three patients underwent complete resection of recurrence, and 10 underwent reirradiation. Twelve of 14 patients with assessable tumor had an objective response after reinduction; 2 experienced progression and were not given the myeloablative courses. Remission lasted a median of 16 months. Additional relapses appeared in 13 patients continuing the treatment. Fifteen patients died of progression and 1 died of pneumonia 13 months after relapse. The only survivor at 93 months had a single spinal metastasis that was excised and irradiated. Survival for the series as a whole was 11-93 months, with a median of 41 months. CONCLUSIONS Despite responses being obtained and ample use of surgery and reirradiation, second-line therapy with myeloablative schedules was not curative, barring a few exceptions. A salvage therapy for medulloblastoma after CSI still needs to be sought.

Further Improvement in Outcomes of Nasopharyngeal Carcinoma With Optimized Radiotherapy and Induction Plus Concomitant Chemotherapy: An Update of the Milan Experience

PURPOSE To report the outcome of a consecutive series of patients with nonmetastatic nasopharyngeal carcinoma (NPC), focusing on the impact of treatment-related factors. METHODS AND MATERIALS Between 2000 and 2006, 87 patients with NPC were treated with either conventional (two- or three-dimensional) radiotherapy (RT) or with intensity-modulated RT (IMRT). Of these patients, 81 (93%) received either concomitant CHT (24%) or both induction and concomitant chemotherapy (CHT) (69%). Stage was III in 36% and IV in 39% of patients. Outcomes in this study population were compared with those in the previous series of 171 patients treated during 1990 to 1999. RESULTS With a median follow-up of 46 months, actuarial rates at 3 years were the following: local control, 96%; local-regional control, 93%; distant control (DC), 90%; disease-free survival (DFS), 82%; overall survival, 90%. In Stage III to IV patients, distant control at 3 years was 56% in patients treated with concomitant CHT only and 92% in patients treated with both induction and concomitant CHT (p = 0.014). At multivariate analysis, histology, N-stage, RT technique, and total RT dose had the strongest independent impact on DFS (p < 0.05). Induction CHT had a borderline effect on DC (p = 0.07). Most dosimetric statistics were improved in the group of patients treated with IMRT compared with conventional 3D technique. All outcome endpoints were substantially better in the study population compared with those in the previous series. CONCLUSIONS Outcome of NPC has further improved in the study period compared with the previous decade, with a significant effect of RT technique optimization. The impact of induction CHT remains to be demonstrated in controlled trials.

Set-up errors analyses in IMRT treatments for nasopharyngeal carcinoma to evaluate time trends, PTV and PRV margins

Abstract Introduction. The aims of this study were to analyze the systematic and random interfractional set-up errors during Intensity Modulated Radiation Therapy (IMRT) in 20 consecutive nasopharyngeal carcinoma (NPC) patients by means of Electronic Portal Images Device (EPID), to define appropriate Planning Target Volume (PTV) and Planning Risk Volume (PRV) margins, as well as to investigate set-up displacement trend as a function of time during fractionated RT course. Material and methods. Before EPID clinical implementation, an anthropomorphic phantom was shifted intentionally 5 mm to all directions and the EPIs were compared with the digitally reconstructed radiographs (DRRs) to test the systems capability to recognize displacements observed in clinical studies. Then, 578 clinical images were analyzed with a mean of 29 images for each patient. Results. Phantom data showed that the system was able to correct shifts with an accuracy of 1 mm. As regards clinical data, the estimated population systematic errors were 1.3 mm for left-right (L-R), 1 mm for superior-inferior (S-I) and 1.1 mm for anterior-posterior (A-P) directions, respectively. Population random errors were 1.3 mm, 1.5 mm and 1.3 mm for L-R, S-I and A-P directions, respectively. PTV margin was at least 3.4, 3 and 3.2 mm for L-R, S-I and A-P direction, respectively. PRV margins for brainstem and spinal cord were 2.3, 2 and 2.1 mm and 3.8, 3.5 and 3.2 mm for L-R, A-P and S-I directions, respectively. Set-up error displacements showed no significant changes as the therapy progressed (p>0.05), although displacements >3 mm were found more frequently when severe weight loss or tumor nodal shrinkage occurred. Discussion. These results enable us to choose margins that guarantee with sufficient accuracy the coverage of PTVs and organs at risk sparing. Collected data confirmed the need for a strict check of patient position reproducibility in case of anatomical changes.

Multi-variable models of large International Prostate Symptom Score worsening at the end of therapy in prostate cancer radiotherapy

PURPOSE/OBJECTIVE Prospectively assessing clinical/dosimetry factors affecting the acute worsening of urinary functionality after radiotherapy for prostate cancer. MATERIAL/METHODS DUE01 population was considered, including patients treated with conventional or moderate hypo-fractionation (2.2-2.7 Gy/fr). Relevant clinical factors were collected, urinary symptoms were self-reported through the International Prostate Symptom Score (IPSS) before and at the end of radiotherapy; while absolute weekly dose-surface histograms (DSHw) were chosen as dosimetry descriptors. An IPSS increase of at least 10 and 15 points (ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15) were chosen as endpoints. Patients with baseline IPSS>20 were excluded. Relevant factors were chosen through a bootstrap-based in silico methodology. RESULTS Complete information was available for 380 patients: 77/380 (20%) and 28/380 (7%) with ΔIPSS ⩾ 10 and ΔIPSS ⩾ 15, respectively. Neoadjuvant hormone was protective (OR=0.49 and 0.69). DSHw at 8.5 Gy/week and 12 Gy/week were risk factors, with additional risk for patients who use cardiovascular drugs and anti-hypercholesterolemia drugs. In the hypo-fractionated subgroup (n=209) the role of cardiovascular drugs (OR=2.16) for ΔIPSS ⩾ 10 and anti-hypercholesterolemia drugs (OR=2.80) for ΔIPSS⩾15, together with DSHw (10 Gy/week and 12.5 Gy/week, respectively), was confirmed. CONCLUSION Current study shows a dose-surface/volume effect for acute large worsening of urinary functionality; several clinical variables largely impact the risk and especially all the factors related with vascular diseases.

Radiotherapy for unresectable sinonasal cancers: Dosimetric comparison of intensity modulated radiation therapy with coplanar and non-coplanar volumetric modulated arc therapy

BACKGROUND AND PURPOSE To compare volumetric modulated arc therapy (VMAT) and intensity modulated radiation therapy (IMRT) plans for treatment of unresectable paranasal sinuses cancers (PNSCs) with different clinical presentations. MATERIAL AND METHODS Four patients treated for primary target volume only (group 1), four requiring elective nodal irradiation (group 2) and four with positive nodes in macroscopic disease (group 3) were selected. For each patient were generated 7 fields IMRT, coplanar VMAT (c-VMAT) and non-coplanar VMAT (nc-VMAT) treatment plans. Total doses were 70Gy and 54Gy to high dose planning target volume (HD-PTV) and low-dose-PTV, respectively. Dose-volume histogram, conformity and homogeneity index (CI and HI), and monitor units (MUs) per Gy were evaluated. RESULTS VMAT provided significantly better target coverage, in terms of V100% (Volume encompassed by the isodose 100%), than IMRT, in particular when nc-VMAT was used. In general, organ at risk sparing is similar with the three approaches, although nc-VMAT can allow a statistically significant reduction of dose to contralateral parotid gland and cochlea for all three groups. CONCLUSIONS VMAT can offer significant improvement of treatment for all unresectable PNSCs over existing IMRT techniques. In particular, nc-VMAT may be a further advantage for those patients with sinonasal cancers and involvement of the nodes in whom large volumes and complex/irregular shape have to be irradiated, even if clinical benefits should be established in the future.

Postoperative radiotherapy for synovial sarcoma of the head and neck during pregnancy: clinical and technical management and fetal dose estimates.

Aims and background In vivo and phantom dosimetry is reported to estimate the fetal dose and evaluate the effectiveness of a special shielding device to reduce fetal exposure in a woman undergoing postoperative radiation therapy for synovial oral cavity sarcoma at the 30th week of pregnancy. Methods In vivo measurements were performed by placing thermoluminescent dosimeters on 3 points for fetal dose estimation: uterine fundus, umbilicus and pubis. A Rando anthropomorphic phantom was used to simulate radiotherapy. We also performed off-axis dose measurements for wedged beams to estimate the dose contribution of this accessory used in the treatment. Results The special shielding device reduced the fetal dose by 70% on average, despite the presence of wedges, which increased the dose by a factor of about 2.5. Before delivery the patient received 48 Gy, and from the in vivo measurements a fetal dose of 8.5, 1.7 and 0.7 cGy was estimated to the uterine fundus, umbilicus and pubis, respectively. Conclusions Pre-treatment simulation in the same irradiation conditions is the only reliable approach to predict the fetal dose. By using a special shielding device, radiotherapy can be optimized while keeping the fetal exposure below the risk of deterministic damage.