Extended nodal radiotherapy for prostate cancer relapse guided with [11C]-choline PET/CT: ten-year results in patients enrolled in a prospective trial.

AIMS: To report long-term outcomes of relapsed prostate cancer (PC) patients treated in a prospective single-arm study with extended-nodal radiotherapy (ENRT) and [11C]-choline positron emission tomography (PET)/computed tomography (CT)-guided simultaneous integrated boost (SIB) to positive lymph nodes (LNs). METHODS: From 12/2009 to 04/2015, 60 PC patients with biochemical relapse and positive LNs only were treated in this study. ENRT at a median total dose (TD) = 51.8 Gy/28 fr and PET/CT-guided SIB to positive LNs at a median TD = 65.5 Gy was prescribed. Median PSA at relapse was 2.3 (interquartile range, IQR:1.3-4.0) ng/ml. Median number of positive LNs: 2 (range: 1-18). Androgen deprivation therapy (ADT) was prescribed for 48 patients for a median of 30.7 (IQR: 18.5-43.1) months. RESULTS: Median follow-up from the end of salvage treatment was 121.8 (IQR: 116.1, 130.9) months; 3-, 5-, and 10-year BRFS were 45.0%, 36.0%, and 24.0%, respectively; DMFS: 67.9%, 57.2%, and 45.2%; CRFS: 62.9%, 53.9%, and 42.0%; and OS: 88.2%, 76.3%, and 47.9%, respectively. Castration resistance (p < 0.0001) and ≥ 6 positive LN (p = 0.0024) significantly influenced OS at multivariate analysis. Castration resistance (p < 0.0001 for both) influenced DMFS and CRFS in multivariate analysis. CONCLUSIONS: In PC relapsed patients treated with ENRT and [11C]-choline-PET/CT-guided SIB for positive LNs, with 10-year follow-up, a median Kaplan-Meier estimate CRFS of 67 months and OS of 110 months were obtained. These highly favorable results should be confirmed in a prospective, randomized trial.

Comprehensive Intra-Institution stepping validation of knowledge-based models for automatic plan optimization.

PURPOSE: To develop and apply a stepping approach for the validation of Knowledge-based (KB) models for planning optimization: the method was applied to the case of concomitant irradiation of pelvic nodes and prostate + seminal-vesicles bed irradiation in post-prostatectomy patients. METHODS: The clinical VMAT plans of 52 patients optimized by two reference planners were selected to generate a KB-model (RapidPlan, v.13.5 Varian). A stepping-validation approach was followed by comparing KB-generated plans (with and without planner-interaction, RP and only-RP respectively) against delivered clinical plans (RA). The validation followed three steps, gradually extending its generalization: 20 patients used to develop the model (closed-loop); 20 new patients, same planners (open-loop); 20 new patients, different planners (wide-loop). All plans were compared, in terms of relevant dose-volume parameters and generalized equivalent uniform dose (gEUD). RESULTS: KB-plans were generally better than or equivalent to clinical plans. For RPvsRA, PTVs coverage was comparable, for OARs RP was always better. Comparing only-RPvsRA, PTVs coverage was always better; bowel\bladder V50Gy and D1%, bowel\bladder\rectum Dmean, femoral heads V40Gy and penile bulb V50Gy were significantly improved. For RPvsRA gEUD reduction >1 Gy was seen in 80% of plans for rectum, bladder and bowel; for only-RPvsRA, this was found in 50% for rectum/bladder and in 70% for bowel. CONCLUSION: An extensive stepping validation approach of KB-model for planning optimization showed better or equal performances of automatically generated KB-plan compared to clinical plans. The interaction of a planner further improved planning performances.

Bladder spatial-dose descriptors correlate with acute urinary toxicity after radiation therapy for prostate cancer.

PURPOSE: To assess bladder spatial-dose parameters predicting acute urinary toxicity after radiotherapy for prostate cancer (PCa) through a pixel-wise method for analysis of bladder dose-surface maps (DSMs). MATERIALS & METHODS: The final cohort of a multi-institutional study, consisting of 539 patients with PCa treated with conventionally (CONV:1.8-2Gy/fr) or moderately hypo-fractionated radiotherapy (HYPO:2.2-2.7Gy/fr) was considered. Urinary toxicity was evaluated through the International Prostate Symptoms Score (IPSS) administered before and after radiotherapy. IPSS increases ⩾10 and 15 points at the end of radiotherapy (ΔIPSS⩾10 and ΔIPSS⩾15) were chosen as endpoints. Average DSMs (corrected into 2Gy-equivalent doses) of patients with/without toxicity were compared through a pixel-wise method. This allowed the extraction of selected spatial descriptors discriminating between patients with/without toxicity. Previously logistic models based on dose-surface histograms (DSH) were considered and replaced with DSM descriptors. Discrimination power, calibration and log-likelihood were considered to evaluate the impact of the inclusion of spatial descriptors. RESULTS: Data of 375/539 patients were available. ΔIPSS⩾10 was recorded in 76/375 (20%) patients, while 30/375 (8%) experienced ΔIPSS⩾15. The posterior dose at 12mm from the bladder base (roughly corresponding to the trigone region) resulted significantly associated to toxicity in the whole/HYPO populations. The cranial extension of the 75Gy isodose along the bladder central axis was the best DSM-based predictor in CONV patients. Multi-variable models including DSM descriptors showed better discrimination (AUC=0.66-0.77) when compared to DSH-based models (AUC=0.58-0.71) and higher log-likelihoods. CONCLUSION: DSMs are correlated with the risk of acute GU toxicity. The incorporation of spatial descriptors improves discrimination and log-likelihood of multi-variable models including dosimetric and clinical parameters.

Deformable registration-based segmentation of the bowel on Megavoltage CT during pelvic radiotherapy.

During pelvic radiotherapy bowel loops (BL) are subject to inter-fraction changes. MVCT images have the potential to provide daily bowel segmentation. We assess the feasibility of deformable registration and contour propagation in replacing manual BL segmentation on MVCT. Four observers delineated BL on the planning kVCT and on one therapy MVCT in eight patients. Inter-observer variations in BLs contouring were quantified using DICE index. BLs were then automatically propagated onto MVCT by a commercial software for image deformation and subsequently manually corrected. The agreement between propagated BL/propagated+manually corrected BL vs manual were quantified using the DICE. Contouring times were also compared. The impact on DVH of using the deformable-registration method was assessed. The same procedures were repeated on high-resolution planning-kVCT and therapy-kVCT. MVCTs are adequate to visualize BL (average DICE: 0.815), although worse than kVCT (average DICE:0.889). When comparing propagated vs manual BL, a poor agreement was found (average DICE: 0.564/0.646 for MVCT/KVCT). After manual correction, average DICE indexes increased to 0.810/0.897. The contouring time was reduced to 15min with the semi-automatic approach from 30min with manual contouring. DVH parameters of propagated BL were significantly different from manual BL (p<0.0001); after manual correction, no significant differences were seen. MVCT are suitable for BL visualization. The use of a software to segment BL on MVCT starting from BL-kVCT contours was feasible if followed by manual correction. The method resulted in a substantial reduction of contouring time without detrimental effect on the quality of bowel segmentation and DVH estimates.

Bladder dose-surface maps and urinary toxicity: Robustness with respect to motion in assessing local dose effects.

The purpose of this study was to quantify the impact of inter-fraction modifications of bladder during RT of prostate cancer on bladder dose surface maps (DSM). Eighteen patients treated with daily image-guided Tomotherapy and moderate hypofractionation (70-72.8Gy at 2.5-2.6Gy/fr in 28 fractions and full bladder) were considered. Bladder contours were delineated on co-registered daily Megavoltage CT (MVCT) by a single observer and copied on the planning CT to generate dose-volume/surface histograms (DVH/DSH) and bladder DSMs. Discrepancies between planned and daily absorbed doses were analyzed through the average of individual systematic errors, the population systematic errors and the population random errors for the DVH/DSHs and DSMs. In total, 477 DVH/DSH and 472 DSM were available. DSH and DVH showed small population systematic errors of absolute surfaces (<3.4cm(2)) and volumes (<8.4cm(3)) at the highest doses. The dose to the posterior bladder base assessed on DSMs showed a mean systematic error below 1Gy, with population systematic and random errors within 4 and 3Gy, respectively. The region surrounding this area shows higher mean systematic errors (1-3Gy), population systematic (8-11Gy) and random (5-7Gy) errors. In conclusion, DVH/DSH and DSMs are quite stable with respect to inter-fraction variations in the high-dose region, within about 2cm from bladder base. Larger systematic variations occur in the anterior portion and cranially 2.5-3.5cm from the base. Results suggest that dose predictors related to the high dose area (including the trigone dose) are likely to be sufficiently reliable with respect to the expected variations due to variable bladder filling.

Moderate Hypofractionation with Simultaneous Integrated Boost in Prostate Cancer: Long-term Results of a Phase I-II Study.

AIMS: To report 5 year outcome and late toxicity in prostate cancer patients treated with image-guided tomotherapy with a moderate hypofractionated simultaneous integrated boost approach. MATERIALS AND METHODS: In total, 211 prostate cancer patients, 78 low risk, 53 intermediate risk and 80 high risk were treated between 2005 and 2011. Intermediate- and high-risk patients received 51.8 Gy to pelvic lymph nodes and concomitant simultaneous integrated boost to prostate up to 74.2 Gy/28 fractions, whereas low-risk patients were treated to the prostate only with 71.4 Gy/28 fractions. Daily megavoltage computed tomography (MVCT) image guidance was applied. Androgen deprivation was prescribed for a median duration of 6 months for low-risk patients (for downsizing), 12 months for intermediate-risk and 36 months for high-risk patients. The 5 year biochemical relapse-free survival (bRFS), cancer-specific survival (CSS), overall survival and late gastrointestinal and genitourinary CTCAE.v3 toxicity were assessed. The effect of several clinical variables on both outcome and gastrointestinal/genitourinary toxicity was tested by uni- and multivariate Cox regression analyses. RESULTS: After a median follow-up of 5 years, the late toxicity actuarial incidence was: genitourinary ≥ grade 2: 20.2%; genitourinary ≥ grade 3: 5.9%; gastrointestinal ≥ grade 2: 17%; gastrointestinal ≥ grade 3: 6.3% with lower prevalence at the last follow-up visit (≥ grade 3: genitourinary: 1.9%; gastrointestinal: 1.9%). Major predictors of ≥ grade 3 genitourinary and gastrointestinal late toxicity were genitourinary acute toxicity ≥ grade 2 (hazard ratio: 4.9) and previous surgery (hazard ratio: 3.4). The overall 5 year bRFS was 93.7% (low risk: 94.6%; intermediate risk: 96.2%; high risk: 91.1%), overall survival and CSS were 88.6% (low risk: 90.5%; intermediate risk: 87.4%; high risk: 87%) and 97.5% (low risk: 98.7%; intermediate risk: 95%; high risk: 94.3%), respectively. Risk classes and androgen deprivation were not significantly correlated with either bRFS, overall survival or CSS. Twelve patients experienced a biochemical relapse but none experienced clinically proven local and/or pelvic recurrence. CONCLUSION: A satisfactory 5 year outcome with an acceptable toxicity profile was observed. The combination of image-guided radiotherapy-intensity-modulated radiotherapy, high equivalent 2 Gy dose (EQD2) with a moderate hypofractionated approach and extensive prophylactic lymph node irradiation also leads to very good outcome in high-risk patients.

Biological optimization of simultaneous boost on intra-prostatic lesions (DILs): sensitivity to TCP parameters.

The aim of this investigation was to explore the potential of biological optimization in the case of simultaneous integrated boost on intra-prostatic dominant lesions (DIL) and evaluating the impact of TCP parameters uncertainty. Different combination of TCP parameters (TD50 and γ50 in the Poisson-like model), were considered for DILs and the prostate outside DILs (CTV) for 7 intermediate/high-risk prostate patients. The aim was to maximize TCP while constraining NTCPs below 5% for all organs at risk. TCP values were highly depending on the parameters used and ranged between 38.4% and 99.9%; the optimized median physical doses were in the range 94-116 Gy and 69-77 Gy for DIL and CTV respectively. TCP values were correlated with the overlap PTV-rectum and the minimum distance between rectum and DIL. In conclusion, biological optimization for selective dose escalation is feasible and suggests prescribed dose around 90-120 Gy to the DILs. The obtained result is critically depending on the assumptions concerning the higher radioresistence in the DILs. In case of very resistant clonogens into the DIL, it may be difficult to maximize TCP to acceptable levels without violating NTCP constraints.

Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101).

BACKGROUND AND PURPOSE: Recent investigations demonstrated a significant correlation between rectal dose-volume patterns and late rectal toxicity. The reduction of the DVH to a value expressing the probability of complication would be suitable. To fit different normal tissue complication probability (NTCP) models to clinical outcome on late rectal bleeding after external beam radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: Rectal dose-volume histograms of the rectum (DVH) and clinical records of 547 prostate cancer patients (pts) pooled from five institutions previously collected and analyzed were considered. All patients were treated in supine position with 3 or 4-field techniques: 123 patients received an ICRU dose between 64 and 70 Gy, 255 patients between 70 and 74 Gy and 169 patients between 74 and 79.2 Gy; 457/547 patients were treated with conformal RT and 203/547 underwent radical prostatectomy before RT. Minimum follow-up was 18 months. Patients were considered as bleeders if showing grade 2/3 late bleeding (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. Four NTCP models were considered: (a) the Lyman model with DVH reduced to the equivalent uniform dose (LEUD, coincident with the classical Lyman-Kutcher-Burman, LKB, model), (b) logistic with DVH reduced to EUD (LOGEUD), (c) Poisson coupled to EUD reduction scheme and (d) relative seriality (RS). The parameters for the different models were fit to the patient data using a maximum likelihood analysis. The 68% confidence intervals (CI) of each parameter were also derived. RESULTS: Forty six out of five hundred and forty seven patients experienced grade 2/3 late bleeding: 38/46 developed rectal bleeding within 18 months and were then considered as bleeders The risk of rectal bleeding can be well calculated with a 'smooth' function of EUD (with a seriality parameter n equal to 0.23 (CI 0.05), best fit result). Using LEUD the relationship between EUD and NTCP can be described with a TD50 of 81.9 Gy (CI 1.8 Gy) and a steepness parameter m of 0.19 (CI 0.01); when using LOGEUD, TD50 is 82.2 Gy and k is 7.85. Best fit parameters for RS are s=0.49, gamma=1.69, TD50=83.1 Gy. Qualitative as well as quantitative comparisons (chi-squared statistics, P=0.005) show that the models fit the observed complication rates very well. The results found in the overall population were substantially confirmed in the subgroup of radically treated patients (LEUD: n=0.24 m=0.14 TD50=75.8 Gy). If considering just the grade 3 bleeders (n=9) the best fit is found in correspondence of a n-value around 0.06, suggesting that for severe bleeding the rectum is more serial. CONCLUSIONS: Different NTCP models fit quite accurately the considered clinical data. The results are consistent with a rectum 'less serial' than previously reported investigations when considering grade 2 bleeding while a more serial behaviour was found for severe bleeding. EUD may be considered as a robust and simple parameter correlated with the risk of late rectal bleeding.

Therapeutic outcome according to histologic subtype in 121 patients with malignant pleural mesothelioma.

One-hundred and twenty-one cases of malignant pleural mesothelioma (MPM) seen between 1986 and 1999 at the authors' Institution were reviewed. Histotype was epithelial in 88 patients (73%), sarcomatous in 21 (17%) and mixed in 12 (10%). Ninety-one patients received a treatment (38 palliative pleurectomy and no further therapy, 16 palliative pleurectomy followed by chemotherapy, 37 chemotherapy alone), while 30 were referred to supportive care only. Median survival of the whole population was 10.5 months. The 1-, 2- and 3-year survival were 40, 17 and 8%, respectively. Univariate analysis of subgroups showed that poor performance status (PS), non-epithelial histotype, Butchart stage>I and International Mesothelioma Interest Group (IMIG) stage>I were individually associated with lower survival. Patients receiving any therapy survived longer than patients treated with supportive care only (P=0.0004). Treatment modality had an independent prognostic value (P=0.00005), with a survival advantage for patients receiving surgery and adjuvant chemotherapy. Multivariate analysis confirmed the independent prognostic value of PS (P=0.001; HR=2.48) and treatment modality (P=0.003; HR=1.38). The prognostic role of PS (P=0.02) and treatment modality (P=0.01) was confirmed in the subset of patients with epithelial histology. On the contrary, therapy had no impact on survival in patients with sarcomatoid MPM (P=0.74). Despite the predicted bias of a retrospective non-randomized evaluation of treatment-related factors, patients with good PS and epithelial histology seemed to have a survival benefit from surgery or multimodality therapy, as opposite to patients with poor PS or non-epithelial histotype. However, these results must be confirmed in a larger prospective trial with uniform treatment.

Irradiation fields and doses in glioblastoma multiforme: are current standards adequate?

AIMS AND BACKGROUND: The optimum conventional radiotherapy in glioblastoma multiforme patients has not been clearly defined by prospective trials. To better characterize a standard radiotherapy in glioblastoma multiforme, the impact on survival of different fields and doses was analyzed in a retrospective single center series. METHODS: One hundred and forty-seven patients with glioblastoma multiforme, submitted to biopsy only (n = 15), subtotal (n = 48) or total resection (n = 82) and who completed the planned postsurgical radiotherapy, were considered. The median age was 57 years, the male/female ratio 1.5/1, and the performance status > or =70 in 76%. Whole brain irradiation, followed by a boost to partial brain, was used in 75 cases with a whole brain dose of 44-50 Gy (median, 46) and a partial brain dose of 56-70 Gy (median, 60 Gy). Partial brain irradiation alone was used in 72 patients with a dose of 56-70 Gy (median, 61 Gy). Ninety-eight patients received 56-60 Gy (median, 59 Gy) to partial brain whereas 49 patients received 61-70 Gy (median, 63 Gy). RESULTS: There was an almost significantly longer survival in patients irradiated to the partial brain alone with respect to those also receiving whole brain radiotherapy (P = 0.056). Doses >60 Gy significantly prolonged survival (P = 0.006). Multivariate analysis confirmed that the impact on survival of radiation dose was independent of age, performance status, extent of surgery, field of irradiation and the use of chemotherapy. The extent of irradiation field was not independently related to improved survival. CONCLUSIONS: Our retrospective findings suggest that we reflect on the adequacy of the current standard irradiation parameters. Well-designed prospective trials are necessary to standardize the radiotherapy control group in patients with glioblastoma multiforme to be compared in phase III trials with innovative therapeutic approaches.

A retrospective analysis of postradiation chemotherapy in 133 patients with glioblastoma multiforme.

The impact on survival of postradiation nitrosourea-containing chemotherapy (CHT) in patients with glioblastoma multiforme (GM) was analyzed retrospectively in 133 patients who completed the planned radiotherapy out of 173 observed cases. Thirty-five patients were < 50 years old, 89 were males, 20 had performance status (PS) < 70 and 72 > or = 70. Surgery was followed by radiotherapy in all cases (50-60 Gy in 95 patients, 61-70 Gy in 38 patients). At the end of radiotherapy, 43 patients received CHT, whereas 90 patients did not receive further therapy. At univariate analysis, age < 50 years, feminine gender, subtotal or total resection, radiotherapy doses > 60 Gy, and CHT had an independent prognostic value. Our results suggest that chemotherapy improves 2-year survival rates from 12% to 28% in GM. The sequence of treatment, new drugs, and combinations should be further explored.

Consolidation radiotherapy to bulky or semibulky lesions in the management of stage III-IV diffuse large B cell lymphomas.

BACKGROUND: To assess the impact on survival of consolidation radiotherapy to bulky or semibulky lesions in patients with advanced diffuse large B cell lymphoma (DLCL) in complete remission after primary chemotherapy. PATIENTS AND METHODS: Ninety-four patients with stage III-IV DLCL and bulky ( > or =10 cm) or semibulky lesions (6-9 cm) in complete remission after primary chemotherapy were reviewed. Forty patients received consolidation radiotherapy to bulky (n = 20) or semibulky lesions (n = 20), while 54 (18 with bulky disease) did not. Twenty-eight patients were irradiated to the involved field and 12 to the extended field with a dose of 30-46 Gy. RESULTS: In patients with bulky disease, consolidation radiotherapy prevented relapses involving exclusively the bulky area, prolonged time to relapse (TTR) (median 41+ vs. 18 months; p = 0.05) and improved 5-year overall survival (OS) (73 vs. 57%; p = 0.05). Consolidation radiotherapy reduced relapses within the semibulky area, prolonged TTR (median 26+ vs. 20 months; p = 0.01) and improved 5-year OS (59 vs. 41%; p = 0.09) also in patients with semibulky lesions. Multivariate analyses confirmed the independent association between consolidation radiotherapy and survival, and showed that a dose > or =36 Gy was related to a longer OS, while the extension of the radiotherapy field did not modify outcome. No treatment-related deaths were observed. Four patients developed a second malignancy, none of whom had undergone consolidation radiotherapy. CONCLUSIONS: Consolidation radiotherapy to bulky or semibulky lesions significantly improved the outcome in patients with advanced DLCL in complete remission after primary chemotherapy. Involved-field irradiation with 36-45 Gy made a prolonged disease control possible without either lethal toxicity or a higher incidence of second malignancies.

Neoadjuvant CMV chemotherapy plus radical cystectomy in locally advanced bladder cancer: the impact of pathologic response on long-term results.

AIMS AND BACKGROUND: Neoadjuvant systemic chemotherapy in infiltrating transitional cell carcinoma of the bladder has proved to be effective and to provide a pathologic complete response in about 30% of patients. No survival benefit has yet been proved. METHODS: We analyzed the outcome of 75 patients with advanced bladder cancer (stages T2-T4 N+/N0 M0) treated from 1985 to 1993 at two institutions in the same geographic area with 2 or 3 cycles of neoadjuvant CMV (cisplatin, methotrexate and vinblastine) chemotherapy plus cystectomy. Transurethral resection of the tumor was expressly avoided in order to keep the tumor intact as a marker lesion to evaluate response to chemotherapy. RESULTS: At the time of analysis, the median follow-up of 67 assessable patients was 51.5 +/- 3.9 (SE) months. Forty-six patients (69%) had clinical evidence of extravesical spread of the bladder tumor and 6 of lymph node metastases at presentation. After cystectomy, a pathologic complete response (pT0, pN0) was achieved in only 6 cases (9%) and a pathologic partial response in 32 patients (48%). The overall 5-year survival rate of all patients was 61 +/- 6%. Those patients who had a major response to chemotherapy (pCR +pPR) had a 5-year disease-free survival rate of 74%, which was statistically higher (P = 0.0021) than the 44% for the remaining nonresponding patients (pNR). Overall, 43% of the patients with stage T2-T3a disease achieved tumor downstaging (CR, 5%; PR, 38%) compared with 63% of the patients with T3b-T4 (CR, 11%; PR, 52%), although there was no significant difference in 5-year survival curves between the two groups. CONCLUSIONS: A pathologic complete response was achieved in less than 10% of the cases without a preoperative tumor resection. Unfortunately, most of the responses were only partial. Even though the study appears to suggest a survival advantage for those patients who achieved a downstaging, CMV chemotherapy had a limited curative potential in most of the patients. It seems unlikely that determinant proof will be obtained that neoadjuvant chemotherapy may improve survival over a nontreatment control arm. The intrinsic chemoresistance or the suboptimal response to chemotherapy of bladder cancer remains the most adverse prognostic factor.