Angelo Bolognesi

Intra- and inter-observer variability in contouring prostate and seminal vesicles: implications for conformal treatment planning

BACKGROUND AND PURPOSE Accurate contouring of the clinical target volume (CTV) is a fundamental prerequisite for successful conformal radiotherapy of prostate cancer. The purpose of this study was to investigate intra- and inter-observer variability in contouring prostate (P) and seminal vesicles (SV) and its impact on conformal treatment planning in our working conditions. MATERIALS AND METHODS Inter-observer variability was investigated by asking five well-trained radiotherapists of contouring on CT images the P and the SV of six supine-positioned patients previously treated with conformal techniques. Short-term intra-observer variability was assessed by asking the radiotherapists to contour the P and SV of one patient for a second time, just after the first contouring. The differences among the inserted volumes were considered for both intra- and inter-observer variability. Regarding intra-observer variability, the differences between the two inserted contours were estimated by taking the relative differences in correspondence to the CT slices on BEV plots (antero-posterior and left-right beams). Concerning inter-observer variability, the distances between the internal and external envelopes of the inserted contours (named projected diagnostic uncertainties or PDUs) and the distances from the mean inserted contours (named mean contour distances or MCDs) were measured from BEV plots (i.e. parallel to the CT slices). RESULTS Intra-observer variability was relatively small (the average percentage variation of the volume was approximately 5%; SD of the differences measured on BEV plots within 1.8 mm). Concerning inter-observer variability, the percentage SD of the inserted volumes ranged from 10 to 18%. Differences equal to 1 cm in the cranio-caudal extension of P + SV were found in four out of six patients. The largest inter-observer variability was found when considering the anterior margin in the left-right beam of P top (MCD = 7.1 mm, 1 SD). Relatively high values for MCDs were also found for P bottom, for the posterior and lateral margins of P top (2.6 and 3.1 mm, respectively, I SD) and for the anterior margin of SV (2.8 mm, 1 SD). Relatively small values were found for P central (from 1.4 to 2.0 mm, 1 SD) and the posterior margin of SV (1.5 mm, 1 SD). CONCLUSIONS The application of larger margins taking inter-observer variability into account should be taken into consideration for the anterior and the lateral margins of SV and P top and for the lateral margin of P. The impact of short-term intra-observer variability does not seem to be relevant.

Long-Term Follow-up of Patients with Prostate Cancer and Nodal Metastases Treated by Pelvic Lymphadenectomy and Radical Prostatectomy: The Positive Impact of Adjuvant Radiotherapy

BACKGROUND Recent large, prospective, randomised studies have demonstrated that adjuvant radiotherapy (RT) is a safe and effective procedure for preventing disease recurrence in locally advanced prostate cancer (PCa) patients. However, no study has ever tested the role of adjuvant RT in node-positive patients after radical prostatectomy (RP). OBJECTIVE We hypothesised that adjuvant RT with early hormone therapy (HT) might improve long-term outcomes of patients with PCa and nodal metastases treated with RP and extended pelvic lymph node dissection (ePLND). DESIGN, SETTING, AND PARTICIPANTS This retrospective study included 250 consecutive patients with pathologic lymph node invasion. We assessed factors predicting long-term biochemical recurrence (BCR)-free and cancer-specific survival (CSS) in node-positive PCa patients treated with RP, ePLND, and adjuvant treatments between 1988 and 2002 in a tertiary academic centre. INTERVENTION All patients received adjuvant treatments according to the treating physician after detailed patient information: 129 patients (51.6%) were treated with a combination of RT and HT, while 121 patients (48.4%) received adjuvant HT alone. MEASUREMENTS BCR-free survival and CSS in patients with node-positive PCa. RESULTS AND LIMITATIONS Mean follow-up was 95.9 mo (median: 91.2). BCR-free survival and CSS rates at 5, 8, and 10 yr were 72%, 61%, 53% and 89%, 83%, 80%, respectively. In multivariable Cox regression models, adjuvant RT and the number of positive nodes were independent predictors of BCR-free survival (p=0.002 and p=0.003, respectively) as well as of CSS (p=0.009 and p=0.01, respectively). Moreover, there was significant gain in predictive accuracy when adjuvant RT was included in multivariable models predicting BCR-free survival and CSS (gain: 3.3% and 3%, respectively; all p<0.001). CONCLUSIONS Our data showed excellent long-term outcome for node-positive PCa patients treated with radical surgery plus adjuvant treatments. This study is the first to report a significant protective role for adjuvant RT in BCR-free survival and CSS of node-positive patients.

Significant correlation between rectal DVH and late bleeding in patients treated after radical prostatectomy with conformal or conventional radiotherapy (66.6 –70.2 Gy

PURPOSE Investigating the correlation between dosimetric/clinical parameters and late rectal bleeding in patients treated with adjuvant or salvage radiotherapy after radical prostatectomy. METHODS AND MATERIALS Data of 154 consecutive patients, including three-dimensional treatment planning and dose-volume histograms (DVHs) of the rectum (including filling), were retrospectively analyzed. Twenty-six of 154 patients presenting a (full) rectal volume >100 cc were excluded from the analysis. All patients considered for the analysis (n = 128) were treated at a nominal dose equal to 66.6-70.2 Gy (ICRU dose 68-72.5 Gy; median 70 Gy) with conformal (n = 76) or conventional (n = 52) four-field technique (1.8 Gy/fr). Clinical parameters such as diabetes mellitus, acute rectal bleeding, hypertension, age, and hormonal therapy were considered. Late rectal bleeding was scored using a modified Radiation Therapy Oncology Group scale, and patients experiencing >or=Grade 2 were considered bleeders. Median follow-up was 36 months (range 12-72). Mean and median rectal dose were considered, together with rectal volume and the % fraction of rectum receiving more than 50, 55, 60, and 65 Gy (V50, V55, V60, V65, respectively). Median and quartile values of all parameters were taken as cutoff for statistical analysis. Univariate (log-rank) and multivariate (Cox hazard model) analyses were performed. RESULTS Fourteen of 128 patients experienced >or=Grade 2 late bleeding (3-year actuarial incidence 10.5%). A significant correlation between a number of cutoff values and late rectal bleeding was found. In particular, a mean dose >or=54 Gy, V50 >or=63%, V55 >or=57%, and V60 >or=50% was highly predictive of late bleeding (p <or= 0.01). A rectal volume <60 cc and type of treatment (conventional vs. conformal) were also significantly predictive of late bleeding (p = 0.05). Concerning clinical variables, acute bleeding (p < 0.001) was significantly related to late bleeding, and a trend was found for hypertension (p = 0.11). After patients were grouped into those with V50 >or=63% and those with V50 <63% (DVH grouping), data were fitted with a Cox regression hazard model using DVH grouping, rectal volume, and the main clinical parameters as independent variables. Results of the analysis showed that DVH grouping (relative risk 3.3; p = 0.04) and acute bleeding (relative risk 7.1; p = 0.001) are independently predictive of late bleeding. CONCLUSIONS DVHs of the rectum are significantly correlated with late bleeding for patients irradiated at 66.6-70.2 Gy after radical prostatectomy.

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.

Set-up error in supine-positioned patients immobilized with two different modalities during conformal radiotherapy of prostate cancer

BACKGROUND Conformal radiotherapy requires reduced margins around the clinical target volume (CTV) with respect to traditional radiotherapy techniques. Therefore, high set-up accuracy and reproducibility are mandatory. PURPOSE To investigate the effectiveness of two different immobilization techniques during conformal radiotherapy of prostate cancer with small fields. MATERIALS AND METHODS 52 patients with prostate cancer were treated by conformal three- or four-field techniques with radical or adjuvant intent between November 1996 and March 1998. In total, 539 portal images were collected on a weekly basis for at least the first 4 weeks of the treatment on lateral and anterior 18 MV X-ray fields. The average number of sessions monitored per patient was 5.7 (range 4-10). All patients were immobilized with an alpha-cradle system; 25 of them were immobilized at the pelvis level (group A) and the remaining 27 patients were immobilized in the legs (group B). The shifts with respect to the simulation condition were assessed by measuring the distances between the same bony landmarks and the field edges. The global distributions of cranio-caudal (CC), posterior-anterior (PA) and left-right (LR) shifts were considered; for each patient random and systematic error components were assessed by following the procedure suggested by Bijhold et al. (Bijhold J, Lebesque JV, Hart AAM, Vijlbrief RE. Maximising set-up accuracy using portal images as applied to a conformal boost technique for prostatic cancer. Radiother. Oncol. 1992;24:261-271). For each patient the average isocentre (3D) shift was assessed as the quadratic sum of the average shifts in the three directions. RESULTS Group B showed a better accuracy and reproducibility than group A for PA shifts (2.6 versus 4.4 mm, 1 SD), LR shifts (2.4 versus 3.6 mm, 1 SD) and CC shifts (2.7 versus 3.3 mm, 1 SD). Furthermore, group B showed a rate of large PA shifts (>5 mm) equal to 4.4% with respect to the 21.6% of group A (P<0.0001). This value was also better than the corresponding value found in a previously investigated group of 21 non-immobilized patients (Italia C, Fiorino C, Ciocca M, et al. Quality control by portal film analysis of the conformal radiotherapy of prostate cancer: comparison between two different institutions and treatment techniques (abstract). Radiother. Oncol. 1997;43(Suppl. 2):S16, 16.8%, P = 0.001). For both groups there was no clear prevalence of one component (systematic or random) with respect to the other. The average isocentre shifts (averaged on all patients) were 3.0 mm (+/-1.4 mm, 1 SD) for group B and 5.0 mm (+/-2.8 mm, 1 SD) for group A against a value of 4.4 mm (+/-2.4 mm, 1 SD) for the previously investigated non-immobilized patient group. CONCLUSIONS Immobilization of the legs with an alpha-cradle system seems to improve both the accuracy and reproducibility of the positioning of patients treated for prostate cancer with respect to alpha-cradle pelvic-abdomen immobilization. Based on these data, we decided to use the legs immobilization system and to reduce the margin around the CTV (from 10 to 8 mm) in the PA direction.

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.

Comparing 3-, 4- and 6-fields techniques for conformal irradiation of prostate and seminal vesicles using dose-volume histograms

BACKGROUND AND PURPOSE Comparing some isocentric coplanar techniques for conformal irradiation of prostate and seminal vesicles. MATERIALS AND METHODS Five conformal techniques have been considered: (A) a 3-fields technique with an antero-posterior (AP) field and two lateral (LAT-LAT) 30 degrees wedged fields; (B) a 3-fields technique with an AP field and two oblique posterior (OBL) 15 degrees wedged fields with relative weights of 0.8, 1 and 1, respectively; (C) a 4-fields technique (AP-PA and LAT-LAT); (D) a 6-fields technique (LAT-LAT and four OBL at gantry angles 45 degrees, 135 degrees, 235 degrees and 315 degrees) with all the fields having the same weight; (E) the same 6-fields technique with lateral fields double-weighted with respect to the oblique fields. The conformal plans have been simulated on 12 consecutive patients (stages B and C) by using our 3D treatment planning system (Cadplan 2.7). The contours of the rectum, the bladder and the left femoral head were outlined together with the clinical target volume (CTV) which included the prostate and the seminal vesicles. A margin of 10 mm was added to define the planning target volume (PTV) through automatic volume expansion. Then a 7 mm margin between the PTV and block edges was added to take the beam penumbra into account. Dose distributions were normalised to the isocentre and the reference dose was considered to be 95% of the isocentre dose. Dose-volume histograms and dose statistics of the rectum, the bladder and the left femoral head were collected for all plans. For the rectum and the bladder the mean dose (Dm) and the fraction of volume receiving a dose higher than the reference dose (V95) were compared. For the femoral head, the mean dose together with the fraction of volume receiving a dose higher than 50% (V50) were compared. RESULTS Differences among the techniques have been found for all three considered organs at risk. When considering the rectum, technique A is better than the others both when considering Dm and V95 (P = 0.002), while technique D is the worst when considering Dm (P < 0.002) and is also worse than techniques A, E (P = 0.002) and C (P = 0.003) when considering V95. Technique E is the best when considering the bladder mean dose (P = 0.002 against A and D, P < 0.01 against B and C) and technique C is the worst (P < 0.012). No relevant differences were found for the bladder V95. In the femoral heads, techniques A and E are worse than B, C and D (P < 0.003) when considering Dm and V50. Moreover, techniques B and D are better than C (P < 0.004) when considering V50. CONCLUSIONS There is no technique that is absolutely better than the others. Technique A gives the best sparing of the rectum; the bladder is better spared with technique E. These results are reached with a worse sparing of the femoral heads which should be carefully taken into account.

Docetaxel neuropathy : a distal axonopathy

Abstract Docetaxel has been implicated as a causative agent in peripheral neuropathy, but pathological changes in peripheral nerve have not been described. During docetaxel treatment a 54-year-old man developed a sensorimotor polyneuropathy when the overall docetaxel dosage was 540 mg/m2. Neurophysiological investigation revealed a sensorimotor axonal neuropathy. Fascicular sural nerve biopsy showed an axonal neuropathy with a preferentially loss of large myelinated fibers. There was evidence of considerable fiber regeneration. Sensory and motor symptoms progressively improved after docetaxel withdrawal.

Systemic preoperative chemotherapy with cisplatin, methotrexate and vinblastine for locally advanced bladder cancer: Local tumor response and early followup results

A total of 44 patients with infiltrating, locally advanced bladder cancer (stages T 3a-b, T 4a-b and N+/N0) were treated with the systemic chemotherapy regimen of cisplatin, methotrexate and vinblastine (CMV) in the neoadjuvant setting, of whom 39 were evaluable for response. After planned radical cystectomy and 2 to 3 cycles of chemotherapy no tumor was found on the pathological specimen of 4 patients (10%), the tumor was downstaged in 19 (49%) and no change was observed in 16 (41%). Toxicity included leukopenia in 29 patients (66%), 1 of whom died of granulocytopenic sepsis, nausea and vomiting in 39 (89%) and mild to moderate mucositis in 18 (41%). Median followup is 12 months with a range of 6 to 39 months. Of 32 patients followed for longer than 6 months 6 (19%) experienced progression or recurrence of disease. We conclude that preoperative CMV chemotherapy is effective in inducing downstaging of the tumor, although systemic toxicity limits its use to cautiously selected patients.

Anatomic variations due to radical prostatectomy. Impact on target volume definition and dose-volume parameters of rectum and bladder.

Background and Purpose:A quantitative estimate of the impact of prostatectomy on pelvic anatomy is unavailable, even if it would be an important prerequisite for a precise definition of clinical target volume (CTV) in post-prostatectomy radiotherapy. The purpose of this study was to investigate the impact of prostatectomy on the definition of CTV, on the position of bladder and rectum and their implications for three-dimensional conformal radiotherapy (3-D CRT).Patients and Methods:Six patients eligible for radical retropubic prostatectomy were considered. Each patient underwent a planning CT between 1 week and 1 month before surgery (CTpre), and then CT was repeated in the same positioning 1–2 months after surgery (CTpost). For each patient the CTpre/post scans were matched; rectum, bladder and CTV were contoured on both CT scans for each patient by one observer. Two different CTVs were contoured: CTV1: prostate + seminal vesicles in CTpre; prostate + seminal vesicles surgical bed in CTpost; CTV2: prostate in CTpre; prostate surgical bed in CTpost. After image registration, the contours of rectum, bladder and CTV1/2 drawn on CTpost were transferred on CTpre. The corresponding planning target volumes (PTVs) were generated, and for each PTV, a conformal four field technique using 18-MV X-rays was planned. The volumes of CTV1, CTV2, PTV1, PTV2, rectum and bladder pre- and post-surgery were compared. Differences in 3-D position of these structures before and after surgery were analyzed by beam’s eye view (BEV) images. Pre- and post-surgery dose-volume histograms (DVHs) of rectum and bladder were compared together with the fraction of rectum/bladder receiving at least 95% of the ICRU dose (V95), the treated volume (TV, body included in the 95% isodose) and the irradiated volume (IV, body included in the 50% isodose).Results:For both CTV1 and CTV2, the volumes were significantly reduced after prostatectomy (average reduction around 30 cm3 for both; range 0–60 cm3). This reduction was mainly due to a more caudal definition of the cranial edge of CTV after prostatectomy (average difference for CTV2: 1.5 cm; range 0–2.5 cm). Concerning the bladder, a systematic posterior shift of the bladder base (average: 1.5 cm) was found and was correlated with a significant reduction of V95 for bladder (around 10 cm3; p = 0.03). V95 of the rectum, TV and IV also resulted to be significantly lower after surgery. The average reduction of V95 for the rectum was relatively small (2.5 cm3 of rectal wall).Conclusion:The impact of prostatectomy on CTV definition is high. A significant reduction of CTV, PTV, TV and IV may be expected after surgery with a consequent reduction of the portions of rectum/bladder irradiated with adjuvant radiotherapy.Hintergrund und Ziel:Eine Methode zur quantitativen Bestimmung der Auswirkungen einer Prostatektomie auf die Anatomie des Beckenraums gibt es nicht, obwohl dies eine wichtige Voraussetzung für eine genaue Festlegung des klinischen Zielvolumens (CTV) für die postoperative Radiotherapie wäre. Ziel dieser Studie war, die Auswirkungen der Prostatektomie auf die Zielvolumendefinition, auf die anatomische Lage von Blase und Rektum und die Folgen für die dreidimensionale konformale Radiotherapie (3-D CRT) zu untersuchen.Patienten und Methodik:Sechs Patienten, bei denen eine radikale retropubische Prostatektomie indiziert war, unterzogen sich einer Planungs-CT 1 Woche bis 1 Monat präoperativ (CTpre); die CT wurde in der gleichen Positionierung 1-2 Monate postoperativ wiederholt (CTpost). Für jeden Patienten wurden die CTpre- und CTpost-Aufnahmen verglichen sowie Rektum, Blase und CTV auf beiden CTs für jeden Patienten vom selben Untersucher eingetragen. Es wurden unterschiedliche CTVs eingetragen: CTV1: Prostata + Samenbläschen in CTpre; Operationsfeld von Prostata + Samenbläschen in CTpost; CTV2: Prostata in CTpre; Prostataoperationsfeld in CTpost. Nach der Bildaufzeichnung wurden die Umrisse von Rektum, Blase und CTV1/2 von CTpost auf CTpre übertragen. Die entsprechenden Planungszielvolumina (PTV) wurden ermittelt und für jedes PTV wurde eine konformale Vier-Felder-Technik mit 18-MV-Röntgenstrahlung geplant. Die Werte von CTV1, CTV2, PTV1, PTV2, Rektum und Blase jeweils prä- und postoperativ wurden verglichen. Die Unterschiede in der dreidimensionalen Position dieser Volumina wurden prä- und postoperativ mittels BEV-(Beam’s-Eye-View-)Darstellung verglichen. Prä- und postoperative Dosis-Volumen-Histogramme (DVHs) von Rektum und Blase wurden verglichen und der Anteil von Rektum und Blase, die mindestens 95% der ICRU-Dosis (V95) erhielten, sowie das Behandlungsvolumen (TV, innerhalb der 95%-Isodose) und das Bestrahlungsvolumen (IV, innerhalb der 50%-Isodose).Ergebnisse:Für CTV1 wie auch CTV2 waren die Werte nach Prostatektomie signifikant geringer (durchschnittliche Abnahme ca. 30 cm3 für beide Werte; Range 0-60 cm3). Diese Reduktion war im Wesentlichen einer weiter kaudalen Lage des kranialen CTV-Randes nach Prostatektomie (durchschnittliche Abweichung für CTV2: 1,5 cm; Spannweite 0-2,5 cm) zuzuschreiben. Für die Blase wurde regelmäßig eine posteriore Verschiebung des Blasenbodens (Durchschnitt: 1,5 cm) festgestellt, die mit einer signifikanten Verminderung von V95 der Blase (ca. 10 cm3; p = 0,03) korrelierte. V95 des Rektums, TV and IV waren postoperativ ebenfalls signifikant kleiner. Die durchschnittliche Abnahme von V95 des Rektums war relativ klein (2,5 cm3 der Rektumwand).Schlussfolgerung:Die Auswirkungen der Prostatektomie auf die CTV-Definition sind bedeutend. Postoperativ ist eine signifikante Abnahme von CTV, PTV, TV und IV zu erwarten mit der Folge einer Verminderung der bei der adjuvanten Radiotherapie von Strahlung erfassten Anteile von Rektum und Blase.