To assess the predictive role of multiparametric MR imaging (mpMRI) in the setting of salvage RT (sRT) for a presumed local failure after radical prostatectomy (RP). This is a cross-sectional study including all patients treated with sRT at a single Institution from Feb 2014 to Sept 2016. All patients had failed biochemically after RP and underwent pre-sRT mpMRI (including a dynamic contrast-enhanced-DCE MRI) on a 3-T system with the evidence of a presumed local recurrence. All patients were treated with a homogeneous approach delivering 73.5 Gy and 69 Gy to the nodule and to the prostatic bed, respectively, in 30 fractions (IGRT-VMAT, SIB technique). Patients underwent a re-evaluation mpMRI at the time of the study. Patients without a complete response (CR), underwent repeated mpRM at 3-6 month-intervals until CR and/or a maximum of 3 repeated mpMRI. CR was defined as complete disappearance of the nodular area of early contrast enhancement in DCE-MRI or persistence of an area of contrast enhancement with a slower wash-in rate and/or a hypointense (more than muscles) appearance on T2-weighted sequence. On baseline DCE-MRI, the wash-in and wash-out were derived from the whole-volume time-intensity curve using home-made software as per Casciani et al, AJR, 2008. The two-sided Mann–Whitney rank test was used to compare the variables. Receiver operating characteristic (ROC) curves were performed for the most significant DCE-MRI parameters. Thirty-seven patients were identified. The mean (SD) time interval between RP and sRT was 71.1 (58.1) mths. At sRT, mean (SD) serum PSA was 1.47 (1.58) ng/ml and the mean (SD) volume of the recurrence delineated on mpMR plus a 8 mm margin (rPTV) was 12.5 cc (6.3 cc). Eleven (29.7%) patients received also androgen deprivation (AD). All patients ended up showing a complete response, 28 (75.7%), 7 (18.9%) and 2 (5.4%) at the 1st, 2nd or 3rd re-eval mpMRI. The mean (SD) time from the end of sRT to CR was 16.5 (10.0) and 24.1 (5.8) mths for patients who responded at the 1st mpMRI (N=28) vs the slower ones (N=9), p= 0.0436. Compared to slower responders, patients achieving a CR at the 1st re-eval mpRM had significantly smaller rPTVs (9.4cc vs 13.1cc, p=0.0214) and a trend towards lower pre-sRT PSA values (1.21 vs 2.28, p=0.06). However, the stronger correlation was found for the wash-out parameter with a lower value highly predicting a delayed response (0.06 s-1 vs -0.99 s-1,continuum, p=0.0087). The sensitivity and specificity of the wash out parameter were 78.6% and 75%, respectively (area under ROC curve 0.808 p=0.0001, cut-off value ≥0.46 s-1). No correlation was found between time to response and AD (p= 0.3030). sRT is highly effective in achieving a complete response at mpMRI. There is a strong correlation between the time to response and baseline wash-out features.

Purpose or ObjectiveArtificial neural networks (ANNs) were used in the last years for the development of models for the prediction of radiation-induced toxicity following RT.In fact, ANNs are powerful tools for pattern classification in light of their ability to model extremely complex functions and huge numbers of data.However, their major counterpoint is that in some specific cases they might not deliver realistic results due to their missing critical capacity.The objective of this study was to develop a method for assessing reliability of ANNs response over the entire range of possible input variables.In particular, in this study the method was applied to the selection of an ANN for the prediction of late faecal incontinence (LFI) following prostate cancer RT. Material and MethodsThe analysis was carried out on 664 patients (pts) of two multicentre trials.The following information was available for each pt: i) self completed pt reported questionnaire (PRO) for LFI determination, ii) clinical data (co-morbidity, previous abdominal surgery and use of drugs), iii) dosimetric data (DVH and mean dose).Several feed-forward ANNs with a proper balance between complexity and number of training cases were developed, with input variables and hidden neurons ranging between 3 and 5. Once the best ANNs were obtained, a method was developed and applied to verify the reliability of their response over the entire range of possible input variables.The method consists in the development of a virtual library of variables covering all the possible ranges/permutations of continuous/discrete inputs.These are all classified and penalties (pen) are assigned if ANN outputs are not coherent with the real world expectance (i.e., decreasing LFI probability with increasing dose to the rectum). ResultsMore than 1,000,000 different ANN configurations (i.e., architecture and internal weights and thresholds) were developed.For the 200 ANNs showing the best performance, area under the ROC curve (AUC), sensitivity (Se), specificity (Sp) and pen were quantified.The best ANN in terms of classification capability (i.e.AUC=0.79,Se=74%, Sp=72%) was an ANN with 5 inputs (i.e., mean dose, use of antihypertensive, previous presence of haemorrhoids, previous colon disease, hormone therapy) and 5 hidden neurons.However, the application of the method to investigate its coherence with the real life classification expectancy resulted in pen=3, indicating that this wasn't the most 'intelligent" ANN to select.The best ANN with pen=0 was a less complex ANN (i.e. 3 inputs, 5 hidden neurons), resulting in AUC=0.67,Se=70%, Sp=57%. ConclusionA new method consisting in the development of a virtual library of cases was established to evaluate ANN reliability after its training process.Application of this method to the development of an ANN for LFI prediction following prostate cancer RT allowed us to select an ANN with the best generalization capability.

ABSTRACT Purpose To asses activity, safety and secondary resectability in unresectable locally advanced pancreatic cancer (LAPC) patients (pts). Methods Unresectable LAPC pts were eligible for this phase II study. Primary endpoint was clinical benefit (CB = CR + PR + SD). A sample size of 37 pts was considered sufficient to give an 80% probability of rejecting a baseline clinical benefit rate of 55%, with an exact 5% one-sided significance test when the true disease control rate was 75%. The drug regimen would have been considered interest if at least 26 patients showed clinical benefit. Neoadjuvant induction chemotherapy (CHT) encompassed gemcitabine (GEM) 1000 mg/m2 (100-min infusion on d1) and oxaliplatin 100 mg/m2 (2-hr infusion on d2) every 2 wks, for 6 cycles. After CHT pts were restaged for surgery and/or chemoradiation (CRT) consolidation (EBRT up to a total dose of 50.4 Gy plus concomitant GEM 300 mg/m2/week). After CRT completion, pts were restaged to evaluate secondary surgery. Results From January 2005 to January 2012, 35 pts (M/F: 17/18; median age: 68 yrs, range: 46-78; ECOG PS 0-1/2: 28/7) entered the study. A median of 5 (range 1-7) CHT induction cycles were delivered. Toxicity was mild, with G3-4 neutropenia in 2 pts (6%), G3 thrombocytopenia in 1 pt (3%), G3 transaminase elevation in 5 pts (14%), and G3 diarrhea in 2 pts (6%). CHT dose was reduced or delayed in 8 and 7 pts, respectively. Nine confirmed PR and 17 SD were observed for a CB of 74% (95% confidence interval [CI], 56.7-87.5%). A decrease in serum CA 19.9 ≥50% of the baseline was observed in 14 of 23 evaluable pts. Nine-teen pts completed CRT, including 5 pts who subsequently underwent surgery; 1 pt underwent surgery without CRT. Toxicity for the CRT phase was mild, with G3 thrombocytopenia in 1 pt (3%) and G3 neutropenia in 3 pts (8%). Median overall survival (OS) and progression free survival (PFS) for all 35 patients were 10 (95% CI, 8-12) and 9 mos (95% CI, 6-12), respectively. One-yr OS and PFS rates were 26% and 30%, respectively. Conclusions The regimen under study is active and well tolerated. Although an encouraging response rate was reported, OS remains poor, calling for a better selection strategy for LAPC pts who are candidates to neoadjuvant treatment. Disclosure All authors have declared no conflicts of interest.

Purpose: To report long-term results and patterns of failure after conventional and hypofractionated radiation therapy in high-risk prostate cancer.Methods and Materials: This randomized phase III trial compared conventional fractionation (80 Gy at 2 Gy per fraction in 8 weeks) vs hypofractionation (62 Gy at 3.1 Gy per fraction in 5 weeks) in combination with 9-month androgen deprivation therapy in 168 patients with high-risk prostate cancer. Freedom from biochemical failure (FFBF), freedom from local failure (FFLF), and freedom from distant failure (FFDF) were analyzed.Results: In a median follow-up of 70 months, biochemical failure (BF) occurred in 35 of the 168 patients (21%) in the study. Among these 35 patients, local failure (LF) only was detected in 11 (31%), distant failure (DF) only in 16 (46%), and both LF and DF in 6 (17%). In 2 patients (6%) BF has not yet been clinically detected. The risk reduction by hypofractionation was significant in BF (10.3%) but not in LF and DF. We found that hypofractionation, with respect to conventional fractionation, determined only an insignificant increase in the actuarial FFBF but no difference in FFLF and FFDF, when considering the entire group of patients. However, an increase in the 5-year rates in all 3 endpoints-FFBF, FFLF, and FFDF-was observed in the subgroup of patients with a pretreatment prostate-specific antigen (iPSA) level of 20 ng/mL or less. On multivariate analysis, the type of fractionation, iPSA level, Gleason score of 4+3 or higher, and T stage of 2c or higher have been confirmed as independent prognostic factors for BF. High iPSA levels and Gleason score of 4+3 or higher were also significantly associated with an increased risk of DF, whereas T stage of 2c or higher was the only independent variable for LF.Conclusion: Our results confirm the isoeffectiveness of the 2 fractionation schedules used in this study, although a benefit in favor of hypofractionation cannot be excluded in the subgroup of patients with an iPSA level of 20 ng/mL or less. The alpha/beta ratio might be more appropriately evaluated by FFLF than FFBF results, at least in high-risk disease. (C) 2012 Elsevier Inc.

ABSTRACT Background TH-302 is a hypoxia targeted prodrug with a hypoxia-triggered 2-nitroimidazole component designed to release the DNA alkylator, bromo-isophosphoramide mustard (Br-IPM), when reduced in severe hypoxia. A randomized Phase 2B study (NCT01144455) was conducted to assess the benefit of G + T to standard dose G as first-line therapy of PAC. Materials and methods An open-label multi-center study of two dose levels of TH-302 (240 mg/m2 or 340 mg/m2) in combination with G versus G alone (randomized 1:1:1). G (1000 mg/m2) and T were administered IV over 30-60 minutes on Days 1, 8 and 15 of a 28-day cycle. Patients on the G could crossover after progression and be randomized to a G + T arm. The primary efficacy endpoint was a comparison of progression-free survival (PFS) between the combination arms and G alone (80% power to detect 50% improvement in PFS with one-sided alpha of 10%). Summary PFS outcome has previously been reported; more detailed PFS as well as the initial overall survival (OS) data are presented. Results 214 pts were treated; 164 (77%) Stage IV and 50 (23%) Stage IIIB. Median age 65 (range 29-86); 126 M/88 F; 40% ECOG 0/60% ECOG 1. Receiving 6 or more cycles: 32% G; 45% G + T240; 55% G + T340. Median PFS was 3.6 mo in G vs 5.5 mo in G + T240 (p = 0.031) and 6.0 mo in G + T340 (p = 0.008). Poorer prognostic factors (older age, poorer performance status, reduced albumin) were associated with larger treatment effect. Median OS was 7.0 mo in G vs 9.0 in G + T240 and 9.5 mo in G + T340. RECIST best response was 12% in G vs 17% in G + T240 and 27% in G + T340. CA19-9 decreases were significantly greater G + T340. A >50% CA19-9 decrease was 52% with G vs 50% with G + T240 and 70% with G + T340. AEs leading to discontinuation were: 16% G, 15% G + T240 and 11% G + T340. Rash (45% in G + T340) and stomatitis (36% in G + T340) were greater in combination, 4 pts Grade 3 rash. Grd 3/4 thrombocytopenia were 11% G, 39% G + T240 and 59% G + T340 and Grd 3/4 neutropenia were 28% G, 56% G + T240 and 59% G + T340. Conclusions The combination of G plus TH-302 improved the efficacy of G. A TH-302 dose of 340 mg2 was identified for future studies. Skin and mucosal toxicity and myelosuppression were the most common TH-302 related AEs with no increase in treatment discontinuation. Disclosure All authors have declared no conflicts of interest.

Purpose/Objective(s)To compare the efficacy and toxicity of hypofractionated (62 Gy/20 fractions/5 weeks, 4 fractions per week) vs. conventional fractionation radiotherapy (80 Gy/40 fractions/8 weeks) in patients with high-risk prostate cancer.Materials/MethodsFrom January 2003 to December 2007, a total of 168 patients were randomized to receive either hypofractionated (85 patients) or conventional (83 patients) fractionated schedules of 3D conformal radiotherapy (CRT) to the prostate and seminal vesicles. All patients received a 9-month course of total androgen blockade (TAB). The CRT started 2 months after TAB initiation. All patients underwent an accurate clinical evaluation before treatment, including PSA determination, rectal endoscopy, AUA score evaluation, testosterone determination, DRE, abdomino-pelvic TC, and prostate US scan or MR endorectal coil. All biopsy specimens were reviewed by the same pathologist (S.S.). Patient assignment to a risk category was done following the NCCN guidelines. Biochemical failure was determined according to the nadir+2 Phoenix definition.ResultsNo differences between the two groups were found with regard to age, GS, T-Stage, and pretreatment PSA level (iPSA). The median follow-up was 32 (23–43 interquartiles) and 35 (24–45 interquartiles) months in the experimental and conventional arm, respectively. A nadir PSA ≤0.5 ng/mL was observed in 100% and 94% of patients in the experimental and control group, respectively. The 3-year freedom from biochemical failure (FFBF) rates were 87% and 79% in the former and latter group, respectively, (p = 0.035). The 3-year FFBF in patients at a very high risk (i.e., iPSA >20 ng/mL, GS ≥8, or T ≥2c), were 88% and 76% (p = 0.014) in the experimental and control arm, respectively. The multivariate Cox analysis confirmed fractionation, iPSA, and bGS as significant prognostic factors. No patient died. The 3-year rates of freedom from distant metastases were 88% and 82% in the experimental and control arm (p = 0.82), respectively. Based on RTOG/EORTC toxicity criteria, no patient experienced a G4 acute toxicity; and G3 toxicity was observed in only 1 patient. Acute G2 toxicity developed and disappeared earlier in the experimental vs. control group. No difference was found for late toxicity between the two treatment groups, with 3-year G2 rates of 17% and 16% for GI and 14% and 11% for GU in experimental and control group, respectively.ConclusionsOur findings suggest that the hypofractionated schedule used in this trial is superior to conventional fractionation in terms of FFBF, and that late toxicity is equivalent between the two treatment groups. Purpose/Objective(s)To compare the efficacy and toxicity of hypofractionated (62 Gy/20 fractions/5 weeks, 4 fractions per week) vs. conventional fractionation radiotherapy (80 Gy/40 fractions/8 weeks) in patients with high-risk prostate cancer. To compare the efficacy and toxicity of hypofractionated (62 Gy/20 fractions/5 weeks, 4 fractions per week) vs. conventional fractionation radiotherapy (80 Gy/40 fractions/8 weeks) in patients with high-risk prostate cancer. Materials/MethodsFrom January 2003 to December 2007, a total of 168 patients were randomized to receive either hypofractionated (85 patients) or conventional (83 patients) fractionated schedules of 3D conformal radiotherapy (CRT) to the prostate and seminal vesicles. All patients received a 9-month course of total androgen blockade (TAB). The CRT started 2 months after TAB initiation. All patients underwent an accurate clinical evaluation before treatment, including PSA determination, rectal endoscopy, AUA score evaluation, testosterone determination, DRE, abdomino-pelvic TC, and prostate US scan or MR endorectal coil. All biopsy specimens were reviewed by the same pathologist (S.S.). Patient assignment to a risk category was done following the NCCN guidelines. Biochemical failure was determined according to the nadir+2 Phoenix definition. From January 2003 to December 2007, a total of 168 patients were randomized to receive either hypofractionated (85 patients) or conventional (83 patients) fractionated schedules of 3D conformal radiotherapy (CRT) to the prostate and seminal vesicles. All patients received a 9-month course of total androgen blockade (TAB). The CRT started 2 months after TAB initiation. All patients underwent an accurate clinical evaluation before treatment, including PSA determination, rectal endoscopy, AUA score evaluation, testosterone determination, DRE, abdomino-pelvic TC, and prostate US scan or MR endorectal coil. All biopsy specimens were reviewed by the same pathologist (S.S.). Patient assignment to a risk category was done following the NCCN guidelines. Biochemical failure was determined according to the nadir+2 Phoenix definition. ResultsNo differences between the two groups were found with regard to age, GS, T-Stage, and pretreatment PSA level (iPSA). The median follow-up was 32 (23–43 interquartiles) and 35 (24–45 interquartiles) months in the experimental and conventional arm, respectively. A nadir PSA ≤0.5 ng/mL was observed in 100% and 94% of patients in the experimental and control group, respectively. The 3-year freedom from biochemical failure (FFBF) rates were 87% and 79% in the former and latter group, respectively, (p = 0.035). The 3-year FFBF in patients at a very high risk (i.e., iPSA >20 ng/mL, GS ≥8, or T ≥2c), were 88% and 76% (p = 0.014) in the experimental and control arm, respectively. The multivariate Cox analysis confirmed fractionation, iPSA, and bGS as significant prognostic factors. No patient died. The 3-year rates of freedom from distant metastases were 88% and 82% in the experimental and control arm (p = 0.82), respectively. Based on RTOG/EORTC toxicity criteria, no patient experienced a G4 acute toxicity; and G3 toxicity was observed in only 1 patient. Acute G2 toxicity developed and disappeared earlier in the experimental vs. control group. No difference was found for late toxicity between the two treatment groups, with 3-year G2 rates of 17% and 16% for GI and 14% and 11% for GU in experimental and control group, respectively. No differences between the two groups were found with regard to age, GS, T-Stage, and pretreatment PSA level (iPSA). The median follow-up was 32 (23–43 interquartiles) and 35 (24–45 interquartiles) months in the experimental and conventional arm, respectively. A nadir PSA ≤0.5 ng/mL was observed in 100% and 94% of patients in the experimental and control group, respectively. The 3-year freedom from biochemical failure (FFBF) rates were 87% and 79% in the former and latter group, respectively, (p = 0.035). The 3-year FFBF in patients at a very high risk (i.e., iPSA >20 ng/mL, GS ≥8, or T ≥2c), were 88% and 76% (p = 0.014) in the experimental and control arm, respectively. The multivariate Cox analysis confirmed fractionation, iPSA, and bGS as significant prognostic factors. No patient died. The 3-year rates of freedom from distant metastases were 88% and 82% in the experimental and control arm (p = 0.82), respectively. Based on RTOG/EORTC toxicity criteria, no patient experienced a G4 acute toxicity; and G3 toxicity was observed in only 1 patient. Acute G2 toxicity developed and disappeared earlier in the experimental vs. control group. No difference was found for late toxicity between the two treatment groups, with 3-year G2 rates of 17% and 16% for GI and 14% and 11% for GU in experimental and control group, respectively. ConclusionsOur findings suggest that the hypofractionated schedule used in this trial is superior to conventional fractionation in terms of FFBF, and that late toxicity is equivalent between the two treatment groups. Our findings suggest that the hypofractionated schedule used in this trial is superior to conventional fractionation in terms of FFBF, and that late toxicity is equivalent between the two treatment groups.

BACKGROUND. organ preservation has been investigated in patients with muscle-invasive bladder carcinoma over the past decades as an alternative to radical cystectomy. The majority of studies reported that trimodal schedules, including transurethral resection of bladder tumor (TURB), radiotherapy (RT), and chemotherapy, are a feasible and safe organ-sparing approach without deferring the survival probability. However, to the authors' knowledge the best combination of RT and chemotherapy has yet to be well defined. The current study evaluated the long-term results of a schedule of concurrent cisplatin and 5-fluorouracil (5-FU) administered as protracted intravenous infusions (PVI) during hyperfractionated radiotherapy (HFRT) with organ-sparing intent in patients with infiltrating transitional cell carcinoma of the bladder (TCCB).METHODS. Seventy-seven patients with a classification of T2-T4aNOMO TCCB were enrolled in the current study. After a complete TURB and bladder mapping, 42 of 77 patients underwent 2 cycles of induction chemotherapy. All 77 patients underwent HFRT and a schedule of cisplatin (4-6 mg/m(2) per day) and 5-FU (180-220 mg/m(2) per day) as concomitant PVI (radiochemotherapy [RCT]). Six to 8 weeks after RCT, patient response was evaluated by computed tomography scan, urine cytology, and TURB. Patients who achieved a complete response (CR) were followed at regular intervals. For patients with residual or recurrent invasive tumor, salvage cystectomy was recommended.RESULTS. Seventy-two patients were evaluable for response: 65 achieved a CR (90.3%) and 7 (9.7%) achieved a partial response. No significant difference was observed for the different prognostic factors with the exception of stage of disease (T2 [95.7%] vs. T3-T4a [80.0%]; P = 0.04). The observed toxicity, mainly hematologic, was higher among the patients who received induction chemotherapy compared with the patients who did not receive induction chemotherapy, even though the difference was not statistically significant. After a median follow-up of 82.2 months (range, 30-138 months), 44 of 65 (57.1%) patients who achieved a CR were alive. Of these 44 patients, 33 had tumor-free bladders. The 5-year overall, bladder-intact, tumor-specific, disease-free, and cystectomy-free survival rates for all 77 patients were 58.5%, 46.6%, 75.0%, 53.5%, and 76.1%, respectively. No associations were observed in overall and tumor-specific survival with different prognostic factors.CONCLUSIONS. Combined treatment appeared to provide high response rates and can be offered as an alternative option to radical cystectomy in selected patients who refuse or are unsuitable for surgery. (C) 2004 American Cancer Society.

Background: The 5-year survival of patients with completely resected node-positive gastric cancer ranges from 15% to 25%. We explored the feasibility of a chemoradiation regime consisting of concomitant hyperfractionated radiotherapy and 5-fluorouracil protracted venous infusion (5-FU PVI).Materials and Methods: Forty patients received a total or partial gastrectomy operation and D2 nodal resection for Stage III gastric cancer; they were then irradiated by linac with 6-15-MV photons. The target included the gastric bed, the anastomosis, stumps, and regional nodes. A total dose of 55 Gy was given in 50 fractions using 1.1 Gy b.i.d. All patients received a concomitant 200 mg/m(2)/day 5-FU PVI. Patients were examined during the follow-up period as programmed. Toxicity was recorded according to RTOG criteria.Results: After a median follow-up of 75.6 months (range: 22-136 months), 24 (60%) patients had died, and 16 (40%) were alive and free of disease. The 5-year actuarial incidence of relapse was 39%, 22%, and 2% for distant metastases, out-field peritoneal seeding, and in-field local regional recurrences, respectively. The 5-year actuarial cause-specific survival was 43 %. Three patients survived more than 11 years. Acute greater than or equal to Grade 3 toxicity consisted of hematologic (22.5%) and gastrointestinal toxicity (nausea and vomiting 22.5%, diarrhea 2.8%, and abdominal pain 2.6%). No late toxicity was observed.Conclusion: This regime of concomitant 5-FU PVI and hyperfractionated radiotherapy was well tolerated and resulted in successful locoregional control and satisfactory survival. (C) 2002 Elsevier Science Inc.

Concurrent radiotherapy and chemotherapy result in a significant benefit with respect to induction chemotherapy followed by radiotherapy or radiotherapy alone, although with a significant increase of toxicity. To discover a more tolerated and effective chemoradiation regimen, the feasibility and efficacy of a hyperfractionated accelerated irradiation with concurrent protracted venous infusion chemotherapy was investigated. Sixty-five patients with advanced head and neck cancer underwent a definitive (53 patients) or a postoperative adjuvant (12 patients) chemoradiation treatment. Chemotherapy consisted of an intravenous protracted infusion of 5 and 200 mg/m2/d cisplatin and 5-fluorouracil, respectively. Radiotherapy consisted of a split-course accelerated hyperfractionation of two 150-cGy (split twice a day) or three 100-cGy fractions per day (split three times a day) at more than 6-hour intervals, for 2 weeks followed, after a 1-week interruption, by 2-to-3-week treatment, with the same fractionation schedule, to a total dose of 60 Gy to 69 Gy. Confluent mucositis was tolerable and was the cause of treatment delay of more than 10 days in only 20% of patients. Grade 3 or greater systemic toxicity occurred only in 9 of 65 (14%) patients and was never the cause of drug dose reduction. Complete responses were observed in 69% of patients with gross diseases. At a median follow-up of 43.5 months, 45% of patients were alive and free of disease and 38% died of cancer. The 5-year actuarial local regional failure was 35%. The 5-year actuarial disease-specific survival was 50%. Preservation of larynx function was achieved in 47% of living patients and in 74% of all patients, with advanced tumors of the laryngopharynx. The long-term results of this study suggest that this chemoradiation regimen has the potential of achieving a significant improvement over standard therapy while avoiding significant toxicity.

This study analyzes the results of disease relapse and survival in two series of patients treated between 1974 and 1991 with definitive irradiation, with or without early androgen deprivation, for carcinoma of the prostate localized to the pelvis. All 264 patients were irradiated to the prostate and pelvic lymph nodes with a dose of 50 to 54 Gy in 25 to 27 fractions, followed by a 16- to 20-Gy boost in 8 to 10 fractions to the prostate and periprostatic region. Ninety percent of patients received a total dose to the prostate (pelvis + boost) of 70 Gy. Ninety-nine of the 264 patients underwent early androgen deprivation. The endocrine manipulation program was initiated 0 to 9 months before the beginning of the radiotherapy course and was continued for 2 or more years or until disease progression. All patients who relapsed after radiotherapy alone received late hormonal manipulation. After a median follow-up of 100 months, no difference in the incidence of local and distant failure rate and cancer-specific mortality was detected between the two treatment groups. The local and distant failure rates were, respectively, 19% and 40% in patients who had undergone radiotherapy and early androgen deprivation and 20% and 36% in patients who received radiotherapy alone. Cancer mortality was similar, with 35% and 30% of deaths in the former and latter group, respectively. Death for intercurrent disease, however, was significantly more frequent (p = 0.03) in patients treated with radiotherapy and hormones (19%) than in those who received radiotherapy alone (8%). Actuarial analysis of both metastasis-free and disease-free survival detected no difference between the two treatment groups, with 10-year rates of 53.3% and 42.5%, respectively, in the radiation-alone group and 45.5% and 47%, respectively, in the radiation-plus-androgen deprivation group. A statistically significant difference (p = 0.03) in overall survival in favor of patients treated with radiotherapy alone was noted, with a 10-year rate of 47%, compared with 26% observed in the radiotherapy-plus-androgen deprivation group. In conclusion, results of our study confirm numerous reports based on retrospective analyses that failed to show any benefit of hormonal management adjuvant to a definitive irradiation. The disappointing finding was the significantly better overall survival in patients who underwent radiotherapy alone.

PURPOSE:In order to better define variables and factors that may influence the pain response to radiation, and to look for a radiation regimen that can assure the highest percentage and the longest duration of pain relief, we performed a prospective, although not randomized, study on patients with bone metastases from various primary sites. METHODS AND MATERIALS:From December 1988 to March 1994, 205 patients with a total of 255 solitary or multiple bone metastases from several primary tumors were treated in our radiotherapy center with palliative intent. Irradiation fields were treated with three main fractionation schedules: (1) Conventional fractionation: 40-46 Gy/20-23 fractions in 5-5.5 weeks; (2) Short course: 30-36 Gy/10-12 fractions in 2-2.3 weeks; (3) Fast course: 8-28 Gy/1-4 consecutive fractions. Pain intensity was self-assessed by patients using a visual analogic scale graduated from 0 (no pain) to 10 (the strongest pain one can experience). Analgesic requirement was assessed by using a five-point scale, scoring both analgesic strength and frequency (0 = no drug or occasional nonopioids; 1 = Nonopioids once daily; 2 = Nonopioids more than once daily; 3 = Mild opioids (oral codeine, pentazocine, etc.), once daily; 4 = Mild opioids more than once daily; 5 = Strong opioids (morphine, meperidine, etc.). Complete pain relief meant the achievement of a score < or = 2 in the pain scale or 0 in the analgesic requirement scale. Partial pain relief indicated a score of 3 to 4 or of 1 to 2 on the former and latter scale, respectively. RESULTS:Total pain relief (complete + partial) was observed in 195 (76%) sites, in 158 of which (62%) a complete response was obtained. Metastases from NSC lung tumors appeared to be the least responsive among all primary tumors, with 46% complete pain relief in comparison to 65% and 83% complete relief in breast (p = 0.04) and in prostate metastases (p = 0.002), respectively. A significant difference in pain relief was detected among the several ranges of total dose delivered to the painful metastases, with 81%, 65%, and 46% complete relief rates in the 40-46 Gy, 30-36 Gy (p = 0.03), and 8-28 Gy (p = 0.0001) dose ranges respectively. A straight correlation between total dose and complete pain relief was confirmed by the curve calculated by the logistic model which shows that doses of 30 Gy or more are necessary to achieve complete pain relief in 70% or more of bone metastases. This correlation holds also for the duration of pain control, as shown by the actuarial analysis of time to pain progression. Multivariate analyses, with complete pain relief and time to pain progression as endpoints show a highly significant effect of radiation dose (p = 0.0007) and performance status (p = 0.003), with lower rates of complete pain relief and shorter time to pain progression observed after smaller radiation total doses or higher Eastern Cooperative Oncology Group (ECOG) scores. CONCLUSION:Although single-dose or short course irradiation is an attractive treatment in reducing the number of multiple visits to radiotherapy departments for patients with painful bone metastases, it is nevertheless clear that aggressive protracted treatments seem to offer significant advantages especially for patients in whom the expected life span is not short.