Prostate Cancer Treatment-Related Toxicity: Comparison between 3D-Conformal Radiation Therapy (3D-CRT) and Volumetric Modulated Arc Therapy (VMAT) Techniques.

Objective: This paper illustrates the results of a mono-institutional registry trial, aimed to test whether gastrointestinal (GI) and genitourinary (GU) toxicity rates were lower in localized prostate cancer patients treated with image-guided volumetric modulated arc therapy (IG-VMAT) compared to those treated with IG-3D conformal radiation therapy (IG-3DCRT). Materials and Methods: Histologically proven prostate cancer patients with organ-confined disease, treated between October 2008 and September 2014 with moderately hypofractionated radiotherapy, were reviewed. Fiducial markers were placed in the prostate gland by transrectal ultrasound guide. The prescribed total dose was 70 Gy in 28 fractions. The mean and median dose volume constraints for bladder and rectum as well as total volume of treatment were analyzed as potentially prognostic factors influencing toxicity. The Kaplan−Meier method was applied to calculate survival. Results: Overall, 83 consecutive patients were included. Forty-two (50.6%) patients were treated with 3D-CRT and 41 (49.4%) with the VMAT technique. The median follow-up for toxicity was 77.26 months for the whole cohort. The VMAT allowed for a dose reduction to the rectum and bladder for the large majority of the considered parameters; nonetheless, the only parameter correlated with a clinical outcome was a rectal dose limit V66 > 8.5% for late GI toxicity G ≥ 2 (p = 0.045). Rates of G ≥ 2 toxicities were low among the whole cohort of these patients treated with IGRT. The analysis for rectum dose volume histograms (DVHs) showed that a severe (grade ≥ 2) late GI toxicity was related with the rectal dose limit V66 > 8.5% (p = 0.045). Conclusions: This study shows that moderate hypofractionation is feasible and safe in patients with intermediate and high-risk prostate cancer. Daily IGRT may decrease acute and late toxicity to organs at risk and improve clinical benefit and disease control rate, cutting down the risk of PTV geographical missing. The adoption of VMAT allows for promising results in terms of OAR sparing and a reduction in toxicity that, also given the small sample, did not reach statistical significance.

Accurate prediction of long-term risk of biochemical failure after salvage radiotherapy including the impact of pelvic node irradiation.

BACKGROUND AND PURPOSE: Explainable models of long-term risk of biochemical failure (BF) after post-prostatectomy salvage radiotherapy (SRT) are lacking. A previously introduced radiobiology-based formula was adapted to incorporate the impact of pelvic nodes irradiation (PNI). MATERIALS AND METHODS: The risk of post-SRT BF may be expressed by a Poisson-based equation including pre-SRT PSA, the radiosensitivity α, the clonogen density C, the prescribed dose (in terms of EQD2, α/ß = 1.5 Gy) and a factor (1-BxλxPSA) accounting for clonogens outside the irradiated volume, being λ the recovery due to PNI. Data of 795 pT2-pT3, pN0/pN1/pNx (n = 627/94/74) patients with follow-up ≥ 5 years and pre-RT PSA ≤ 2 ng/mL were randomly split into training (n = 528) and validation (n = 267) cohorts; the training cohort data were fitted by the least square method. Separate fits were performed for different risk groups. Model performances were assessed by calibration plots and tested in the validation group. RESULTS: The median follow-up was 8.5y, median pre-SRT PSA and EQD2 were 0.43 ng/mL and 71.3 Gy respectively; 331/795 pts received PNI. The most clinically significant prognostic grouping was pT3b and/or ISUP4-5 versus pT2/3a and ISUP1-3. Best-fit parameters were αeff = 0.26/0.23 Gy-1, C = 107/107, B = 0.40/0.97, λ = 0.87/0.41 for low/high-risk group. Performances were confirmed in the validation group (slope = 0.89,R2 = 0.85). Results suggested optimal SRT dose at 70-74 Gy. The estimated reduction of post-SRT BF due to PNI at these dose values was > 5 % for PSA > 1/>0.15 ng/mL for low/high-risk patients, being > 10 % for high-risk patients with pre-SRT PSA > 0.25 ng/mL. CONCLUSION: An explainable one-size-fits-all equation satisfactorily predicts long-term risk of post-SRT BF. The model was independently validated. A calculator tool was made available.

Multiparametric magnetic resonance imaging versus Partin tables and the Memorial Sloan-Kettering cancer center nomogram in risk stratification of patients with prostate cancer referred to external beam radiation therapy.

PURPOSE: To evaluate the agreement between multiparametric Magnetic Resonance Imaging (mpMRI), Partin tables (PT) and the Memorial Sloan Kettering Cancer Center nomogram (MSKCCn) in assessing risk category in prostate cancer (PCa) patients referred to External Beam Radiotherapy (EBRT). MATERIALS AND METHODS: In this bicentric study, we prospectively enrolled 80 PCa patients who underwent pre-EBRT mpMRI on a 3.0T magnet with a multiparametric protocol including high-resolution, multiplanar T2-weighted sequences, diffusion-weighted imaging and dynamic contrast-enhanced imaging. National comprehensive cancer network risk categories were assessed using prostate-specific-antigen level, Gleason score and the T-stage as defined by mpMRI or nomograms. Cohen's kappa statistic was used to calculate the agreement between mpMRI and nomograms in assessing the T-stage (organ-confined (OC) vs. non-organ-confined (nOC) disease) and risk category (≤ low risk vs. intermediate risk vs. ≥ high risk). RESULTS: mpMRI showed poor agreement with PT and MSKCCn in assessing nOC versus OC (k = 0.16 for both), translating into an mpMRI-induced reclassification of PT- and MSKCCn-related risk category in 36.3% (k = 0.43) and 41.3% (k = 0.31) of cases, respectively, with most changes occurring towards intermediate risk category. CONCLUSIONS: mpMRI showed low agreement with nomograms as a tool to stratify PCa risk, leading to significant risk reclassification. Assuming that mpMRI is a more reliable surrogate standard of reference for pathology, this technique should refine or replace nomograms in risk classification before EBRT.

Can multiparametric MRI replace Roach equations in staging prostate cancer before external beam radiation therapy?

PURPOSE: To investigate the agreement between Roach equations (RE) and multiparametric magnetic resonance imaging (mpMRI) in assessing the T-stage of prostate cancer (PCa). MATERIALS AND METHODS: Seventy-three patients with biopsy-proven PCa and previous RE assessment prospectively underwent mpMRI on a 3.0T magnet before external beam radiation therapy (EBRT). Using Cohen's kappa statistic, we assessed the agreement between RE and mpMRI in defining the T-stage (≥T3 vs.T≤2) and risk category according to the National comprehensive cancer network criteria (≤intermediate vs. ≥high). We also calculated sensitivity and specificity for ≥T3 stage in an additional group of thirty-seven patients with post-prostatectomy histological examination (mpMRI validation group). RESULTS: The agreement between RE and mpMRI in assessing the T stage and risk category was moderate (k=0.53 and 0.56, respectively). mpMRI changed the T stage and risk category in 21.9% (95%C.I. 13.4-33-4) and 20.5% (95%C.I. 12.3-31.9), respectively, prevalently downstaging PCa compared to RE. Sensitivity and specificity for ≥T3 stage in the mpMRI validation group were 81.8% (95%C.I. 65.1-91.9) and 88.5% (72.8-96.1). CONCLUSION: RE and mpMRI show moderate agreement only in assessing the T-stage of PCa, translating into an mpMRI-induced change in risk assessment in about one fifth of patients. As supported by high sensitivity/specificity for ≥T3 stage in the validation group, the discrepancy we found is in favour of mpMRI as a tool to stage PCa before ERBT.

Impact of multiparametric magnetic resonance imaging on risk group assessment of patients with prostate cancer addressed to external beam radiation therapy.

PURPOSE: To investigate the impact of multiparametric magnetic resonance imaging (mpMRI) on risk group assessment of patients with prostate cancer (PCa) initially addressed to external beam radiation therapy (EBRT). MATERIALS AND METHODS: We prospectively performed mpMRI (3.0Tsystem) in 44 patients addressed to EBRT, using a multiparametric protocol (high-resolution multiplanar T2-weighted, diffusion-weighted and dynamic contrast-enhanced imaging). Risk group was assessed in accordance with the National comprehensive cancer network (NCCN) categories, by combining prostate-specific-antigen level, Gleason score and the T-stage as established by digital rectal examination (clinical risk assessment; c-RA) versus mpMRI (mpMRI-risk assessment; mpMRI-RA). The agreement between c-RA and mpMRI-RA was investigated using Cohen's kappa. RESULTS: Patients were included in very low/low risk, intermediate risk, high risk, very high risk and metastatic NCCN categories in 10 (22.7%), 18 (40.9%), 15 (34.1%), 1 (2.3%) and 0 cases using c-RA vs. 8 (18.2%), 14 (31.8%), 14 (31.8%), 4 (9.1%) and 4 (9.1%) cases using mpMRI-RA, respectively, with only moderate agreement (k=0.43). mpMRI-RA determined risk downgrading in 2/44 patients (4.5%), and risk upgrading in 16/44 patients (36.3%). After mpMRI, EBRT remained indicated in all patients. CONCLUSION: mpMRI changed clinical risk stratification in about 41% of patients with PCa, with potential impact on EBRT planning.

Changes in patterns of practice for prostate cancer radiotherapy in Italy 1995-2003. A survey of the Prostate Cancer Study Group of the Italian Radiation Oncology Society.

AIMS AND BACKGROUND: In 2002, a survey including 1759 patients treated from 1980 to 1998 established a "benchmark" Italian data source for prostate cancer radiotherapy. This report updates the previous one. METHODS: Data on clinical management and outcomes of 3001 patients treated in 15 centers from 1999 through 2003 were analyzed and compared with those of the previous survey. RESULTS: Significant differences in clinical management (-10% had abdominal magnetic resonance imaging; +26% received ≥70 Gy, +48% conformal radiotherapy, -20% pelvic radiotherapy) and in G3-4 toxicity rates (-3.8%) were recorded. Actuarial 5-year overall, disease-specific, clinical relapse-free, and biochemical relapse-free survival rates were 88%, 96%, 96% and 88%, respectively. At multivariate analysis, D'Amico risk categories significantly impacted on all the outcomes; higher radiotherapy doses were significantly related with better overall survival rates, and a similar trend was evident for disease-specific and biochemical relapse-free survival; cumulative probability of 5-year late G1-4 toxicity was 24.8% and was significantly related to higher radiotherapy doses (P <0.001). CONCLUSIONS: The changing patterns of practice described seem related to an improvement in efficacy and safety of radiotherapy for prostate cancer. However, the impact of the new radiotherapy techniques should be prospectively evaluated.

Diarrhoea in irradiated patients: a prospective multicentre observational study.

AIMS: To determine the incidence of cancer treatment-induced diarrhoea in patients submitted to irradiation. METHODS: Forty-five Italian radiation oncology departments took part in this prospective observational study and a total of 1020 patients were enrolled. The accrual lasted three consecutive weeks; evaluation was based on diary cards filled in daily by patients during radiotherapy and one week after cessation. Diary cards recorded both the onset and intensity of diarrhoea. RESULTS: A total of 1004 patients were eligible for this analysis. 147/1004 (14.6%) patients had diarrhoea. The median minimum number of daily events was 1 (range 1-7) with a median maximum events of 3 (range 1-23). 82/147 patients (56.2%) had a drug prescription for diarrhoea. In the evaluation of the onset of diarrhoea, in multivariate analysis, we found the following factors to be statistically significant predictors of an increased likelihood of diarrhoea: primitive tumour site, therapeutic purpose and field size. CONCLUSIONS: Patients with abdominal-pelvic cancer, treated with curative purpose and using large field sizes are at high risk of cancer treatment-induced diarrhoea. Diarrhoea was also observed in patients treated at other sites. In this population group there is the need for more stringent monitoring during the delivery of radiation therapy.

A prospective observational trial on emesis in radiotherapy: analysis of 1020 patients recruited in 45 Italian radiation oncology centres.

PURPOSE: A prospective observational multicentre trial was carried out to assess the incidence, pattern, and prognostic factors of radiation-induced emesis (RIE), and to evaluate the use of antiemetic drugs in patients treated with radiotherapy or concomitant radio-chemotherapy. The application in clinical practice of the Multinational Association of Supportive Care in Cancer guidelines was also studied. MATERIALS AND METHODS: Forty-five Italian radiation oncology centres took part in this trial. The accrual lasted for 3 consecutive weeks and only patients starting radiotherapy or concomitant radio-chemotherapy in this period were enrolled. Evaluation was based on diary card filled in daily by patients during treatment and one week after stopping it. Diary card recorded the intensity of nausea/vomiting and prophylactic/symptomatic antiemetic drug prescriptions. RESULTS: A total of 1020 patients entered into the trial, and 1004 were evaluable. Vomiting and nausea occurred in 11.0% and 27.1% of patients, respectively, and 27.9% patients had both vomiting and nausea. In multifactorial analysis, the only statistically significant patient-related risk factors were concomitant chemotherapy and previous experience of vomiting induced by chemotherapy. Moreover, two radiotherapy-related factors were significant risk factors for RIE, the irradiated site (upper abdomen) and field size (>400 cm(2)). An antiemetic drug was given only to a minority (17%) of patients receiving RT, and the prescriptions were prophylactic in 12.4% and symptomatic in 4.6%. Different compounds and a wide range of doses and schedules were used. CONCLUSIONS: These data were similar to those registered in our previous observational trial, and the radiation oncologists' attitude in underestimating RIE and under prescribing antiemetics was confirmed.

Long-term results of conventional radiotherapy versus accelerated hyperfractionated radiotherapy versus concomitant radiotherapy and chemotherapy in locoregionally advanced carcinoma of the oropharynx.

AIMS AND BACKGROUND: To compare conventional fractionation (CF) radiation therapy (RT), arm A, versus a split-course accelerated hyperfractionated schedule (S-AHF), arm B, versus CFRT plus concomitant chemotherapy (CT), arm C, in terms of five-year survival and toxicity for squamous cell tumors of the oropharynx. METHODS AND STUDY DESIGN: Between January 1993 and June 1998, 192 previously untreated patients with stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were enrolled in a multicenter randomized phase III trial (ORO 93-01). In arms A and C, 66 to 70 Gy in 33 to 35 fractions was administered five days a week for six and a half to seven weeks. In arm B, the dose delivered was 64 to 67.2 Gy in two fractions of 1.6 Gy every day, five days a week, with a planned two-week split at 38.4 Gy. In arm C the CT regimen consisted of three cycles of carboplatin and 5-fluorouracil (CBDCA 75 mg/m2 on days 1 to 4 and 5-FU 1000 mg/m2 i.v. on days 1 to 4 every 28 days). RESULTS: No statistically significant difference was found in five-year overall survival (P = 0.39): 21% for arm A, 21% for arm B, and 40% for arm C. Similarly, there was no statistically significant difference in terms of five-year relapse-free survival: 15% for arm A, 17% for arm B, and 36% for arm C. There was a slight trend towards better five-year locoregional control (P = 0.07) for the combined arm: patients without locoregional relapse were 48% in arm C, 21% in arm A and 18% in arm B. Locoregional control was significantly better when arm C was compared with arms A and B combined (P = 0.02; arm A+B 20%; arm C 48%). Distant metastases were fairly balanced in the three arms (A: 14; B: 9; C: 11), with a tendency towards more frequent isolated distant metastasis development in arm C (8 of 11 [72%] versus 7 of 23 [30%] in arms A+B). Five-year second-tumor-free survival was 85%. The 13 second tumors were equally distributed and were mainly correlated with tobacco and alcohol consumption (five lung, two esophagus, two oral cavity, one larynx, one pancreas, one hepatocarcinoma, one myeloma). Arm C showed slightly more G3+ late side effects involving subcutaneous tissues and mucosa, although significant late sequelae were relatively uncommon and the mucosal side effects were mostly transient. The occurrence of persistent G3 xerostomia was comparable in the three treatment arms. CONCLUSIONS: The results obtained with the combination of CT and RT compared with RT alone did not reach statistical significance, but combined treatment almost doubled the five-year overall survival, relapse-free survival and locoregional control rate. Patients with advanced squamous cell carcinomas of the oropharynx who are medically suitable for the combined approach should be treated with a combination of radiotherapy and chemotherapy. The occurrence of second tumors is relatively common in these patients and may contribute substantially to the causes of death.

Italian survey in postoperative radiation therapy for prostate carcinoma by the AIRO National Working Group on Prostate Radiotherapy: definitive results.

AIMS AND BACKGROUND: The National Working Group on Prostate Radiotherapy of AIRO (Associazione Italiana Radioterapia Oncologica, Italian Association of Radiotherapeutic Oncology) was established in March 2001. A retrospective multi-center survey was performed to analyze the patterns of care for prostate cancer patients treated with postoperative radiotherapy following radical prostatectomy in Italy with regard to the year 2000. MATERIALS AND METHODS: A structured questionnaire was mailed to 47 Italian radiotherapy centers to assess patient accrual in the postoperative setting in the interval comprised between period January-December 2000. Numbers of patients treated for different stages, specific prognostic factors indicating the need for adjuvant radiotherapy, fractionation schedules and prescription doses were acquired as well as other clinically important factors such as radiotherapy timing and the use of hormone therapy. More technical features of the treatment, such as patient positioning, mode of simulation, typical field setup and dose prescription criteria were also included in the questionnaire. RESULTS: The questionnaire was returned by 24 radiotherapy Institutions (51%) with a total number of 470 patients treated postoperatively in the year 2000. An average of about 20 patients were enrolled by each radiotherapy center. The age range was 45-81 years. Radiotherapy was delivered within 6 months of radical prostatectomy in 297 patients (65.4%) (mean, 3.4 months). In 157 (34.6%), the treatment was delivered as a salvage approach for biochemical or micro-macroscopic recurrence. Most of patients had locally advanced stage disease (pT3-pT4) (76%). Unfavorable prognostic factors, such as positive margins, capsular invasion, Gleason pattern score > 7 were present in about 50% of patients. CONCLUSIONS: The study confirmed that important risk factors for recurrences are present in a significant percentage of patients treated by radical prostatectomy. The number of patients that would benefit from adjuvant radiotherapy is therefore potentially very large. Future prospective studies should be conducted to assess and to clarify the respective roles of adjuvant and salvage radiotherapy in prostate cancer patients.

Locoregionally advanced carcinoma of the oropharynx: conventional radiotherapy vs. accelerated hyperfractionated radiotherapy vs. concomitant radiotherapy and chemotherapy--a multicenter randomized trial.

PURPOSE: To compare conventional fractionation radiation therapy (RT), Arm A, vs. split-course accelerated hyperfractionated RT (S-AHF), Arm B, vs. conventional fractionation RT plus concomitant chemotherapy (CT), Arm C, in terms of survival and toxicity for advanced, unresectable epidermoid tumors of oropharynx. METHODS AND MATERIALS: Between January 1993 and June 1998, 192 previously untreated patients affected with Stage III and IV oropharyngeal carcinoma (excluding T1N1 and T2N1) were accrued in a multicenter, randomized Phase III trial (ORO 93-01). For Arms A and C, 66-70 Gy in 33-35 fractions, 5 days a week, were administered in 6.5-7 weeks to tumor and positive nodes. In Arm B, the dose delivered to tumor and involved nodes was 64-67.2 Gy, giving 2 fractions of 1.6 Gy every day with an interfraction interval of at least 4 h and preferably 6 h, 5 days a week. At 38.4 Gy, a 2-week split was planned; after the split, RT was resumed with the same modality. In Arm C, CT regimen consisted of carboplatin and 5-fluorouracil (CBDCA 75 mg/m(2), Days 1-4; 5-FU 1,000 mg/m(2) i.v. over 96 h, Days 1-4, recycling every 28 days (at 1st, 5th, and 9th week). RESULTS: No statistically significant difference was detected in overall survival (p = 0.129): 40% Arm A vs. 37% Arm B vs. 51% Arm C were alive at 24 months. Similarly, there was no statistically significant difference in terms of event-free survival (p = 0.196): 20% for Arm A, 19% for Arm B, and 37% for Arm C were event free at 24 months. On the contrary, the 2-year disease-free survival was significantly different among the three arms (p = 0.022), with a superiority for Arm C. At 24 months, the proportion of patients without relapse was 42% for Arm C vs. 23% for Arm A and 20% for Arm B. Patients in Arm A less frequently developed G3+ acute mucositis than their counterparts in Arm B or C (14.7% vs. 40.3% vs. 44%). Regarding the CT-related acute toxicity, apart from 1 case of fatal nephrotoxicity, only hematologic G3+ (Grade 3 or higher) acute sequelae were observed (World Health Organization scale), most commonly leukopenia (22.7%). Arm C showed slightly more G3+ skin, s.c. tissue, and mucosal late side effects (RTOG scale), although significant sequelae were relatively uncommon, and mucosal sequelae were most commonly transient. The occurrence of persistent G3 xerostomia was comparable in all three treatment arms. CONCLUSIONS: The combination of simultaneous CT and RT with the regimen of this trial is better than RT alone in advanced oropharyngeal squamous-cell carcinomas, by increasing disease-free survival. This improvement, however, did not translate into an overall survival improvement, and was associated with a higher incidence of acute morbidity.