Dose to Pelvic Bone Marrow Defined with FDG-PET Predicts for Hematologic Nadirs in Anal Cancer Patients Treated with Concurrent Chemo-radiation.

PURPOSE: To investigate whether irradiated volume of pelvic active bone marrow (ACTBM) may predict decreased blood cells nadirs in anal cancer patients undergoing concurrent chemo-radiation. METHODS: Forty-four patients were analyzed and pelvic active bone marrow (ACTBM) was characterized employing 18FDG-PET. Dosimetric parameters on dose-volume histograms were correlated to nadirs with generalized linear modeling. RESULTS: ACTBM mean dose was significantly correlated to white blood cell (ß = -1.338; 95%CI: -2.455/-0.221; p = 0.020), absolute neutrophil count (ß = -1.651; 95%CI: -3.284/-0.183; p = 0.048), and platelets (ß = -0.031; 95%CI: -0.057/-0.004; p = 0.024) nadirs. Other dosimetric parameters were found to be correlated (ACTBM-V10,-V20,-V30and-V40). CONCLUSIONS: 18FDG-PET is able to define active bone marrow and may predict for decreased blood cells count nadirs.

Intensity-modulated radiation therapy with simultaneous integrated boost combined with concurrent chemotherapy for the treatment of anal cancer patients: 4-year results of a consecutive case series.

PURPOSE: To report the 4-year outcomes of a consecutive series of anal cancer patients treated with concurrent chemo-radiation delivered with intensity-modulated radiotherapy (IMRT), employing a simultaneous integrated boost (SIB) approach. METHODS: A consecutive series of 54 patients was enrolled between 2007 and 2013. Treatment schedule consisted of 50.4 Gy/28 fractions (1.8 Gy daily) to the gross tumor volume, while the elective nodal volumes were prescribed 42 Gy/28 fractions (1.5 Gy/daily) for patients having a cT2N0 disease. Patients with cT3-T4/N0-N3 tumors were prescribed 54 (T3) or 60 (T4) Gy/30 fractions (1.8-2 Gy daily) to the gross tumor volume; gross nodal volumes were prescribed 50.4 Gy/30 fr (1.68 Gy daily) if sized ≤ 3 cm or 54 Gy/30 fr (1.8 Gy daily) if > 3 cm; elective nodal regions were given 45 Gy/30 fractions (1.5 Gy daily). Chemotherapy was administered concurrently according to the Nigro's regimen. Primary endpoint was colostomy-free survival (CFS). Secondary endpoints were local control (LC), disease-free survival (DFS), cancer-specific survival (CSS), overall survival (OS), and toxicity profile. RESULTS: Median follow up was 32.6 months (range 12-84). The actuarial probability of being alive at 4 years without a colostomy (CFS) was 68.9% (95% CI: 50.3%-84.7%). Actuarial 4-year OS, CSS, DFS, and LC were 77.7% (95% CI: 60.7-88.1%), 81.5% (95% CI: 64%-91%), 65.5% (95% CI: 47.7%-78.5%), and 84.6% (95% CI: 71.6%-92%). Actuarial 4-year metastasis-free survival was 74.4% (95% CI: 55.5%-86.2%). Maximum detected acute toxicities were as follows: dermatologic -G3: 13%; GI-G3: 8%; GU-G3: 2%; anemia-G3: 2%; neutropenia-G3:11%; G4: 2%; thrombocytopenia- G3:2%. Four-year G2 chronic toxicity rates were 2.5% (95% CI: 3.6-16.4) for GU, 14.4% (95% CI: 7.1-28) for GI, 3.9% (95% CI: 1%-14.5%) for skin, and 4.2% (95% CI: 1.1-15.9) for genitalia. CONCLUSIONS: Our study shows the feasibility of IMRT in the combined modality treatment of anal cancer, with comparable results to the literature with respect to LC, sphincter preservation and survival. Acute toxicity is lower if compared to series employing standard techniques. Our results support the use of IMRT on a routine basis for the treatment of anal cancer.

Efficacy and safety of tadalafil 20 mg on demand vs. tadalafil 5 mg once-a-day in the treatment of post-radiotherapy erectile dysfunction in prostate cancer men: a randomized phase II trial.

INTRODUCTION: The role of phosphodiesterase type 5 inhibitors in the treatment of post-radiotherapy erectile dysfunction (ED) has not been extensively investigated. AIM: To compare the efficacy and safety of on-demand 20-mg tadalafil (arm A) with the newly released tadalafil 5-mg once-a-day dosing (arm B) in patients with ED following radiotherapy for prostate cancer (PC). METHODS: Randomized study to receive on-demand 20-mg or once-a-day 5-mg tadalafil for 12 weeks. Main Outcome Measures. Changes in the International Index of Erectile Function (IIEF) domain scores and Sexual Encounter Profile (SEP) question 2 and 3 positive response rates. RESULTS: Fifty-two out of 86 screened patients were randomized. Forty-four patients were evaluable for efficacy. A significant improvement in all domains of the IIEF was observed in both arms (P = 0.0001) with mean erectile function domain scores values of 25 and 27.1 for the 20-mg and 5-mg tadalafil, respectively (P = 0.19). SEP 2 and 3 positive response rates increased from 0% in both arms at baseline to 81% and 70% in the 20-mg arm and 90% and 73% in the 5-mg arm, respectively, at the end of treatment (P = 0.27). End of treatment global efficacy question positive answers were 86% in the 20-mg arm and 95% in the 5-mg arm (P = 0.27). Higher treatment compliance was shown in arm B (100%) as compared with arm A (86%). There was a nonstatistically significant trend toward fewer side effects in favor of the 5-mg daily dose arm. CONCLUSIONS: In the study population, both tadalafil formulations generated significantly high response rates according to the outcome measures and were well tolerated. The once-a-day 5-mg dosing showed higher compliance and marginally reduced side effects, thus making it an attractive alternative to on-demand therapy for ED in post-radiotherapy PC patients.

Image-guided IMRT with simultaneous integrated boost as per RTOG 0529 for the treatment of anal cancer.

AIM: To report on clinical outcomes of simultaneous integrated boost intensity-modulated radiation therapy (IMRT) and concurrent chemotherapy as per Radiation Therapy Oncology Group (RTOG) 0529 protocol in anal cancer patients. METHODS: Clinical stage T1-T4 N0-N3 anal cancer patients were submitted to concomitant chemoradiation. Patients with cT2N0 disease were prescribed 50.4 Gy/28 fractions to the gross tumor planning target volume (PTV) and 42 Gy/28 fractions to the elective nodal PTV. Patients staged as cT3-T4/N0-N3 were given 54 Gy/30 fractions to the macroscopic anal PTV, while clinical nodes were prescribed 50.4 Gy/30 fractions if <3 cm or 54 Gy/30 fractions if ≥3 cm; elective nodal PTV was prescribed 45 Gy/30 fractions. Two cycles of concomitant 5-fluorouracil and mitomycin C were planned for all patients. Oncological outcomes, acute and late toxicity profiles and pattern of failure were reported. RESULTS: The 3-year colostomy-free survival rate was 64% (95% CI 0.52-0.75). The 3-year local control, disease-free and overall survival rates were 69% (95% CI 0.57-0.79), 71% (95% CI 0.59-0.80) and 79% (95% CI 0.66-0.87), respectively. The cumulative incidence of colostomies was 15.1% (95% CI 8.15-23.88) at 24 months. The cumulative incidence of cancer-specific deaths was 16.4% (95% CI 8.60-26.47) at 36 months. Major acute toxicity consisted of hematological (G3-G4: 26%) and cutaneous (G3-G4: 16%) events. Only one case of ≥G3 late toxicity was documented. CONCLUSIONS: Simultaneous integrated boost IMRT and concurrent chemotherapy as per RTOG 0529 protocol seems to be safe and feasible with consistent oncological outcomes and a mild acute and late toxicity profile in anal cancer patients.

Volumetric modulated arc therapy (VMAT) to deliver nodal irradiation in breast cancer patients.

To evaluate feasibility, safety, toxicity profile and dosimetric results of volumetric modulated arc therapy (VMAT) to deliver regional nodal irradiation (RNI) after either mastectomy or breast conservation (BCS) in high-risk breast cancer patients. Between January 2015 and January 2017, a total of 45 patients were treated with VMAT to deliver RNI together with whole breast or post-mastectomy radiotherapy. The fractionation schedule comprised 50 Gy in 25 fractions given to supraclavicular and axillary apex nodes and to whole breast (after BCS) or chest wall (after mastectomy). Two opposite 50°-60° width arcs were employed for breast ad chest wall irradiation, while a single VMAT arc was used for nodal treatment. Treatment was generally well tolerated. Acute skin toxicity was G2 in 13.3% of patients. Late skin toxicity consisted of G1 induration/fibrosis in six patients (13.3%) and G2 in 1 (2.2%). Dosimetric results were consistent in terms of both target coverage and normal tissue sparing. In conclusion, VMAT proved to be a feasible, safe and effective strategy to deliver RNI in breast cancer patients after either BCS or mastectomy with promising dosimetric results and a mild toxicity profile.

Lumbar-sacral bone marrow dose modeling for acute hematological toxicity in anal cancer patients treated with concurrent chemo-radiation.

The aim of the study was to model acute hematologic toxicity (HT) and dose to pelvic osseous structures in anal cancer patients treated with definitive chemo-radiation (CT-RT). A total of 53 patients receiving CT-RT were analyzed. Pelvic bone marrow and corresponding subsites were contoured: ilium, lower pelvis and lumbosacral spine (LSBM). Dose-volume histograms points and mean doses were collected. Logistic regression was performed to correlate dosimetric parameters and ≥G3 HT as endpoint. Normal tissue complication probability (NTCP) was evaluated with the Lyman-Kutcher-Burman (LKB) model. Logistic regression showed a significant correlation between LSBM-mean dose and ≥G3 leukopenia (ß coefficient 0.122; p = 0.030; 95% CI 0.012-0.233). According to NTCP modeling, the predicted HT probability had the following parameters: TD50: 37.5 Gy, γ 50: 1.15, m: 0.347. For node positive patients, TD50: 35.2 Gy, γ 50: 2.27, m: 0.176 were found. Node positive patients had significantly higher PBM-V15 (Mean 81.1 vs. 86.7%; p = 0.04), -V20 (Mean 72.7 vs. 79.9%; p = 0.01) and V30 (Mean 50.2 vs. 57.3%; p = 0.03). Patients with a mean LSBM dose >32 Gy had a 1.81 (95% CI 0.81-4.0) relative risk to develop ≥G3 leukopenia. For node positive patients, those risks were 2.67 (95% CI 0.71-10). LKB modeling seems to suggest that LSBM-mean dose should be kept below 32 Gy to minimize ≥G3 HT in anal cancer patients treated with IMRT and concurrent chemotherapy. The contribution of LSBM dose in the development of HT above 25 Gy seems steeper in node positive patients.

Early-stage Node-negative (T1-T2N0) Anal Cancer Treated with Simultaneous Integrated Boost Radiotherapy and Concurrent Chemotherapy.

AIM: To report clinical outcomes of a consecutive series of patients with early-stage (T1-T1N0) anal cancer treated with intensity-modulated radiotherapy (IMRT) and a simultaneous integrated boost (SIB) approach similarly to the RTOG 05-29 trial. PATIENTS AND METHODS: A cohort of 43 patients underwent SIB-IMRT employing a schedule consisting of 50.4 Gy/28 fractions to the gross tumor volume and 42 Gy/28 fractions to the elective nodal volumes for cT1N0 cases, and 54 Gy/30 fractions and 45 Gy/30 fractions to the same volumes for cT2N0 cases. Chemotherapy was administered concurrently following Nigro's regimen. The primary endpoint was colostomy-free survival (CFS). Secondary endpoints were locoregional control (LRC), disease-free (DFS), cancer-specific (CSS) and overall (OS) survival. RESULTS: Median follow-up was 39.7 months. The actuarial 3-year CFS was 79.4% [95% confidence interval (CI)=61.4-89.7%]. Actuarial 3-year OS and CSS were 90.8% (95% CI=74.1-96.9%) and 93.8% (95% CI=77.3-98.4%), while DFS was 75.5% (95% CI=56.4-87.1%). Actuarial 3-year LRC was 86.1% (95% CI=69.6-94%). On multivariate analysis, tumor size >3 cm showed a trend towards significance in predicting CFS [hazard ratio (HR)=8.6, 95% CI=84.7-88.1%; p=0.069]. Maximum detected adverse events included: skin (G3): 18%; gastrointestinal tract (G2): 67%; genitourinary tract (G3): 3%; genitalia (G2): 30%; anemia (G2): 7%; leukopenia (G3): 26%, leukopenia (G4):7%; neutropenia (G3): 15%; neutropenia (G4): 12%; thrombocytopenia (G3): 9%. CONCLUSION: Our clinical results support the use of SIB-IMRT in the combined modality treatment of patients with anal cancer.

Locally Advanced (T3-T4 or N+) Anal Cancer Treated with Simultaneous Integrated Boost Radiotherapy and Concurrent Chemotherapy.

AIM: To report on clinical outcomes of a consecutive series of locally advanced (T3-T4N0-N3) anal cancer patients treated with intensity-modulated radiotherapy (IMRT) and a simultaneous integrated boost (SIB) approach similarly to the RTOG 05-29 trial. PATIENTS AND METHODS: A cohort of 45 patients underwent SIB-IMRT employing a schedule consisting of 54 Gy/30 fractions to the macroscopic anal planning target volume (PTV), while clinical nodes were prescribed 50.4 Gy/30 fractions if sized ≤3 cm or 54 Gy/30 fractions if >3 cm. Elective nodal PTV was prescribed 45 Gy/30 fractions. Chemotherapy was administered concurrently following the Nigro regimen. Primary end-point was colostomy-free survival (CFS). Secondary end-points were locoregional control (LRC), disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). RESULTS: Median follow-up was 39.7 months. The actuarial 3-year CFS was 63.4 % (95% confidence interval (CI=44.8-77.1%). Actuarial 3-year OS and CSS were 67.7% (95%CI=48.7-80.9%) and 72.9% (95%CI=53.8-85.1%), while DFS was 55.8% (95%CI=37.5.4-70.7%). Actuarial 3-year LRC was 74.1% (95%CI=56.7-85.4%). On multivariate analysis, male sex (hazard ratio (HR)=10.9; p=0.004; 95%CI=2.2-55.5%) had a significant impact on CFS, while higher clinical stage (Stage IIIB vs. others) had borderline significance (HR=2.7; p=0.062; 95%CI=1.8-5.9%). A shorter package time (HR=0.94; p=0.007; 95%CI=0.91-0.98%) predicted for higher CFS. Maximum detected events included: skin (G3): 13%; gastrointestinal (GI) (G3): 13%; genitourinary (GU) (G2): 38%; genitalia (G2): 45%; anemia (G2): 4%; leukopenia (G3): 24%, (G4):7%; neutropenia (G3): 16%; (G4): 11%; thrombocytopenia (G3): 9%, (G4): 2%. CONCLUSION: Our clinical results support the use of SIB-IMRT in the combined modality treatment of locally advanced anal cancer patients.

Volumetric modulated arc therapy (VMAT) in the combined modality treatment of anal cancer patients.

OBJECTIVE: To report clinical and dosimetric outcomes of a consecutive series of patients with anal cancer treated with volumetric-modulated arc therapy (VMAT) concomitant to chemotherapy (CT). METHODS: A cohort of 39 patients underwent VMAT employing a schedule consisting of 50.4 Gy/28 fractions to the gross tumour volume (GTV) and 42 Gy/28 fractions to the elective nodal volumes for patients with cT2N0 disease. Patients with cT3-T4/N0-N3 tumours were prescribed 54 Gy/30 fractions to the GTV and 50.4 Gy/30 fractions to the gross nodal volumes if sized ≤3 cm or 54 Gy/30 fractions if > 3 cm. Elective nodal regions were given 45 Gy/30 fractions. CT was administered concurrently following Nigro's regimen. The primary end point was acute toxicity. Secondary end points were colostomy-free survival (CFS), disease-free survival (DFS), cancer-specific survival (CSS) and overall survival (OS). Dosimetric data are also provided. RESULTS: Median follow-up was 21 months. Maximum acute toxicities were: dermatologic-G3: 18%; gastrointestinal-G3: 5%; genitourinary-G3: 2%; anaemia-G2: 7%; leukopenia-G3: 28%; G4: 8%; neutropenia-G3: 13%; G4: 18%; thrombocytopenia-G3: 11%; and G4: 2%. The actuarial 2-year CFS was 77.9% [95% confidence interval (CI): 54-90.4%]. Actuarial 2-year OS and CSS were 85.2% (95% CI: 60.1-95.1%), while DFS was 75.1% (95% CI: 52.4.7-88.1%). CONCLUSION: Our clinical results support the use of VMAT as a safe and effective intensity-modulated radiotherapy (IMRT) option in the combined modality treatment of anal cancer, with consistent dosimetry, mild toxicity and promising sphincter preservation and survival rates. ADVANCES IN KNOWLEDGE: IMRT is a standard of care for patients with anal cancer, and VMAT is a robust technical solution in this setting.

Dose to specific subregions of pelvic bone marrow defined with FDG-PET as a predictor of hematologic nadirs during concomitant chemoradiation in anal cancer patients.

To test the hypothesis that irradiated volume of specific subregions of pelvic active bone marrow as detected by (18)FDG-PET may be a predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation, we analyzed 44 patients submitted to IMRT and concurrent chemotherapy. Several bony structures were defined: pelvic and lumbar-sacral (LSBM), lower pelvis (LPBM) and iliac (IBM) bone marrow. Active BM was characterized employing (18)FDG-PET and characterized in all subregions as the volume having standard uptake values (SUVs) higher than SUVmean. All other regions were defined as inactive BM. On dose-volume histograms, dosimetric parameters were taken. Endpoints included white blood cell count (WBC), absolute neutrophil count (ANC), hemoglobin (Hb) and platelet (Plt) nadirs. Generalized linear modeling was used to find correlations between dosimetric variables and blood cells nadirs. WBC nadir was significantly correlated with LSBM mean dose (ß = -1.852; 95 % CI -3.205/-0.500; p = 0.009), V10 (ß = -2.153; 95 % CI -4.263/-0.721; p = 0.002), V20 (ß = -2.081; 95 % CI -4.880/-0.112; p = 0.003), V30 (ß = -1.971; 95 % CI -4.748/-0.090; p = 0.023) and IBM V10 (ß = -0.073; 95 % CI -0.106/-0.023; p = 0.016). ANC nadir found to be significantly associated with LSBM V10 (ß = -1.878; 95 % CI -4.799/-0.643; p = 0.025), V20 (ß = -1.765; 95 % CI -4.050/-0.613; p = 0.030) and IBM V10 (ß = -0.039; 95 % CI -0.066/-0.010; p = 0.027). Borderline significance was found for correlation between Plt nadir and LSBM V30 (ß = -0.056; 95 % CI -2.748/-0.187; p = 0.060), V40 (ß = -0.059; 95 % CI -3.112/-0.150; p = 0.060) and IBM V30 (ß = -0.028; 95 % CI -0.074/-0.023; p = 0.056). No inactive BM subsites were found to be correlated with any blood cell nadir. (18)FDG-PET is able to define active bone marrow within pelvic osseous structures. LSBM is the strongest predictor of decreased blood cells nadirs in anal cancer patients undergoing concurrent chemoradiation.

Hypofractionation with no boost after breast conservation in early-stage breast cancer patients.

The aim of this study was to evaluate local control, survival and toxicity profile of a consecutive cohort of early-stage breast cancer (EBC) patients treated with adjuvant hypofractionated radiotherapy (HF) with no boost delivered to the lumpectomy cavity, after breast-conserving surgery (BCS). Between 2005 and 2015, a total of 493 women affected with EBC were treated with HF (46 Gy/20 fractions or 40.05 Gy/15 fractions) to the whole breast without boost to tumor bed, because of age and/or favorable tumor characteristics. The primary endpoint was 5-year actuarial local control (LC); secondary endpoints included survival, toxicity profile and cosmesis. Median follow-up was 57 months (range 6-124). Actuarial 5-year overall, cancer-specific, disease-free survival and LC were 96.3, 98.9, 97.8 and 98.6 %, respectively. On multivariate analysis, tumor stage (T1 vs. T2) and hormonal status (positive vs. negative estrogen receptors) were significantly correlated with LC. Only 2 % of patients experienced ≥G3 acute skin toxicity. Late toxicity was mild with only 1 case of G3 fibrosis. Most of the patients (95 %) had good-excellent cosmetic results. HF to the whole breast with no boost delivered to the tumor bed is a safe and effective option for a population of low-risk breast cancer patients after BCS, with excellent 5-year LC, mild toxicity profile and promising cosmetic outcome. A subgroup of patients with larger tumors and/or with no estrogen receptor expression may potentially benefit from treatment intensification with a boost dose to the lumpectomy cavity.

Biochemical and clinical outcomes after high-dose salvage radiotherapy as monotherapy for prostate cancer.

PURPOSE: To retrospectively evaluate the role of high-dose salvage radiotherapy (SRT) alone with regard to biochemical and clinical outcomes in patients with biochemical failure (BF) after radical prostatectomy (RP). METHODS: Between January 2003 and August 2011, 168 hormone-naïve localized prostate cancer patients received SRT alone for post-RP BF in a single institution and were retrospectively analyzed. Multivariate analysis was performed to determine the independent prognostic impact of clinical factors on biochemical and clinical outcomes [biochemical relapse-free survival (bRFS), clinical relapse-free survival (cRFS), cancer-specific survival (CSS) and overall survival (OS)]. RESULTS: Median follow-up was 54 months. Actuarial bRFS, cRFS, CSS and OS at 5 years were, respectively, 64, 86.2, 94.5 and 96.3 %. On multivariate analysis, nadir PSA (nPSA) after SRT was significantly associated with bRFS (HR 15, p = 0.001) and cRFS (HR 9, p = 0.001), while CSS was associated with RT dose (≥70 Gy; HR 1.9 p = 0.023), pre-RT PSA (<1.5 vs. ≥1.5 ng/mL; HR 1.3, p = 0.008) and age (>75 years; HR 1.2, p = 0.05). OS was significantly correlated with pre-SRT PSA (linear correlation; HR 1.1, p = 0.023) and age (<75 vs. ≥ 75 years; HR 1.1, p = 0.026). CONCLUSIONS: Effective biochemical and clinical control rates may be safely achieved administering SRT with high doses (≥72 Gy) and using conformal techniques, especially in older patients presenting with lower pre-SRT PSA values. A lower nPSA after SRT predicts for better 5 years bRFS and cRFS rates.

Prospective phase II trial of neoadjuvant chemo-radiotherapy with Oxaliplatin and Capecitabine in locally advanced rectal cancer (XELOXART).

Neo-adjuvant chemo-radiotherapy (CT-RT) has been shown to decrease local recurrence rate in locally advanced rectal cancer. This multicenter phase II trial was conducted to evaluate the feasibility, safety and effectiveness of a combination of pre-operative radiotherapy and concurrent Capecitabine plus Oxaliplatin (XELOXART Trial). From October 2008 to May 2011, fifty consecutive patients affected with T3/T4 and/or N+ rectal cancer were enrolled. Treatment protocol consisted of 50.4 Gy in 28 fractions, Oxaliplatin 60 mg/m(2) once a week for 6 weeks and oral Capecitabine 825 mg/m(2) twice daily from day 1 to 14 and from day 22 to 35. Surgery was planned 6-8 weeks after. Main endpoints were pathological complete response rate (pCR) and the type of surgery performed compared to the planned one at diagnosis. 50 patients were included; pCR (ypT0N0M0) was achieved in 6 patients (12 %). Tumour downstaging was observed in 27 patients (54 %), and nodal downstaging in 32 patients (64 %). A total of 32 patients had lower rectal cancer, with 24 candidate for abdominal-perineal resection. At the end of CT-RT, a total of 12/24 (50 %) underwent conservative surgery. Grade 3 toxicity (fatigue and diarrhoea) occurred in 4 % of patients; grade 4 sensory neuropathy occurred in 2 % of patients. Perioperative complications of any grade occurred in 10 % of patients. Pre-operative CT-RT with Capecitabine-Oxaliplatin was well tolerated and resulted in an encouraging sphincter preservation and tumour downstaging rate. No improvements in terms of pathological complete response rate were shown.