Are we ready for a paradigm shift from high-dose conventional to moderate hypofractionated radiotherapy in intermediate-high risk prostate cancer? A systematic review of randomized controlled trials with trial sequential analysis.

AIM: to evaluate efficacy and late toxicity of moderate hypofractionated (HFRT) over high-dose (>76 Gy) conventional radiotherapy (CRT) in a non-inferiority perspective. METHODS: Randomized controlled trials (RCTs) were included. HFRT regimens were deemed non-inferior to high-dose CRT if the computed CI for the overall RR did not exceed the non-inferiority margin of 7%. RESULTS: When the prespecified margin, corresponding to a critical RR of 0.930 for CCS, OS and BFS, was used all efficacy outcomes satisfied the criteria for the non-inferiority analysis indicating the non-inferiority of HFRT regimens over high-dose CRT in the medium term period. Differently, the evidence concerning the late toxicity was inconclusive. CONCLUSIONS: Noninferiority analysis indicates that moderate HFRT regimes are non-inferior over high-dose CRT in the medium-term. Inconclusive is the evidence for the late toxicity. Longer follow-up will provide a more clear answer concerning the non-inferiority of HFRT regimens in the long-term period.

The possible different roles of denosumab in prevention and cure breast cancer bone metastases: A 'hypothesis-generator' study from clinical practice.

The most frequent site of recurrence in breast cancer (BC) is the bone, particularly in patients with 'luminal-like' disease. Denosumab has been shown to prevent aromatase inhibitors (AIs) induced bone resorption in postmenopausal early BC patients and reduce skeletal-related events (SREs) in bone metastatic breast cancer (BMBC). A 'real life' analysis of 90 BMBC patients treated with denosumab was performed. Eighty-six patients (95.6%) had 'luminal-like' disease, 72 (80%) had bone metastases at the time of first recurrence of disease. Among 50 patients with metachronous 'luminal-like' disease, 40 (80%) had first recurrence to the bone. Among these patients median time to skeletal recurrence (TSkR) was shorter for patients who were previously exposed to AIs compared to those who were not (53.0 vs. 102.0 months, respectively; P=0.0300) and longer for patients previously treated with tamoxifen compared to those who were not (102.0 vs. 59.0 months, respectively; P=0.0466). Both of them were not confirmed at multivariate analysis. In the overall population, 17 first SREs were observed (16 radiation therapy) and median time to first SRE was not reached. A statistically significant difference in the incidence of SREs was detected only between patients with exclusively osteolytic bone metastases vs. those without (P=0.013). The presence of exclusively-osteolytic bone metastases was the only factor significantly associated with a shorter time to first SRE (P=0.011). The only G3 toxicity reported was hypocalcemia in one patient. No osteonecrosis of the jaw events (ONJ) occurred. This study demonstrated that a pro-active attitude enables the treatment of the majority of patients with denosumab without significant class-related toxicities. The majority of SREs were from radiation therapy, so pain still remains the clinical hallmark of bone metastases, particularly for osteolytic ones. The suggestion that estrogen deprivation with AIs can favor a 'bone-related' risk conditions for developing bone metastases must be considered with caution and surely needs further validations.

Moderate Hypofractionation in Patients with Low-risk Prostate Cancer: Long-term Outcomes.

BACKGROUND/AIM: To evaluate outcomes in patients with low-risk prostate cancer treated with hypofractionated radiotherapy (HyRT). PATIENTS AND METHODS: Between April 2004 and December 2015, 175 patients with low-risk prostate cancer were treated with HyRT 60 Gy in 20 fractions with or without image guidance and reduction of margin from clinical target volume to planning target volume. RESULTS: The median follow-up was 66 months. The 8-year overall survival for the whole patient cohort was 88.9%. The 8-year biochemical no evidence of disease was higher in patients treated with image-guided HyRT (98.8% vs. 88%, p=0.023). During treatment, patients treated with image-guided HyRT presented a lower rate of grade 1-2 gastrointestinal toxicity (25.3% vs. 42.2%, p=0.001). At the last follow-up, the grade 1 Gastro-intestinal toxicity rate was 4.0% and the grade 1-2 genito-urinary toxicity rate was 25.1%. CONCLUSION: Our study demonstrated the efficacy of the schedule used with a low rate of acute and late toxicities. Therefore, reduction of margins with image-guided HyRT is safe.

Oral Platelet Gel Supernatant Plus Supportive Medical Treatment Versus Supportive Medical Treatment in the Management of Radiation-induced Oral Mucositis: A Matched Explorative Active Control Trial by Propensity Analysis.

OBJECTIVES: In this active control trial, the rate of radio-induced WHO grade 3/4 oral mucositis and the change in quality of life, assessed by OMWQ-HN, were measured in subjects with head and neck cancer treated by platelet gel supernatant (PGS) and supportive medical treatment versus subjects treated by supportive medical treatment alone. MATERIALS AND METHODS: Eighty patients with nonmetastatic head and neck cancer underwent curative or adjuvant radiotherapy. All patients underwent supportive medical treatment and/or PGS at the beginning and during radiotherapy. Sixteen patients received PGS in association with supportive medical treatment. To obtain 2 groups virtually randomized for important clinical characteristics subjects were matched, by propensity analysis, with a group of subjects (64 patients) treated with supportive medical treatment alone. RESULTS: Subjects treated with standard supportive treatment experienced significant higher WHO grade 3/4 toxicity (55%; 35/64) than subjects treated by PGS (13%; 3/16). The reduced toxicity found in PGS group paralleled with the evidence that they developed later symptoms with respect to controls. The Cox proportional hazard model indicated that patients treated with standard supportive medical treatment experienced 2.7-fold increase (hazard ratio=2.7; 95% confidence interval, 1.3-5.7) in the occurrence of WHO grade 3/4 toxicity. PGS group significantly experienced higher quality of life than control groups as measured by OMWQ-HN. A significant decrease in the opioid analgesics usage was found in the PGS group. CONCLUSIONS: These preliminary data should be interpreted with caution and could serve as a framework around which to design future trials.

Treatment of osteolytic solitary painful osseous metastases with radiofrequency ablation or cryoablation: A retrospective study by propensity analysis.

The present study aimed to measure the improvement in pain relief and quality of life in patients with osteolytic solitary painful bone metastasis treated by cryoablation (CA) or radiofrequency ablation (RFA). Fifty patients with solitary osteolytic painful bone metastases were retrospectively studied and selected by propensity analysis. Twenty-five patients underwent CA and the remaining twenty-five underwent RFA. Pain relief, in terms of complete response (CR), the number of patients requiring analgesia and the changes in self-rated quality of life (QoL) were measured following the two treatments. Thirty-two percent of patients treated by CA experienced a CR at 12 weeks versus 20% of patients treated by RFA. The rate of CR increased significantly with respect to baseline only in the group treated by CA. In both groups there was a significant change in the partial response with respect to baseline (36% in the CA group vs. 44% in the RFA group). The recurrence rate in the CA and RFA groups was 12% and 8%, respectively. The reduction in narcotic medication requirements with respect to baseline was only significant in the group treated by CA. A significant improvement in self-rated QoL was observed in both groups. The present study seems to suggest that CA only significantly improves the rate of CR and decreases the requirement of narcotic medications. Both CA and RFA led to an improvement in the self-rated QoL of patients after the treatments. However, the results of the present study should be considered as preliminary and to serve as a framework around which future trials may be designed.

Treatment of Solitary Painful Osseous Metastases with Radiotherapy, Cryoablation or Combined Therapy: Propensity Matching Analysis in 175 Patients.

PURPOSE: aim of this study was to identify outcomes in pain relief and quality of life in patients with a solitary painful osseous metastasis treated by radiotherapy, cryoablation or the combination using a propensity score matching study design. MATERIALS AND METHODS: 175 patients with painful bone metastases were included in the study. Twenty-five of them underwent a radiation course (20 Gy in five daily fractions) 15 days after the cryoablation. These subjects were retrospectively matched by propensity analysis with a group of subjects treated by radiotherapy (125 subjects) and with a group treated byCryoablation (25 subjects). The pain relief in terms of complete response, rate of subjects requiring analgesics after treatments and the changes in self-rated quality of life were measured. Informed consent was obtained from the subject and the study was approved by the local Ethical Committee. RESULTS: An higher proportion of subjects treated by cryoablation (32%) or cryoablation followed by RT (72%;) experienced a complete response compared with patients treated by radiotherapy alone (11.2%). After Bonferroni correction strategy, the addition of radiotherapy to cryoablation significantly improved the rate of complete response compared with cryoablation alone (p = 0.011) and this paralleled with an improved self-rated quality of life. Seventeen subjects (13.6%) of patients in the radiotherapy group, 9 (36%) in the cryoablation group, and 19 (76)% in the cryoablation- radiotherapy group did not require narcotic medications. CONCLUSIONS: The addition of radiotherapy to cryoablation favorably impacts on perceived pain, with a favorable toxicity profile. However, our data should be interpreted with caution and could serve as a framework around which to design future trials.

Intravesical instillations with polydeoxyribonucleotides reduce symptoms of radiation-induced cystitis in patients treated with radiotherapy for pelvic cancer: a pilot study.

PURPOSE: Chronic radiation cystitis (CRC) is a serious complication that can arise in patients with pelvic malignancies treated with radiotherapy. Polydeoxyribonucleotides (PDRNs) are known to reduce inflammation and improve tissue perfusion and angiogenesis. In this manuscript, we describe our observational experience regarding intravesical instillation of PDRNs in improving symptoms of CRC in subjects unresponsiveness to conventional medical therapy. METHODS: Eight patients with persistent and/or worsening CRC symptoms, despite conventional therapy, received biweekly intravesical instillation of PDRNs for two consecutive months. Symptoms were scored according to the Late Effects of Normal Tissues-Subjective, Objective, Management, Analytic (LENT-SOMA) scale, before, at the end, and after 4 months following the PDRNs treatment. RESULTS: Four months after instillations, a significant improvement in the subjective perception of CRC symptoms was experienced by participants. The mean LENT-SOMA score was reduced from 1.16+0.26 before to 0.34+0.035 after 4 months from instillations (p<0.001). No adverse effect related to instillations was reported. CONCLUSIONS: Subjective perception of persistent and/or worsening CRC symptoms, despite conventional therapy, is improved after intravesical instillation with PDRNs without adverse events. Even though we deduced suggestive insights, the results need to be collected and verified from a large-scale study.

Strategies for imaging androgen receptor signaling pathway in prostate cancer: implications for hormonal manipulation and radiation treatment.

Prostate cancer (Pca) is a heterogeneous disease; its etiology appears to be related to genetic and epigenetic factors. Radiotherapy and hormone manipulation are effective treatments, but many tumors will progress despite these treatments. Molecular imaging provides novel opportunities for image-guided optimization and management of these treatment modalities. Here we reviewed the advances in targeted imaging of key biomarkers of androgen receptor signaling pathways. A computerized search was performed to identify all relevant studies in Medline up to 2013. There are well-known limitations and inaccuracies of current imaging approaches for monitoring biological changes governing tumor progression. The close integration of molecular biology and clinical imaging could ease the development of new molecular imaging agents providing novel tools to monitor a number of biological events that, until a few years ago, were studied by conventional molecular assays. Advances in translational research may represent the next step in improving the oncological outcome of men with Pca who remain at high risk for systemic failure. This aim may be obtained by combining the anatomical properties of conventional imaging modalities with biological information to better predict tumor response to conventional treatments.

Advances in imaging and in non-surgical salvage treatments after radiorecurrence in prostate cancer: what does the oncologist, radiotherapist and radiologist need to know?

OBJECTIVES: In this article the state of art the of prostate cancer (Pca) imaging and non-surgical salvage treatments (STs) is surveyed in order to explore the impact of imaging findings on the identification of radiorecurrent Pca after external beam radiotherapy (EBRT). METHODS: A computerised search was performed to identify all relevant studies in Medline up to 2012. Additional articles were extracted based on recommendations from an expert panel of authors. RESULTS: Definitive EBRT for Pca is increasingly used as treatment. After radiorecurrent Pca, non-surgical STs are emerging and shifting from investigational status to more established therapeutic options. Therefore, several scientific societies have published guidelines including clinical and imaging recommendations, even if the timing, efficacy and long-term toxicity of these STs have to be established. In some measure, accurately delineating the location and the extent of cancer is critical in selecting target lesions and in identifying patients who are candidates for STs. However, there is increasing awareness that anatomical approaches based on measurements of tumour size have substantial limitations, especially for tumours of unknown activity that persist or recur following irradiation CONCLUSIONS: To date, the main focus for innovations in imaging is the combination of excellence in anatomical resolution with specific biological correlates that depict metabolic processes and hallmarks at the tumour level. The emergence of new molecular markers could favour the development of methods that directly determine their presence, thereby improving tumour detection. KEY POINTS: Imaging may influence therapeutic decisions during non-surgical STs. MRI findings correlate with parametric maps derived from multiple functional techniques. Non-surgical salvage treatments allow local tumour control in patients with radiorecurrent PCa.

Late morbidity and oncological outcome after radical hypofractionated radiotherapy in men with prostate cancer.

OBJECTIVE: To test the hypothesis that three-dimensional hypofractionated radiotherapy (3D-HFRT) is well tolerated and not worse than 3-D conventional RT (3D-CRT) for oncological outcome. PATIENTS AND METHODS: In all, 162 men with hystologically confirmed prostate adenocarcinoma were included in the analysis. In all, 82 men were treated with 3D-HFRT (15 fractions of 3.62 Gy delivered 3 times/week; a total dose of 54.3 Gy). This group was retrospectively compared with 80 men who met the same inclusion criteria and who were treated with 3D-CRT (39 fractions of 2 Gy delivered daily; a total dose of 78 Gy). A short course of hormone therapy was administered concomitantly with the RT. RESULTS: Only one (1.7%) patient in the 3D-CRT group and two (4.0%) in the 3D-HFRT group had Grade 3 genitourinary toxicity. There was late gastrointestinal morbidity of ≥ grade 3 in only 5.1% of men treated with 3D-HFRT and in 4.0% of men treated with 3D-CRT. In both groups there was no Grade 4 toxicity. At the median (range) follow-up of 45 (39.4-51) months for the 3D-HFRT group and 57.5 (54.9-59.1) months for 3D-CRT group the progression rate was 18/82 (21.9%) and 20/80 (25.0%), respectively, with no significant worsening in the risk of biochemical failure (BCF; log-rank test, P= 0.222). CONCLUSIONS: In the present study, men with clinically localized prostate cancer had similar levels of morbidity irrespective of whether they received HFRT or CRT without any worsening in the early risk of BCF. Thus, the present data provide some clinical evidence to justify trends already emerging toward HF regimens for treating clinically localised prostate cancer.

Hypofractionated radical radiotherapy in elderly patients with medically inoperable stage I-II non-small-cell lung cancer.

We described the results of a hypofractionated regimen (HFRT) in a cohort of elderly patients (36 subjects) with stage I-II non-small-cell-lung cancer (NSCLC), tumor size> or =3 cm and ineligible for surgery. HFRT was delivered in 20 daily fractions of 3 Gy per fraction with a total dose of 60 Gy. The median PTV was 145 cm(3). The primary purpose of study was to estimate the local tumor control at 2 years as well as the modifications in the lung function parameters at 6 and 12 months. The local tumor control was 63.9% at 2 years. The incidence of distant recurrence rate at 2 years was 50%. The overall-survival (OS), the cause-specific-survival (CSS) and the disease-free-survival (DSF) at 2 years were 55.6, 57.1, and 38.9%, respectively. The median OS, CSS, and DFS was 25.4 (CI 95% 21.7-32.9), 26.7 (CI 95% 22.5-33.5) and 23.4 months (CI 95% 18.6-30.1), respectively. The two clinical parameters with a positive influence on OS were a KPS> or =90 (HR 1.16; p=0.013) and tumor size< or =4 cm (HR 0.763; p=0.011). No grade 3-4 acute toxicity was reported. No significant change in lung function parameters was measured at 6 and 12 months. For patients with larger or centrally located tumors as well as for subjects with lymph nodes involvement SBRT may be of limited valiance. Although the performances of our regimen were lower than the ones achieved by SBRT, our therapeutic option may offer a lower incidence of complications against a satisfactory local tumor control.

High-grade gliomas: results in patients treated with adjuvant radiotherapy alone and with adjuvant radio-chemotherapy.

BACKGROUND: Despite advances in the surgical, radiotherapeutic and chemotherapeutic fields, the outcome for patients with high-grade gliomas remains poor. Our experience of patients treated with and without chemotherapy is reported. MATERIALS AND METHODS: From April 1999 to July 2003, 30 patients with high-grade gliomas were treated: 13 received adjuvant radiotherapy (RT) alone whereas 17 received temozolomide 75 mg/m2/d during the irradiation time and 200 mg/m2 daily per 5 consecutive days, every 28 days for three to six cycles, starting 4 weeks after the end of radiotherapy. RESULTS: The median follow-up was 12.5 months. The median overall survival (OS) was 15 months. In patients treated with RT plus chemotherapy, no statistical difference was observed between those who had undergone partial surgical resection and those with total resection (p=0.5128). In patients with glioblastoma multiforme (GBM) treated with combined radiochemotherapy, the median OS was 18 months, while it was 7 months (p=0.0204) in those treated without chemotherapy. Multivariate analysis (Cox model) evidenced statistical differences for performance status (p =0.002) and for the type of adjuvant therapy (p=0.006). CONCLUSION: Radio-chemotherapy plus adjuvant temozolomide seemed to offer the best results in patients not submitted to debulking surgery. The performance status remained the most important prognostic factor. Tolerance to the combined regimen was very good.