A Systematic Review and a Meta-analysis of Randomized Controlled Trials' Control Groups in Metastatic Hormone-Sensitive Prostate Cancer (mHSPC).

PURPOSE OF REVIEW: Determining the risk for progression or survival after standard androgen deprivation treatment (ADT) in metastatic hormone-sensitive prostate cancer (mHSPC) is essential for stratifying patients according to expected outcomes in future studies of treatment combination. This systematic review and meta-analysis aims to estimate the progression-free survival (PFS) and overall survival (OS) probabilities in the control group of randomized controlled trials (RCTs) of different regimens of standard androgen deprivation treatment (ADT) in mHSPC and to identify possible predictors of outcomes. RECENT FINDINGS: Studies reporting time-dependent outcomes (progression or death) after standard ADT treatment of mHSPC were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through June 2021. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using a distribution-free summary survival curve. Primary outcomes were actuarial probabilities of disease progression and survival. Fifteen studies met the inclusion criteria. The pooled estimate of the actuarial PFS rate was 35.2% at two years. The pooled actuarial OS rate was 62.5% at three years. Heterogeneity among studies was highly significant for all outcomes. By univariate meta-regression analyses, high-volume disease and the presence of visceral metastases were associated with shorter survival. Our findings show that PFS and OS are highly variable in patients with mHSPC treated with ADT, providing a helpful benchmark for indirect comparisons of the benefits of the combination of chemotherapy and second-generation hormonotherapy.

Linac-based stereotactic body radiation therapy for unresectable locally advanced pancreatic cancer: risk-adapted dose prescription and image-guided delivery.

BACKGROUND: Stereotactic body radiation therapy (SBRT) represents a new treatment option for locally advanced pancreatic cancer (LAPC). An accurate treatment planning with risk-adapted dose prescription with adherence to specific dose constraints for organs at risk (OARs) and the use of daily cone beam CT (CBCT) for image guidance could allow an effective and safe treatment delivery. Here, feasibility and efficacy of SBRT in LAPC treated in our cancer care center are reported. PATIENTS AND METHODS: 33 unresectable LAPC patients underwent SBRT. In order to respect OAR dose constraints, a risk-adapted dose prescription strategy was adopted, choosing between the following schedules: 42 Gy or 45 Gy in 6 daily fractions with a biologically effective dose (BED) > 70 Gy10 or 36 Gy/6 fractions (estimating a BED 57.6 Gy10). SBRT was delivered with volumetric modulated arc technique (VMAT) and flattening filter-free (FFF) mode. Image guidance was performed by means of CBCT before every treatment session. The patients were evaluated at the end of treatment for acute toxicity and at 3, 6, and 12 months for late toxicity and treatment response. RESULTS: At the time of analysis, the median follow-up was 18 months (range 5-34 months). Prior to SBRT, 24 out of 33 patients received induction chemotherapy. Although all patients were previously judged as unresectable, 6 out of 33 (18%) underwent surgery after SBRT; all of them received a BED > 70 Gy10. One-year LC and OS were 81% and 75%, respectively. A total of 12 patients (37%) had an extra-pancreatic progression. No cases of ≥G3 acute or late toxicity were reported. CONCLUSION: In our experience, risk-adapted dose prescription and image-guided SBRT represents an effective treatment option for LAPC patients.

Synchronous bilateral breast cancer irradiation: clinical and dosimetrical issues using volumetric modulated arc therapy and simultaneous integrated boost.

OBJECTIVES: The aim of the present retrospective analysis was to evaluate dosimetric parameters, feasibility and outcome for Synchronous Bilateral Breast Cancer (SBBC) patients treated with adjuvant radiotherapy (RT) by Volumetric Modulated Arc Therapy (VMAT). METHODS: From September 2011 to April 2016, 1100 Breast Cancer (BC) patients were referred to our institution to receive adjuvant breast RT, and those with SBBC were selected for the present analysis. A total of 16 patients were identified. A total dose of 50 Gy in 25 fractions was prescribed to the Planning Target Volume of the whole bilateral breast (PTVBN) with or without the supraclavicular and infraclavicular nodes, while a total dose of 60 Gy in 25 fractions was prescribed to the surgical bed (PTVboost). Several V xGy and Dx% parameters were analyzed for the PTVs, together with Conformity and Homogeneity indexes (CI, HI), and for the critical Organs at risk (OARs), lungs and heart first. RESULTS: With a median follow-up of 24 months, no acute or late side effects more than grade 2 were observed. All patients are alive without any sign of disease. For target dose coverage, our observed inter-patients averages (±1 sd) were V 95% Dp = 96.7 ± 1.6% (96.3 ± 1.8%) to the left (right) PTVBN, V 95% Dp = 98.6 ± 2.7% (99.4 ± 0.9%) to the left (right) PTVboost, and D 2% = 64.4 ± 1.8 Gy (65.0 ± 2.0 Gy) to the left (right) PTVboost, respectively. With regard to the heart, the inter-patient average of D mean was 8.3 ± 3.3 Gy. For the lungs, the inter-patient average of D mean, V 5 Gy and V 20 Gy were 11.8 ± 2.3 Gy, 78.9 ± 15.3% and 15.7 ± 5%, respectively. CONCLUSIONS: The present retrospective analysis showed the feasibility, tolerability and safety of VMAT in the treatment of SBBC patients. Further studies are necessary to confirm these preliminary data.

Stereotactic ablative radiation therapy for brain metastases with volumetric modulated arc therapy and flattening filter free delivery: feasibility and early clinical results.

AIM: For selected patients with brain metastases (BMs), the role of stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (SFRT) is well recognized. The recent introduction of flattening filter free (FFF) delivery during linac-based SRS or SFRT allows shorter beam-on-time, improving patients' comfort and facility workflow. Nevertheless, limited experiences evaluated the impact of FFF linac-based SRS and SFRT in BMs treatment. Aim of the current study was to analyze SRS/SFRT linac-based FFF delivery for BMs in terms of dosimetric and early clinical results. MATERIALS AND METHODS: Patients with life expectancy >3 months, number of BMs <5, diameter <3 cm, and controlled or synchronous primary tumor received SRS/SFRT. The prescribed total dose and fractionation, based on BMs size and proximity to organs at risk, ranged from 15 Gy in 1 fraction to 30 Gy in 5 fractions. A FFF volumetric modulated arc therapy (VMAT) plan was generated with one or two coplanar partial arcs. Toxicity was assessed according to CTCAE v4.0. RESULTS: From April 2014 to February 2016, 45 patients (89 BMs) were treated with SRS/SFRT linac-based FFF delivery. The mean beam-on-time was 140 s for each lesion (range 90-290 s) and the average brain Dmean was 1 Gy (range 0.1-4.8 Gy). At the time of analysis, local control was reported in 93.2% (83/89 BMs). With a median follow-up time of 12 months (range 1-27 months), the median overall survival was 14 months and the 6-month overall survival was 77%. Finally, the median intracranial disease control was 11 months. Acute and late toxicities were acceptable without severe events (no adverse events ≥G2 were recorded). CONCLUSIONS: These preliminary results highlighted the feasibility and safety of linac-based SRS/SFRT with FFF mode for BMs patients. A longer follow-up is necessary to confirm the efficacy of this treatment modality in BM patients.

Three-dimensional conformal versus intensity modulated radiotherapy in breast cancer treatment: is necessary a medical reversal?

OBJECTIVES: Aim of the present study is to compare three-dimensional conformal RT (3D-CRT) and 4-fields intensity modulated radiation therapy (4f-IMRT) treatment plans, in terms of target dose coverage, integral dose and dose to Organs at risk (OARs) in early breast cancer (BC). METHODS: Twenty consecutive BC patients, after lumpectomy, were selected for the present analysis. A total dose of 50 Gy and a simultaneous dose of 60 Gy in 25 fractions was prescribed to Planning Target Volume of the whole breast (PTVbreast) and of the surgical bed, respectively. For each patient, a 3D-CRT plan and a sliding-window 4f-IMRT plan were generated. Conformity and homogeneity indexes (CI, HI) and various organ specific VxGy values were analyzed for PTVs, OARs and normal tissue (NT), respectively. RESULTS: In terms of HI, 4f-IMRT was superior to 3D-CRT for the PTVbreast (p < 0.0001), and a significant difference for CI was observed in favor of 4f-IMRT (p < 0.0001).In terms of dose to OARs, a superiority of 4f-IMRT was shown. For NT, all parameters are in favor of IMRT, except the V 5Gy for which the difference was not statistically significant. The average NT-Dmean was 2.7 ± 0.7 for 3D-CRT and 1.8 ± 0.5 for 4f-IMRT (p < 0.0001). CONCLUSIONS: 4f-IMRT technique significantly reduced the dose to OARs and NT, with a better target coverage compared to 3D-CRT.

Outcomes of Locally Advanced Rectal Cancer Patients Treated with Total Neoadjuvant Treatment: A Meta-Anaysis of Randomized Controlled Trials.

BACKGROUND & AIMS: Determining outcomes using the total neoadjuvant therapy (TNT) in patients with local advanced rectal cancer is important for stratifying patients according to expected outcomes in future studies in the era of treatment combination. The present meta-analysis estimated the pathological complete response, disease-free survival, and overall survival probabilities of rectal cancer patients and identified predictors of outcomes. METHODS: Studies reporting pathological complete response rate and time-dependent outcomes (progression or death) after total neoadjuvant treatment of locally advanced rectal cancer (LARC) were identified in MEDLINE through January 2022. Three independent observers extracted data on patient populations and outcomes and combined the data using a distribution-free summary survival curve. The primary outcomes were actuarial probabilities of recurrence and survival. RESULTS: Fourteen RCTs, including 18 TNT arms, met the inclusion criteria. The pooled estimate of pathological complete response (pCR) probability was 23.6%, with moderate heterogeneity between studies. The pooled estimates of actuarial disease-free survival rate were 70.6% at 3 years and 65.4% at 5 years. The pooled estimates of actuarial survival rates were 93% at 3 years and 81.6% at 5 years. In both these outcomes, heterogeneity between studies was highly significant. CONCLUSION: This meta-analysis showed that Total Neoadjuvant Therapy is an optimal approach for LARC patients. The results provide a useful benchmark for future comparisons of the benefits of combinations of other drug families as target therapies or immunotherapies.

Inflammatory Microenvironment in Early Non-Small Cell Lung Cancer: Exploring the Predictive Value of Radiomics.

Patient prognosis is a critical consideration in the treatment decision-making process. Conventionally, patient outcome is related to tumor characteristics, the cancer spread, and the patients' conditions. However, unexplained differences in survival time are often observed, even among patients with similar clinical and molecular tumor traits. This study investigated how inflammatory radiomic features can correlate with evidence-based biological analyses to provide translated value in assessing clinical outcomes in patients with NSCLC. We analyzed a group of 15 patients with stage I NSCLC who showed extremely different OS outcomes despite apparently harboring the same tumor characteristics. We thus analyzed the inflammatory levels in their tumor microenvironment (TME) either biologically or radiologically, focusing our attention on the NLRP3 cancer-dependent inflammasome pathway. We determined an NLRP3-dependent peritumoral inflammatory status correlated with the outcome of NSCLC patients, with markedly increased OS in those patients with a low rate of NLRP3 activation. We consistently extracted specific radiomic signatures that perfectly discriminated patients' inflammatory levels and, therefore, their clinical outcomes. We developed and validated a radiomic model unleashing quantitative inflammatory features from CT images with an excellent performance to predict the evolution pattern of NSCLC tumors for a personalized and accelerated patient management in a non-invasive way.

Beyond Abscopal Effect: A Meta-Analysis of Immune Checkpoint Inhibitors and Radiotherapy in Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Immune checkpoint inhibitors (ICI) plus radiotherapy (RT) have been suggested as an emerging combination in non-small cell lung cancer (NSCLC) patients. However, little is known about the magnitude of its benefits and potential clinical predictors. OBJECTIVE: To assess the effects of this combination on the increase in overall and progression-free survival. DATA SOURCES: The MEDLINE and CANCERLIT (1970-2020) electronic databases were searched, and the reference lists of included studies were manually searched. STUDY SELECTION: Studies were included if they were comparative studies between combination ICI-RT and ICI or RT alone in advanced or metastatic NSCLC patients. Overall survival (OS) was analyzed according to the treatment strategy. DATA EXTRACTION: Data on population, intervention, and outcomes were extracted from each study, in accordance with the intention-to-treat method, by two independent observers and combined using the DerSimonian method and Laird method. RESULTS: Compared to ICI or RT alone, ICI-RT significantly increased the 1-year and 3-year OS RR by 0.75 (95% CI 0.64-0.88; p = 0.0003) and 0.85 (95% CI 0.78-0.93; p = 0.0006), respectively. Furthermore, there was a statistically significant benefit on 1- and 3-year progression-free survival (RR 0.73 (95% CI, 0.61-0.87; p = 0.0005) and RR 0.82 (95% CI 0.67-0.99; p = 0.04), respectively). CONCLUSIONS: In patients with advanced or metastatic NSCLC, combination ICI-RT increases 1- and 3-year OS and progression-free survival compared to ICI or RT alone.

Hippocampal dose during Linac-based stereotactic radiotherapy for brain metastases: An observational study.

INTRODUCTION: Aim of the present study is to evaluate homolateral and contralateral hippocampus (H-H, C-H, respectively) dose during Fractionated Stereotactic Radiotherapy (FSRT) or Radiosurgery (SRS) for brain metastases (BM). MATERIALS & METHODS: Patients with BM<5, size≤30mm, KPS≥80 and a life expectancy>3months, were considered for SRS/FSRT (total dose 15-30Gy, 1-5 fractions). For each BM, a Flattening Filter Free (FFF) Volumetric Modulated Arc Therapy (VMAT) plan was generated with one or two arcs. Hippocampi were not considered during optimizations phase and were contoured and evaluated retrospectively in terms of dose: the Dmedian, Dmean, D0.1cc and the V1Gy, V2Gy, V5Gy and V10Gy were analyzed. RESULTS: From April 2014 to December 2015, 81 BM were treated with FFF-FSRT/SRS. For the H-H, the average values of Dmedian, Dmean and D0.1cc were 1.5Gy, 1.54Gy and 2.2Gy, respectively, while the V1Gy, V2Gy, V5Gy and V10Gy values were 25%, 8.9%, 8.9% and 2.1%, respectively. For the C-H, the average Dmedian, Dmean and D0.1cc were 0.7Gy, 0.7Gy, 0.9Gy, respectively, while the average values of V1Gy, V2Gy, V5Gy and V10Gy were 18%, 10.2%, 2.8% and 1.4%, respectively. Tumor dimension, tumor cranial-caudal length and the distance between BM and H-H were correlated to Dmedian, Dmean and D0.1cc. For C-H, only the distance from PTV was correlated with a dose reduction. CONCLUSION: During FFF-FSRT/SRS, hippocampus received a negligible dose. Despite its clinical significance is still under evaluation, in patients with a long life expectancy, H-H should be considered during Linac-based FSRT/SRS.

Increased efficacy of stereotactic ablative radiation therapy after bevacizumab in lung oligometastases from colon cancer.

AIM: Metastases from colorectal cancer are poorly responsive to stereotactic ablative radiation therapy (SABR) due to intratumoral hypoxia. Intratumoral oxygenation is improved by administration of angiogenesis inhibitors. Thus, there could be a clinical synergistic effect of SABR with bevacizumab on metastases from colorectal cancer. The aim of this study was to evaluate the feasibility and efficacy of SABR after bevacizumab in lung oligometastases from colon cancer. METHODS: The data of patients with lung metastases from colon cancer who underwent SABR were retrospectively evaluated according to the following inclusion criteria: number of metastases ≤3; lung oligometastases from colon cancer in patients who underwent SABR; patients receiving previous chemotherapy alone or in combination with bevacizumab; Karnofsky performance status >80; life expectancy >6 months; at least 6 months' follow-up after SABR; presence of KRAS mutation. The results were compared with those of a similar cohort of patients with irradiated lung lesions from colorectal cancer in whom bevacizumab was not previously administered. RESULTS: A total of 40 lung metastases were analyzed. The complete response rate after SABR was higher in patients who had received bevacizumab than in those who had not (p = 0.04). Additionally, in the bevacizumab group, a higher rate of post-SABR complete response was observed in case of oligopersistent versus oligorecurrent metastases (p = 0.001). CONCLUSIONS: In the setting of lung oligometastases from colon cancer the present study attested the higher efficacy of SABR after bevacizumab administration. Further studies in this field of research are strongly advocated.

Stereotactic body radiation therapy for liver oligometastases: predictive factors of local response by 18F-FDG-PET/CT.

OBJECTIVE: To investigate metabolic parameters as predictive of local response after stereotactic body radiation therapy (SBRT) for liver-oligometastases. METHODS: Inclusion criteria of the present retrospective study were: (a) liver oligometastases with controlled primary tumor; (b) absence of progressive disease ≥6 months; (c) metastases ≤ 3; (d) evaluation of SBRT-response by means of 18-fludeoxyglucose-PET/CT for at least two subsequent evaluations; (e) Karnofsky performance status >80; (f) life-expectancy >6 months. The following metabolic parameters were defined semi-quantitatively for each metastases: (1) standardized uptake value (SUVmax; (2) SUV-mean; (3) metabolic tumor volume (MTV), tumor volume with a SUV ≥3, threshold 40%; (4) total lesion glycolysis (TLG), i.e. the product of SUV-mean and MTV. Local control was defined as absence of recurrence in the field of irradiation. RESULTS: 41 liver metastases were analyzed. Pre-SBRT, median SUV-max was 8.7 (range, 4.5-23.59), median SUV-mean was 4.6 (range, 3-7.5), median MTV was 5.7 cc (range, 0.9-80.6) and median total lesion glycolysis was 24.1 (range, 3.6-601.5). At statistical analysis, metastases with SUV-mean >5 (p 0.04; odds ratio 4.75, sensitivity = 50%, specificity = 82.6%, area under the curve 0.66) and SUV-max >12 (p 0.02; odds ratio 5.03, sensitivity = 69%, specificity = 70%, area under the curve = 0.69) showed higher rates of infield-failure compared to the remaining lesions. CONCLUSION: According to current findings, pre-SBRT SUV-max and SUV-mean could be predictable of local response in liver oligometastases. Advances in knowledge: Present findings could support the hypothesis that fludeoxyglucose-PET/CT may be a powerful tool to predict tumor control. Specifically, current results might be helpful for clinicians in the decision-making process regarding liver oligometastatic patient selection as well as the individual therapy stratification distinguishing between slowly local progressing patients and rapidly progressing patients.

Moderate Hypofractionated Postprostatectomy Volumetric Modulated Arc Therapy With Daily Image Guidance (VMAT-IGRT): A Mono-institutional Report on Feasibility and Acute Toxicity.

INTRODUCTION: The aim of this study was to evaluate the acute toxicity profiles of a moderate hypofractionated regimen with volumetric modulated arc therapy (VMAT) in patients with prostate cancer (PC) who underwent radical prostatectomy. MATERIAL AND METHODS: From December 2012 to February 2016, 125 patients, previously having undergone radical prostatectomy, received adjuvant (64 patients) or salvage (61 patients) radiotherapy (RT) inside an institutional protocol of moderate hypofractionation schedule using the VMAT technique (Varian RapidArc, Palo Alto, CA). Eligible patients were < 85 years old, with an Eastern Cooperative Oncology Group performance status of 0 to 2, histologically proven adenocarcinoma of the prostate without distant metastases, and pathologic stage pT2-4 N0-1, with at least 1 of the following risk factors: capsular perforation, positive surgical margins, seminal vesicle invasion, and/or postoperative prostate-specific antigen > 0.2 ng/mL. Patients were stratified into low (1%), intermediate (9%), and high-risk (90%) groups. The median age was 68 years. The median doses were 66 Gy (range, 65.5-71.4 Gy) to the prostatic bed and 52.5 Gy (range, 50.4-54 Gy) to the pelvic lymph nodes, in 28 or 30 fractions. The acute genitourinary (GU) and gastrointestinal (GI) toxicities were scored according to the Common Terminology Criteria for Adverse Events, v4. RESULTS: All 125 patients completed the planned treatment, with good tolerance. After RT, the median follow-up was 18 months. Acute toxicities were recorded for the GU (G0, 45/125 [36%]; G1, 63/125 [50.4%]; G2, 16/125 [12.8%]; G3, 1/125 [0.8%]) and the GI (G0, 42/125 [33.6%]; G1, 72/125 [57.6%]; G2, 11/125 [8.8%]; no G3). Analyzing data according to RT intent, a higher rate of GU toxicity ≥ 2 was found in the adjuvant setting (17.1%) with respect to the salvage group (9.8%); P = .01 with the Fisher exact text. Furthermore, at statistical analysis, no difference was found between the type of surgery (robotic, laparoscopic, or open) and incidence of urinary incontinence (P = .8). The actuarial Kaplan-Meier rates for biochemical disease-free survival were 94% and 77% for adjuvant and salvage RT, at 36 months. CONCLUSIONS: Moderate hypofractionated postoperative RT with VMAT was feasible and safe with acceptable acute GU and GI toxicities. Longer follow-up is needed to assess late toxicity and clinical outcomes.

Stereotactic Ablative Radiation Therapy for Lung Oligometastases: Predictive Parameters of Early Response by 18FDG-PET/CT.

OBJECTIVES: The objective of this study was to investigate fludeoxyglucose F 18 positron emission tomography/computed tomography (18FDG-PET/CT) parameters as predictive of response after stereotactic ablative radiotherapy (SABR) for lung oligometastases. METHODS: The inclusion criteria of the current retrospective study were as follows: (1) lung oligometastases treated by SABR, (2) presence of 18FDG-PET/CT before and after SABR for at least two subsequent evaluations, (3) Karnofsky performance status higher than 80, and (4) life expectancy longer than 6 months. All patients were treated with a biologically equivalent dose of at least 100 Gy with an alpha/beta ratio of 10. The following metabolic parameters were semiquantitatively defined: maximum standardized uptake value (SUVmax), mean standardized uptake value (SUVmean), metabolic tumor volume, and total lesion glycolysis. RESULTS: A total of 50 patients met the inclusion criteria, for a total of 70 lung metastases. The pre-SABR median SUVmax was 6.5 (range 4-17), the median SUVmean was 3.7 (range 2.5-6.5), and the median metabolic tumor volume was 2.3 cm3 (0.2-31 cm3). The following metabolic parameters were significantly related to complete response at 6 months: SUVmax less than 5 (p < 0.001) and SUVmean less than 3.5 (p = 0.03). ΔSUVmax at 3 to 6 months was +126% for lesions with in-field progression versus -26% for the remaining lesions (p = 0.002). ΔSUVmean at 3 to 6 months was +15% for lesions with in-field progression versus -26% for the remaining metastases (p = 0.008). CONCLUSIONS: In the current analysis, complete response from lung metastasis at 6 months after stereotactic body radiation therapy was significantly associated with both the maximum and mean values of pre-SABR 18FDG-PET/CT SUV. Longer-term trials are strongly advocated to improve the personalization of the monitoring of tumor response in patients with lung oligometastases and, consequently, monitoring of the cost-effectiveness of the health care.

Simultaneous integrated bilateral breast and nodal irradiation with volumetric arc therapy: case report and literature review.

AIM: For simultaneous bilateral breast cancer (SBBC) treatment, conventional radiotherapy (RT) has a number of critical shortcomings. Thus, the usefulness of volumetric arc therapy (VMAT) for SBBC is undeniable. CASE REPORT: A 34-year-old woman with SBBC received neoadjuvant chemotherapy followed by breast-conserving surgery and bilateral lymph node dissection. Given the conservative surgery and the nodal involvement after neoadjuvant chemotherapy, bilateral adjuvant RT to the breasts and regional nodes with doses of 50 Gy in 25 fractions and a simultaneous integrated boost (SIB) of 60 Gy to the surgical bed was proposed. Monoisocentric VMAT using 2 pairs of arcs was performed with adequate target dose coverage and low doses to the organs at risk. The results of this case were compared with those of previous studies in terms of RT technique and irradiated volumes. CONCLUSIONS: VMAT is feasible and safe in the treatment of SBBC with SIB and nodal irradiation.