Combination of radiotherapy and immunotherapy for brain metastases: A systematic review and meta-analysis.

Radiotherapy (RT) represents a mainstay in the treatment of brain metastases (BMs) from solid tumors. Immunotherapy (IT) has improved survival of metastatic cancer patients across many tumor types. The combination of RT and IT for the treatment of BMs has a strong rationale, but data on efficacy and safety of this combination is still limited. A systematic search of PubMed, the Cochrane Central Register of Controlled Trials, and EMBASE was conducted. 33 studies were included for a total of 1520 patients, most of them with melanoma (87%). Median pooled OS was 15.9 months (95%CI 13.9-18.1). One- and 2-year OS rates were 55.2% (95% CI 49.3-60.9) and 35.7% (95% CI 30.4-41.3), respectively. Addition of IT to RT was associated with improved OS (HR = 0.54, 95%CI 0.44-0.67; P < 0.001). For patients with BMs from solid tumors, addition of concurrent IT to brain RT is able to increase survival and provide long term control.

Adjuvant radiotherapy for Merkel cell carcinoma: A systematic review and meta-analysis.

Merkel cell carcinoma (MCC) is a rare and aggressive cutaneous malignancy with a high propensity for local recurrence and regional and distant metastases. The main treatment is surgery with narrow excision margins and draining nodes, plus or minus adjuvant radiotherapy (RT) on the surgical bed and/or lymph nodes. We performed a systematic review and meta-analysis of the benefits of adjuvant RT in MCC treatment. PubMed, EMBASE, and the Cochrane Library were systematically searched to identify relevant studies published before September 2018. Prospective trials and retrospective series comparing adjuvant RT vs. no RT in resected primary MCCs were included. Primary endpoint was to evaluate the outcomes of MCC patients who received adjuvant RT in term of overall survival (OS) and disease-free survival (DFS). Hazard ratios (HRs) for OS and DFS were aggregated according to a fixed or random effect model. Secondary endpoints were local, locoregional, and distant DFS. A total of 17,179 MCCs across 29 studies were analysed. There was a significant difference in OS between the RT and no RT arms (HR = 0.81, 95%CI 0.75-0.86, P < 0.001). There was also a significant difference in DFS in favour of adjuvant RT (HR = 0.45, 95%CI 0.32-0.62, P < 0.001). Adjuvant RT improved locoregional DFS and local DFS but not distant DFS (HR = 0.3, 95%CI 0.22-0.42; HR = 0.21, 95%CI 0.14-0.33, and HR = 0.79, 95%CI 0.49-1.14, respectively). Meta-regression analysis showed that high Newcastle-Ottawa scale scores, stage I-II MCCs, shorter follow-up durations, size >2 cm, and being of a younger age were associated with increased OS. This systematic review and meta-analysis suggests a survival and DFS benefit for postoperative radiation of MCCs. Intermediate stage MCCs derive the maximum benefit with local and regional relapses reduced by 80% and 70%, respectively. Conversely, distant metastases were not significantly prevented.

Addition of radiotherapy to the primary tumour in oligometastatic NSCLC: A systematic review and meta-analysis.

Oligometastatic non-small cell lung cancer (NSCLC) has a discrete number of distant lesions (<5) that can be amenable to radical treatment. The treatment of the primary lung tumour in such stage IV cases is still debated. We conducted a systematic review and meta-analysis to evaluate the outcome of these patients and the added benefit in terms of overall survival (OS) and progression-free survival (PFS) when radical treatment of the primary tumour with radiotherapy (RT) was delivered. PubMed, EMBASE and Cochrane Library were systematically searched to identify relevant studies published up to July 2018. Prospective trials and retrospective series comparing RT vs no RT to the primary NSCLC in the presence of oligometastases were included. Hazard ratios (HRs) for OS and PFS were aggregated according to a fixed or random effect model. Twenty-one studies for a total of 924 synchronous oligometastatic NSCLC were analysed. Median OS and PFS were 20.4 and 12 months. Pooled 1-2-3 and 5-year OS were 70.3%, 43.5%, 29.3% and 20.2% respectively. Overall survival was improved with the addition of thoracic RT (HR = 0.44, 95%CI 0.32-0.6; P < 0.001). Similarly, RT added to the primary tumour increased PFS (HR = 0.42, 95%CI 0.33-0.55; P < 0.001). The only variable associated with the median OS was the year of publication with most recent series associated with a better outcome. In patients with oligometastatic NSCLC and disease controlled with ablative therapy of distant metastases, a consolidation with radical RT to the primary tumour is associated with better survival and could be considered as a treatment modality in selected cases.

Urinary bladder preservation for muscle-invasive bladder cancer: a survey among radiation oncologists of Lombardy, Italy.

AIMS AND BACKGROUND: Bladder preservation is a treatment option in muscle-invasive bladder carcinoma. The most investigated approach is a trimodality schedule including maximum transurethral resection of bladder tumor (TURBT) followed by chemoradiotherapy. Our aim was to evaluate the use of bladder preservation by radiation oncologists of the Lombardy region in Italy. METHODS AND STUDY DESIGN: A survey with 13 items regarding data of 2012 was sent to all 32 radiotherapy centers within the collaboration between the Lombardy Oncological Network and the Lombardy Section of the Italian Society of Oncological Radiotherapy. RESULTS: Thirteen centers (41%) answered the survey; the presented data come from 11 active centers. In these centers, 11,748 patients were treated with external-beam radiotherapy in 2012, 100 of whom having bladder cancer (0.9%). 74/100 patients received radiotherapy as palliative treatment for T, N or M lesions. A further 9 and 5 patients received radiotherapy for oligometastatic disease (ablative doses to small volumes) and postoperatively, respectively. Bladder preservation was performed in 12 cases and included trimodality and other strategies (mainly TURBT followed by radiotherapy). A multidisciplinary urology tumor board met regularly in 5 of 11 centers. All responders declared their interest in the Lombardy multicenter collaboration on bladder preservation. CONCLUSIONS: Our survey showed that bladder preservation is rarely used in Lombardy despite the availability of the latest radiotherapy technologies and the presence of an urology tumor board in half of the centers. The initiative of multicenter and multidisciplinary collaboration was undertaken to prepare the platform for bladder preservation as a treatment option in selected patients.

Determinants of small bowel toxicity in postoperative pelvic irradiation for gynaecological malignancies.

BACKGROUND: Patients treated with postoperative radiotherapy for endometrial and cervical carcinomas from 1981 to 2000 were retrospectively analysed in order to assess the rate of late small bowel toxicity. PATIENTS AND METHODS: Eight hundred and six patients had received pelvic irradiation, with total doses of 40-55 Gy. The mean age was 57 years. Three hundred and eighteen patients had been treated for cervical and 488 for endometrial cancer; 46 had diabetes and 22 vascular diseases; 141 had a history of smoking and 367 were previously submitted to surgery for benign diseases. A CT treatment plan had been applied in 285 patients; 256 had been treated by arc moving therapy, 232 with 2 opposed beams (AP-PA) and 318 with 3 or 4 coplanar beams. Three hundred and forty-six were treated with X photons of 10 MV or more, 202 with 4-5 MV and 258 with cobalt gamma rays. Personalized blocks had been used in 389. Thirty-four women had received chemotherapy. Five hundred and eighty-four had been treated with dose fractions of 180 cGy or more and 56 had received a boost with brachytherapy or external beams. Eighty-one had needed treatment discontinuation due to acute small bowel toxicity. RESULTS: The median follow-up was 70 months. Thirty five patients had bowel obstructions, after a median time of 31 months. The 5- and 10-year toxicity rates were 4 and 7%. Uni- and multivariate comparisons identified age, acute toxicity and dose fraction as predictors for complications. CONCLUSION: Postoperative pelvic irradiation with standard techniques for gynaecological carcinomas results in tolerable rates of clinically significant late bowel damage, while older patients suffering from significant acute toxicity seem to be at higher risk.

Breast conserving treatment (BCT) for stage I-II breast cancer in elderly women: analysis of 927 cases.

INTRODUCTION: Few breast conserving treatment (BCT) data include women older than 70. MATERIAL: 910 women older than 70 were treated by BCT for stage I-II BC, with 670 pT(1) (72.3%), 245 pT(2) (26.4%) and 12 pT(x) (1.3%). Axillary nodal involvement occurred in 30.7% of cases. ER and PgR were positive in 85% and 71% of cases. Radiotherapy (RT) was delivered in all patients, tamoxifen in 55.8% and chemotherapy in 4.8%. RESULTS: With a 65-month median follow-up, 28 (3%) local recurrences (LR) and 83 (9.1%) metastases occurred. Second cancer occurred in 51 (5.6%) patients. The 8-year overall survival (OS) and disease-specific survival (DSS) rates were 74% and 90%. The 8-year OS and DSS rates were 77% and 92% versus 65% and 84% in pT(1) versus pT(2) patients (p=0.01). 676 patients were in complete remission (74.3%); 22 were evolutive (2.4%). 206 patients died (22.6%). CONCLUSION: Our study confirms the excellent local control in elderly patients treated by BCT with RT and identifies subgroups at high risk of distant relapse that should be treated more aggressively.

Strategies for the transfusion of subjects with complex red cell immunisation: the Bank of rare blood donors of the Region of Lombardy.

INTRODUCTION: Selecting units of rare blood for transfusion to patients with complex immunisation is one of the most critical processes of a Transfusion Centre. In January 2005 the 'Rare Blood Components Bank - Reference Centre of the Region of Lombardy' w as established with the following goals: 1) identifying regional rare blood donors; 2) creating a regional registry of rare donors; 3) organising a regional bank of liquid and frozen rare blood units; 4) setting up a regional Immunohaematology Reference Laboratory (IRL) to type donors and resolve complex cases. METHODS: The key elements in establishing the Bank were periodic meetings organised by the directors and representatives of the regional Departments of Transfusion Medicine and Haematology (DTMH) and the institution of three working groups (informatics, regulations, finance). RESULTS: The regional IRL was set up, the relevant operating procedures were distributed region-wide, software features were defined and later validated upon activation, and the funds assigned were allocated to various cost items. The number and characteristics of the donors to be typed were identified and 14 regional DTMHs started to send samples. Overall, 20,714 donors were typed, for a total of 258,003 typings, and 2,880 rare donors were identified. Of these, 97% were rare donors because of combinations of antigens (2,139 negative for the S antigen and 659 negative for the s antigen) and 3% (n=82) because they were negative for high-frequency antigens. In the first 2 years of activity, the IRL carried out investigations of 140 complex cases referred from other Centres and distributed 2,024 units with rare phenotypes to 142 patients. CONCLUSIONS: The main goal achieved in the first 24 months from the start of the project was to set up a regional network able to meet the transfusion needs of patients with complex immunisation.

Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. II. The case of T2N0 disease.

PURPOSE: To retrospectively evaluate local control rates, late damage incidence, functional results, and second-tumor occurrence according to the different patient, tumor, and treatment features in a large bi-institutional series of T2 glottic cancer. METHODS AND MATERIALS: A total of 256 T2 glottic cancer cases treated consecutively with radical intent at the Florence University Radiation Oncology Department (FLO) and at the Radiation Oncology Department of the University of Brescia, Istituto del Radio "O. Alberti" (BS) were studied. Cumulative probability of local control (LC), disease-specific survival (DSS), and overall survival (OS) rates were calculated and compared in the different clinical and therapeutic subgroups by both univariate and multivariate analysis. Types of relapse and their surgical salvage were evaluated, along with the functional results of treatment. Late-damage incidence and second-tumor cumulative probability (STP) were also calculated. RESULTS: In the entire series, 3-year, 5-year, and 10-year OS rates were, respectively, 73%, 59%, and 37%. Corresponding values for cumulative LC probability were 73%, 73%, and 70% and for DSS, 89%, 86%, and 85%, taking into account surgical salvage of relapsed cases. Seventy-three percent of the patients were cured with function preserved. Main determinants of a worse LC at univariate analysis were larger tumor extent and impaired cord mobility. At multivariate analysis, the same factors retained statistical significance. Twenty-year STP was 23%, with second-tumor deaths less frequent than larynx cancer deaths (20 of 256 vs. 30 of 256). Incidence of late damage was higher in the first decade of accrual (22%) than in the last decade (10%, p = 0.03); the same was true for severe late damage (9% vs. 1.8%). CONCLUSION: Present-day radical radiotherapy can be considered a standard treatment for T2 glottic cancer. Better results are obtained in patients with less extended disease. Late damage is relatively infrequent, but a careful follow-up is warranted for early detection not only of relapses (because salvage surgery is feasible) but also of second malignant tumors, which constitute a relevant but not the leading cause of death in these patients and are potentially curable.

Radical radiotherapy for early glottic cancer: Results in a series of 1087 patients from two Italian radiation oncology centers. I. The case of T1N0 disease.

PURPOSE: To retrospectively evaluate local control rates, late damage incidence, functional results, and second tumor occurrence according to the different patient, tumor, and treatment features in a large bi-institutional series of T1 glottic cancer. METHODS AND MATERIALS: A total of 831 T1 glottic cancer cases treated consecutively with radical intent at the Florence University Radiation Oncology Department (FLO) and at the Radiation Oncology Department of the University of Brescia-Istituto del Radio "O. Alberti" (BS) were studied. Actuarial cumulative local control probability (LC), disease-specific (DSS), and overall survival (OS) rates have been calculated and compared in the different clinical and therapeutic subgroups with both univariate and multivariate analysis. Types of relapse and their surgical salvage have been evaluated, along with the functional results of treatment. Late damage incidence and second tumor cumulative probability (STP) have been also calculated. RESULTS: In the entire series, 3-, 5-, and 10-year OS was equal to 86%, 77%, and 57%, respectively. Corresponding values for LC were 86%, 84%, and 83% and for DSS 96%, 95%, and 93%, taking into account surgical salvage of relapsed cases. Eighty-seven percent of the patients were cured with function preserved. Main determinants of a worse LC at univariate analysis were: male gender, earlier treatment period, larger tumor extent, anterior commissure involvement, and the use of Cobalt 60. At multivariate analysis, only gender, tumor extent, anterior commissure involvement, and beam type retained statistical significance. Higher total doses and larger field sizes are significantly related (logistic regression) with a higher late damage incidence. Scatterplot analysis of various combinations of field dimensions and total dose showed that field dimensions >35 and <49 cm2, together with doses of >65 Gy, offer the best local control results together with an acceptably low late damage incidence. Twenty-year STP was equal to 23%, with second tumor deaths being more frequent than larynx cancer deaths (67 of 831 vs. 46/831). CONCLUSION: The results of this study support the opinion, suggested by some international guidelines, that radiotherapy is standard treatment for T1 glottic cancer. Better results are obtained in patients with less extended disease and with 4-6 MV photon beams. The use of doses in excess of 65 Gy and of field sizes of 36-49 cm2 is probably the best technical choice available. Late damage is infrequent, but careful follow-up is warranted to detect early not only relapses (because conservative salvage surgery is feasible), but also second malignant tumors, which constitute the main cause of death in these patients and are potentially curable.

Localized extranodal lymphoma of the head and neck: retrospective analysis of a series of 107 patients from a single institution.

PURPOSE: To retrospectively analyze the outcome and patterns of relapse in localized extranodal non-Hodgkin's lymphoma of the head and neck (HN-NHL) after radiotherapy alone or combined modality treatment. PATIENTS AND METHODS: A retrospective analysis of 107 patients with HN-NHL was performed. Relapse patterns, overall survival (OS) and relapse-free survival (RFS) were analyzed. Only stage I (n=50) and stage II (n=57) patients were included with either low-grade (n=21) or high-grade (n=86) lymphoma. Fifty-nine patients were treated with radiotherapy (RT) alone and 48 patients received combined-modality treatment (CMT) consisting of chemotherapy (CHOP or CHOP-like) followed by radiotherapy. The volumes of irradiation included local field (n=24), involved field (n=13) and extended field (n=70). The median age at diagnosis was 63 years (range, 17-86 years). RESULTS: The overall response rates (CR+PR) in the radiotherapy group and the combined modality group were 100% and 96%, respectively. With a median follow-up of 49.4 months, 29 of 59 patients after RT alone (37%) and 30 of 48 patients after CMT (62%) were disease-free. In the whole series the projected five-year OS and RFS were 58.7% and 61.8%. At univariate analysis of clinical variables with potential impact on survival including age, stage, histology, IPI score, single or combined treatment and volumes of irradiation, only age and, to a limited extent, type of treatment influenced OS (age < or =60 years 79%, >60 years 41%, P < 0.001; RT alone 54.9%, CMT 62.8%, P = 0.0487) and RFS (< or =60 years 75%, >60 years 50%, P < 0.001; RT alone 54%, CMT 71%, P = 0.039). Better OS and RFS rates were obtained in patients with stage II and high-grade disease treated with CMT (five-year OS and RFS 63% and 69%, respectively; the corresponding values for RT alone were 38% and 34%). The final model of the multivariate analysis retained only age (< or =60 years) as a significant prognostic factor for both RFS and OS (P < 0.001). In the whole series, the sites of relapse were mainly systemic (n = 32/40, 80%) and in-field relapses were rare (n = 3/40, 7.5%). CONCLUSION: HN-NHL is characterized by a high risk of relapse, particularly at distant sites. Older patients have a significantly worse prognosis. Radiotherapy offers a very good local control rate although combined modality treatment possibly produces better RFS and OS, especially for stage II and high-grade disease. Better systemic approaches are warranted for a more consistent impact on survival in this particular subset of extranodal lymphoma. However, radiotherapy alone may offer a feasible and effective modality for patients who cannot tolerate more aggressive treatments. Extended-field radiotherapy and the treatment of a larger number of uninvolved lymph nodal regions does not confer a RFS or OS advantage, either after RT alone or after CMT.

[Post-radiation pelvic disease and ureteral stenosis: physiopathology and evolution in the patient treated for cervical carcinoma. Review of the literature and experience of the Radium Institute]. / La malattia pelvica post-attinica e la stenosi ureterale: fisiopatologia ed evoluzione nelle pazienti trattate per carcinoma della cervice. Revisione della letteratura ed esperienza dell'Istituto del Radio.

Ureteral stenosis secondary to radiation-induced fibrosis is a well-known, late complication of radiation treatment in patients with carcinoma of the uterine cervix. This paper focuses on epidemiological data, physiopathology and treatment modalities reviewed from Internet-published literature. Experience from a single institution (Institute of Radiotherapy of Brescia) is reported. Ureteral stenosis has an incidence of 15% in patients treated with standard doses of radiotherapy for carcinoma of the uterine cervix. An asymptomatic low-grade fibrotic ureteral stenosis establishes at doses of 20 Gy in experimental animal models, and both incidence and severity rise with increasing of doses. An emerging role for Transforming Growth Factor beta 1 (TGF-beta 1) is recognized in determining chronic activation of fibroblast/fibrocyte lineage and remodelling extracellular matrix which are known mechanisms in the genesis of any fibrotic disease. Experience of the radiotherapy Institute of Brescia, Italy, is reported. A series of 191 patients with stage IB-IIA cervix carcinoma was treated with radical radiotherapy. About 10% of patients developed late urinary tract complications related to post-actinic fibrosis with only 1% of grade III-IV ureteral fibrosis. These data are consistent with those published by other institutions. In conclusion, late ureteral fibrosis is a common and distressing treatment-related complication in patients treated with radiotherapy for cervix carcinoma. Newer strategies in better defining the target for radiotherapy, conformational radiotherapy and better understanding of biologic factors will contribute to further reducing the frequency of such a complication.