Outcomes of extracranial stereotactic body radiation therapy for induced oligometastatic non-small cell lung cancer on novel systemic therapy.

Background: Stereotactic body radiation therapy (SBRT) is often delivered in patients with oligometastatic disease (OMD). However, the specific subset of patients with polymetastatic non-small cell lung cancer (NSCLC) on novel systemic therapies who develop induced oligopersistant disease (OpersisD) or oligoprogressive disease (OprogD), as defined by the European Organisation for Research and Treatment of Cancer (EORTC) OMD classification, has not been well described. This study explores the outcomes of patients treated with this strategy. Methods: Patients with stage IV NSCLC being treated with osimertinib or immune checkpoint inhibitors (ICIs) who received extracranial SBRT for OpersisD or OprogD were identified in our retrospective analysis. Outcomes reported include progression-free survival (PFS), time to change of systemic treatment (TTCST), overall survival (OS), local control (LC) and treatment-related toxicity. Results: Forty-nine patients received SBRT for OpersisD (34.7%) or OprogD (65.3%) at a median of 5.8 and 15.3 months after start of systemic therapy, respectively. 55.1% received concurrent osimertinib and 44.9% received ICI. Seventy-seven extracranial lesions were treated with various fractionation schemas. At a median of 18.8 months follow-up from first SBRT, LC was achieved in 92.2% of total lesions treated (71). The 1-year OS was 91.7% for OpersisD and 83.3% for OprogD. OpersisD compared to OprogD had a longer median PFS (18.3 vs. 6.1 months) and longer median TTCST (23.6 vs. 13.5 months), median OS was not reached for either cohort. On multivariate analysis, patients treated with osimertinib had shorter PFS (HR: 2.20; 95% CI: 1.01-4.82; P=0.048) and shorter TTCST (HR: 2.83; 95% CI: 1.09-7.33; P=0.032). One patient (2%) experienced grade 3 pneumonitis after SBRT, and no grade 4-5 toxicities were reported with SBRT treatment. Conclusions: This study indicates that SBRT for OpersisD or OprogD in Stage IV NSCLC patients on osimertinib or ICIs is safe, very well tolerated, and may prolong the time before needing a shift in systemic therapy. Further prospective research is needed to validate and expand upon these findings.

Stereotactic radiosurgery for brain metastases arising from gynecological malignancies: A retrospective treatment outcome analysis.

BACKGROUND: This retrospective study aims to assess the efficacy of stereotactic radiosurgery (SRS) in the treatment of brain metastases (BM) originating from gynecological cancers. It focuses on local control (LC), distant tumor control (DTC), and overall survival (OS). METHODS: The analysis comprised 18 individuals with gynecological-origin BM treated with SRS at the Hadassah Medical Center from 2004 to 2021. Statistical analyses evaluate factors impacting LC, DTC, and OS. RESULTS: A total of 36 BM of gynecological origin underwent SRS. The median age at the first SRS treatment was 60 years, with a median time of 24.5 months from the primary malignancy diagnosis to BM detection. The 12-month LC rate per patient was 84.6 %, and 5.6 % per BM. Only two instances of local recurrence were observed. The DTC at 12 months was 75 %, with a 29 % overall. Non-significant trends indicating a correlation with distant brain failure with increased cumulative volume and the occurrence of craniotomy before SRS. The median OS of the cohort was 16.5 months from SRS treatment. The 6, 12, 18, and 24-month survival rates were 77.8 %, 66.7 %, 50 %, and 22.2 % respectively. Higher number of BM was associated with lower OS (p = 0.046). On multivariate analysis, age was a significant factor for OS (p = 0.03), demonstrating that older age was associated with a more favorable prognosis. CONCLUSION: This study supports SRS effectiveness for treating BM from gynecological cancers and suggests similar outcomes to more common malignancies.

Short report: Plasma based biomarkers detect radiation induced brain injury in cancer patients treated for brain metastasis: A pilot study.

BACKGROUND: Radiotherapy has an important role in the treatment of brain metastases but carries risk of short and/or long-term toxicity, termed radiation-induced brain injury (RBI). As the diagnosis of RBI is crucial for correct patient management, there is an unmet need for reliable biomarkers for RBI. The aim of this proof-of concept study is to determine the utility of brain-derived circulating free DNA (BncfDNA), identified by specific methylation patterns for neurons, astrocytes, and oligodendrocytes, as biomarkers brain injury induced by radiotherapy. METHODS: Twenty-four patients with brain metastases were monitored clinically and radiologically before, during and after brain radiotherapy, and blood for BncfDNA analysis (98 samples) was concurrently collected. Sixteen patients were treated with whole brain radiotherapy and eight patients with stereotactic radiosurgery. RESULTS: During follow-up nine RBI events were detected, and all correlated with significant increase in BncfDNA levels compared to baseline. Additionally, resolution of RBI correlated with a decrease in BncfDNA. Changes in BncfDNA were independent of tumor response. CONCLUSIONS: Elevated BncfDNA levels reflects brain cell injury incurred by radiotherapy. further research is needed to establish BncfDNA as a novel plasma-based biomarker for brain injury induced by radiotherapy.

Rapid Classification of Sarcomas Using Methylation Fingerprint: A Pilot Study.

Sarcoma classification is challenging and can lead to treatment delays. Previous studies used DNA aberrations and machine-learning classifiers based on methylation profiles for diagnosis. We aimed to classify sarcomas by analyzing methylation signatures obtained from low-coverage whole-genome sequencing, which also identifies copy-number alterations. DNA was extracted from 23 suspected sarcoma samples and sequenced on an Oxford Nanopore sequencer. The methylation-based classifier, applied in the nanoDx pipeline, was customized using a reference set based on processed Illumina-based methylation data. Classification analysis utilized the Random Forest algorithm and t-distributed stochastic neighbor embedding, while copy-number alterations were detected using a designated R package. Out of the 23 samples encompassing a restricted range of sarcoma types, 20 were successfully sequenced, but two did not contain tumor tissue, according to the pathologist. Among the 18 tumor samples, 14 were classified as reported in the pathology results. Four classifications were discordant with the pathological report, with one compatible and three showing discrepancies. Improving tissue handling, DNA extraction methods, and detecting point mutations and translocations could enhance accuracy. We envision that rapid, accurate, point-of-care sarcoma classification using nanopore sequencing could be achieved through additional validation in a diverse tumor cohort and the integration of methylation-based classification and other DNA aberrations.

Pegylated Liposomal Mitomycin C Lipidic Prodrug in Combination With External Beam Radiation Therapy in Patients With Advanced Cancer: A Phase 1B Study.

PURPOSE: The aim of this study was to evaluate a formulation of pegylated liposomal mitomycin C lipidic prodrug (PL-MLP) in patients concomitantly undergoing external beam radiation therapy (RT). METHODS AND MATERIALS: Patients with metastatic disease or inoperable primary solid tumors requiring RT for disease control or symptom relief were treated with 2 courses of PL-MLP (1.25, 1.5, or 1.8 mg/kg) at 21-day intervals, along with 10 fractions of conventional RT or 5 stereotactic body RT fractions initiated 1 to 3 days after the first PL-MLP dose and completed within 2 weeks. Treatment safety was monitored for 6 weeks, and disease status was re-evaluated at 6-week intervals thereafter. MLP levels were analyzed 1 hour and 24 hours after each PL-MLP infusion. RESULTS: Overall, 19 patients with metastatic (18) or inoperable (1) disease received combination treatment, with 18 completing the full protocol. Most patients (16) had diagnoses of advanced gastrointestinal tract cancer. One grade 4 neutropenia event possibly related to study treatment was reported; other adverse events were mild or moderate. Of the 18 evaluable patients, 16 were free of RT target lesion progression at first re-evaluation. Median survival of the entire patient population was 63.3 weeks. Serum MLP level correlated with dose increases and similar long circulating profiles were observed before and after RT. CONCLUSIONS: PL-MLP up to 1.8 mg/kg in combination with RT treatment is safe, with a high rate of tumor control. Drug clearance is not affected by radiation. PL-MLP is potentially an attractive option for chemoradiation therapy that warrants further evaluation in randomized studies in the palliative and curative settings.

Real-world Israeli single institution experience with PET-PSMA for staging of patients with clinically staged localized prostate carcinoma.

BACKGROUND: A recent prospective trial, the proPSMA study, showed superior specificity and sensitivity of Positron emission tomography (PET) - Prostate-specific membrane antigen (PSMA) imaging compared standard Computerized tomography (CT) and bone scan for staging of recently diagnosed high-risk local prostate carcinoma for curative intent treatment. AIM: To share our experience with false-positive PET PSMA scans in newly diagnosed intermediate-risk prostate cancer. METHODS AND RESULTS: Here, we report a series of eight patients who underwent systemic staging using PET-PSMA with false-positive results who were ultimately treated with definitive radiation or surgery. Of the eight patients, two patients were diagnosed with favorable intermediate disease, four with unfavorable intermediate risk, and two with high-risk disease. Seven of eight were shown to have false-positive bone uptake, one patient had uptake in lung nodules. Three patients underwent bone biopsy and proven benign. The rest of the patients were proven as non-metastatic radiologically by repeat PSMA, CT, or Magnetic resonance imaging (MRI). All subsequently preceded to definitive localized treatment and remain disease free as of this study. CONCLUSION: This study emphasizes the importance of prudent clinical judgment when utilizing this highly sensitive imaging technique.

Transurethral Prostatectomy Before or After External Beam Radiotherapy: Complications and Reoperation Rates.

PURPOSE: Patients treated by external beam radiotherapy (EBRT) for localized carcinoma of the prostate (CAP) often suffer from urinary obstruction. While most patients can be treated medically, some require transurethral prostatectomy (TURP) for alleviation of obstruction. The consequences of combing EBRT and TURP are controversial. The objective of this study was to evaluate the success and complication rates of TURP combined with EBRT. PATIENTS AND METHODS: Between 2001 and 2017, 3501 patients underwent TURP. Sixty-six of them were treated with EBRT for CAP. Surgical complications according to the Clavien-Dindo (CD) scale and the need for secondary interventions were compared to 66 randomly selected patients operated on for benign prostatic hyperplasia (BPH). RESULTS: Patients who underwent TURP for BPH were significantly older compared to the patients with CAP with an average of 76.4 (SD 4.3) vs 71 (SD 8.2) years, p<0.0001. Substantial post-operative complications were rare in both groups with only a single case of CD grade 3 in each group. However, patients with CAP required significantly more secondary surgeries (21% vs 6%, p=0.02) and significantly more additional interventions (37.9% vs 13.6%, p=0.0025). There was no difference in complication rate, in the need for additional interventions or in the oncological outcome when comparing patients operated before or after EBRT. CONCLUSION: The complication rate of TURP done before or after EBRT is low and comparable to surgery for BPH. However, the rates of secondary surgeries and additional interventions in these patients are high (40%). TURP before or after EBRT provides similar results.

Nasopharyngeal carcinoma in children and adolescents: The EXPeRT/PARTNER diagnostic and therapeutic recommendations.

Nasopharyngeal carcinoma (NPC) is a rare pediatric tumor. Collaborative studies performed over the last decades showed improved results compared to historical data, but standardized guidelines for diagnosis and management of pediatric NPC are still unavailable. This study presents a European consensus guideline for the diagnosis and treatment of pediatric NPC developed by the European Cooperative Study Group for Pediatric Rare Tumors (EXPeRT). Main recommendations include induction chemotherapy with cisplatin and 5-flurouracil, concomitant chemoradiotherapy in advanced disease, and to consider maintenance treatment with interferon beta (IFN-ß) for selected high-risk patients. Dose adjustments of radiotherapy based on response to induction chemotherapy may decrease the rates of long-term treatment-related complications that affect most of the survivors.

Trimodal therapy in T2-4aN0M0 bladder cancer--How to select the best candidate?

The reported results of trimodal treatment (TMT) in muscle-invasive bladder cancer vary widely. We attempted to characterize the profile of ideal candidates for this approach. Between 2000 and 2019, 105 patients (median age 78 years) with T2-4aN0M0 bladder cancer were treated with TMT and analyzed retrospectively. Mean radiotherapy dose was 62 Gy (SD 8.4). Ten pretreatment prognostic parameters were evaluated including tumor diameter on pre-TURBT CT. Multivariate analyses was performed and combination of parameters was studied. After a median follow-up of 29 months, 53 patients (50.5%) developed recurrence and 70 patients (67.7%) died. Death was disease-specific in 46 patients (65.7%). Tumor diameter was the most significant prognostic parameter with p < 0.0001 for overall, disease-specific and recurrence-free survivals. For every 1 cm increase in tumor diameter, the risk of disease-specific mortality increased by 1.57. Age, cisplatin eligibility and the Charlson Comorbidity Index were significant predictors of overall survival but not of disease-specific or recurrence-free survival. Patients who were cisplatin-eligible with a tumor diameter ≤3 cm had a 5-year disease-specific survival rate of 79.2% as opposed to 33.9% in patients without one of these features (p < 0.001). When tumor diameter exceeded 5 cm (irrelevant of all other parameters), 5-year disease-specific survival rate was only 28.2%. Patient profiles can accurately predict response to TMT. In cisplatin-eligible patients with a tumor diameter ≤3 cm, TMT provides an excellent disease-specific survival rate. In patients with a tumor diameter >5 cm TMT renders unacceptably poor treatment outcomes.

Iatrogenic postoperative cerebellar cyst.

Cerebellar cyst is a known but uncommon entity. It is congenital in most cases, or may develop after brain parenchyma injuries or interventions. To our knowledge, de novo cerebellar cyst after extra-axial tumor excision, has not been described in the literature. We present the first reported case of a de novo cerebellar cyst developing in a 70-year-old woman following retrosigmoid craniotomy for vestibular schwannoma excision, and discuss the possible causes. Following cyst fenestration, there was no clinical or radiological evidence of a residual cyst.

Delayed contrast extravasation MRI: a new paradigm in neuro-oncology.

BACKGROUND: Conventional magnetic resonance imaging (MRI) is unable to differentiate tumor/nontumor enhancing tissues. We have applied delayed-contrast MRI for calculating high resolution treatment response assessment maps (TRAMs) clearly differentiating tumor/nontumor tissues in brain tumor patients. METHODS: One hundred and fifty patients with primary/metastatic tumors were recruited and scanned by delayed-contrast MRI and perfusion MRI. Of those, 47 patients underwent resection during their participation in the study. Region of interest/threshold analysis was performed on the TRAMs and on relative cerebral blood volume maps, and correlation with histology was studied. Relative cerebral blood volume was also assessed by the study neuroradiologist. RESULTS: Histological validation confirmed that regions of contrast agent clearance in the TRAMs >1 h post contrast injection represent active tumor, while regions of contrast accumulation represent nontumor tissues with 100% sensitivity and 92% positive predictive value to active tumor. Significant correlation was found between tumor burden in the TRAMs and histology in a subgroup of lesions resected en bloc (r(2) = 0.90, P < .0001). Relative cerebral blood volume yielded sensitivity/positive predictive values of 51%/96% and there was no correlation with tumor burden. The feasibility of applying the TRAMs for differentiating progression from treatment effects, depicting tumor within hemorrhages, and detecting residual tumor postsurgery is demonstrated. CONCLUSIONS: The TRAMs present a novel model-independent approach providing efficient separation between tumor/nontumor tissues by adding a short MRI scan >1 h post contrast injection. The methodology uses robust acquisition sequences, providing high resolution and easy to interpret maps with minimal sensitivity to susceptibility artifacts. The presented results provide histological validation of the TRAMs and demonstrate their potential contribution to the management of brain tumor patients.

Long-term outcome of continuous 5-fluorouracil/cisplatin-based chemotherapy followed by chemoradiation in patients with resected gastric cancer.

Despite substantial developments in gastric cancer treatment, the majority of patients relapse after definitive surgery. We have previously described well-tolerated adjuvant regimen that includes a combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin followed by chemoradiation after 3 months of chemotherapy. The aim of this study was to evaluate long-term outcomes of patients treated with this regimen and to determine whether expressions of the excision repair cross-complementing (ERCC1) and thymidylate synthase (TS) predict clinical outcome in those patients. The study population consisted of 36 advanced gastric cancer patients. Patients were treated with six cycles of continuous 5-fluorouracil (600 mg/m(2)) for 24 h, push 5-fluorouracil (400 mg/m(2)), and leucoverin (LCV) (200 mg/m(2)) on day 1-2 every 2 weeks, cisplatin (60 mg/m(2)) on day 1 every 4 weeks followed by combined modality therapy using 45 Gy at 1.8 Gy per day concomitant with weekly bolus 5-fluorouracil (600 mg/m(2)) and LCV (50 mg). After median follow-up of 48.9 months, the median disease-free survival was 45 months and the overall survival was 66.4 months. Sixteen patients (44 %) were alive and disease-free. There was no significant correlation between ERCC1 expression and TS expression pattern and time to relapse (P = 0.302 and P = 0.707, respectively). In conclusion, long-term follow-up demonstrates that postoperative chemoradiation with combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin is a feasible approach.

An interobserver study of prostatic fossa clinical target volume delineation in clinical practice: are regions of recurrence adequately targeted?

OBJECTIVES: To study interphysician variability of delineation of the prostatic fossa clinical target volume (pfCTV) to be irradiated in patients with residual or recurrent microscopic prostate cancer following radical prostatectomy and to estimate the risk for a geographical miss. METHODS: Thirty-eight pfCTV were delineated on postradical prostatectomy computerized tomography scans of 8 patients by 5 observers. To estimate the risk of a geographical miss, a high risk volume (HRV) was defined and the percentage of "missed" HRV was calculated for each pfCTV. RESULTS: Interphysician variability was considerable with a mean pfCTV of 39.09 cm (range, 11.8-72.5 cm). At least 25% of the HRV at the bladder neck/anastomosis and the retro-vesical space was excluded in 11 pfCTVs. The mean "missed" HRV was 27.5% (range, 2.3%-78.7%). A pfCTV of less than 30 cm was associated with a geographical miss in 66% of cases versus 17.2% for pfCTV of 30 cm or more (P = 0.006). Observer identity was significantly associated with excluded HRV (P = 0.03). CONCLUSIONS: pfCTV delineation is subject to considerable interobserver variability associated with a significant risk of inadequate targeting of the anastomosis/bladder neck region and the retrovesical space. The failure to recognize regions at high risk for harboring microscopic disease may be due to a lack of familiarity with tissue redistribution following radical surgery, and a lack of literature-based guidelines for pfCTV delineation. A strategy to improve pfCTV delineation is proposed.

Preoperative radiotherapy and concurrent chemotherapy with bolus 5-fluorouracil for rectal cancer: a prospective analysis of 98 patients.

AIMS AND BACKGROUND: Surgical resection of rectal cancer is associated with a high pelvic recurrence rate. Preoperative large-fraction radiotherapy (RT) with a short interval after local excision has been associated with a significant improvement in locoregional recurrence rates and overall survival, but with high rates of toxicity. We here present the results of our combined-modality treatment protocol for patients with locally advanced rectal cancer. METHODS: Between September 1999 and June 2005, 98 patients were prospectively entered into the protocol. Eligibility criteria included any of the following: cT3-4 disease, clinically positive lymph nodes, or tumor located less than 6 cm from the anal verge. RT was delivered with a three-field technique to a dose of 45 Gy, plus an optional 5.4-9 Gy boost. Chemotherapy, administered concomitantly with RT, consisted of bolus 5-fluorouracil (5-FU) 500 mg days 1-5 followed by 5-FU 600 mg/m2 and leucovorin 50 mg on days 16, 23, 30 and 37. Surgery was performed 6-8 weeks after RT completion and was followed by 8 courses of 5-FU 900 mg/m2 and leucovorin 100 mg/m2 every 14 days. RESULTS: Low anterior resection was performed in 64.5% of the patients and in 38.8% of those with tumors located less than 6 cm from the anal verge. All patients except one had clear pathological margins, 68.8% had negative nodes, and pathological complete response was seen in 13.5%. With a median follow-up of 31.5 months, 3 patients (3.0%) had locoregional recurrence, 19 (19.3%) developed distant metastasis, and 10 patients (10.1%) died. The estimated median disease-free survival was 70.6 months. Grade 3 or 4 gastrointestinal toxicity was seen in 24.5% of the patients and 3.0% had neutropenic fever. One fatal toxicity occurred during treatment. CONCLUSIONS: Our results suggest that our combined-modality treatment protocol is well tolerated and achieves high locoregional control in this unselected population. The overall survival results are also encouraging. Further studies are required to confirm the toxicity profile and survival results of this regimen.

The toxicity and outcomes of continuous 5-fluorouracil/cisplatin-based chemotherapy followed by chemoradiation in patients with resected high-risk gastric cancer: results of a single institute

<p><b>INTRODUCTION</b>The majority of patients with gastric cancer relapse after definitive surgery and 5-year survival after surgery is very poor. The Intergroup 0116 study showed a modest survival benefit for postoperative bolus 5-fluorouracil-based chemoradiation with a high rate of toxicity. We hypothesised that treatment outcome could be further improved with feasible toxicity using a combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin followed by chemoradiation after 3 months of chemotherapy.</p><p><b>MATERIALS AND METHODS</b>Thirty-six patients with stages Ib through IV adenocarcinoma of the stomach or gastrooesophageal junction who had undergone gastric resection and negative margins were assigned to postoperative chemoradiation. The treatment consisted of 6 cycles of continuous 5-fluorouracil (600 mg/m2) for 24 hours, push 5-fluorouracil (400 mg/m2) and leucoverin (LCV) (200 mg/m2) on day 1 to 2 every 2 weeks, cisplatin (60 mg/m2) every 4 weeks followed by combined modality therapy using 45 Gy at 1.8 Gy per day concomitant with weekly bolus 5-fluorouracil (600 mg/m2) and LCV (50 mg).</p><p><b>RESULTS</b>The median age was 59 years (range, 29 to 75) and 25 patients were male. Thirty-five per cent had proximal tumour, T3 or T4 were diagnosed in 92% of the patients and lymph nodes metastases were confirmed in 83%. Grade 3 or 4 neutropaenia was documented in 25%, and gastrointestinal toxicity in 16%. There was no toxic death, but 1 patient had long-term complications. The median disease-free survival was 37.4 months and the overall survival was 40.3 months.</p><p><b>CONCLUSIONS</b>Postoperative chemoradiation with combination of bolus 5-fluorouracil, continuous 5-fluorouracil and cisplatin is a feasible and well-tolerated approach. Larger clinical trials should be conducted to further evaluate the toxicity and the efficacy of this regimen.</p>

Reduced-intensity conditioning regimen using low-dose total body irradiation before allogeneic transplant for hematologic malignancies: Experience from the European Group for Blood and Marrow Transplantation.

PURPOSE: The high rate of toxicity is the limitation of myeloblastive regimens before allogeneic transplantation. A reduced intensity regimen can allow engraftment of stem cells and subsequent transfer of immune cells for the induction of a graft-vs.-tumor reaction. METHODS AND MATERIALS: The data from 130 patients (80 males and 50 females) treated between 1998 and 2003 for various hematologic malignancies were analyzed. The median patient age was 50 years (range, 3-72 years). Allogeneic transplantation using peripheral blood or bone marrow, or both, was performed in 104 (82%), 22 (17%), and 4 (3%) patients, respectively, from HLA identical sibling donors (n = 93, 72%), matched unrelated donors (n = 23, 18%), mismatched related donors (4%), or mismatched unrelated donors (6%). Total body irradiation (TBI) at a dose of 2 Gy delivered in one fraction was given to 101 patients (78%), and a total dose of 4-6 Gy was given in 29 (22%) patients. The median dose rate was 14.3 cGy/min (range, 6-16.4). RESULTS: After a median follow-up period of 20 months (range, 1-62 months), engraftment was obtained in 122 patients (94%). Acute graft-vs.-host disease of Grade 2 or worse was observed in 37% of patients. Multivariate analysis showed three favorable independent factors for event-free survival: HLA identical sibling donor (p < 0.0001; relative risk [RR], 0.15), complete remission (p < 0.0001; RR, 3.08), and female donor to male patient (p = 0.006; RR 2.43). For relapse, the two favorable prognostic factors were complete remission (p < 0.0001, RR 0.11) and HLA identical sibling donor (p = 0.0007; RR 3.59). CONCLUSIONS: In this multicenter study, we confirmed high rates of engraftment and chimerism after the reduced intensity regimen. Our results are comparable to those previously reported. Radiation parameters seem to have no impact on outcome. However, the lack of a statistically significant difference in terms of dose rate may have been due, in part, to the small population size in the subgroup analysis.