Distant Disease Research Articles

A Prospective Phase II Dose Escalation Study Using IMRT for High Risk N0M0 Prostate Cancer.

Published data supports the use of very high dose intensity modulated radiotherapy (IMRT) in achieving high efficacy and low toxicity for high-risk prostate cancer (HRPCa). This phase II multi-institutional non-randomized prospective dose escalation study using intensity modulated radiotherapy (IMRT) for high risk N0M0 prostate cancer was designed to investigate dose escalation using 1.8 Gy increments from baseline 75.6 Gy up to maximum 81 Gy, once dose volume constraints were adhered to. Inclusion criteria were patients undergoing a radical course of RT for high and very high-risk disease, defined as one or more of the criteria ≥ T3*, ≥ Gleason 8, Prostate specific antigen (PSA) > 20ng/ml. All patients received Androgen Deprivation Therapy (ADT) and none had radiological evidence of distant metastatic disease. The primary objective was to determine if dose escalated IMRT for high risk localized prostate cancer could provide freedom from biochemical relapse (BR; PSA rising > nadir +2ng/mL or initiation of salvage hormone therapy) similar to that reported in the literature. The Kaplan-Meier method was used to estimate survival times. Secondary objectives included OS, Disease Free Survival (DFS), and the incidence and severity of Genito-urinary (GU), Gastro-intestinal (GI) and erectile dysfunction (ED) toxicities (CTCAE v.3). Toxicities and performance status were collected and graded weekly during RT, 2 months after completing RT, 8 months' post RT, and 6 monthly thereafter to year five and annually thereafter to year nine. A total of 230 evaluable patients were enrolled between April 2009 and June 2016. The median follow-up was 7.3 years. The cumulative proportion of patients surviving without BR at 5 years was 91% (95% Confidence Interval (CI): 86% to 94%). Overall survival at 5 and 7 years was 92% (88% to 95%) and 89% (83% to 92%) respectively, while the cumulative proportion of patients free from disease was 89% (84% to 93%) at 5 years and 81% (75% to 86%) at 7 years. The incidence of acute G2 and G3 toxicities were; GU; 57.8% G2, 12.6% G3, GI; 15.2% G2, 0.4% G3, ED; 30.0% G2 and 61.7% G3. The incidence of late G2, G3 and G4 toxicities were; GU; 40.9% G2, 8.7% G3, GI; 36.5% G2, 2.2% G3, 0.4% G4, ED; 11.7% G2 and 86.1% G3. The percentage of patients receiving each dose level was; 3.5% received 75.6Gy in 42 fractions, 2.2% received 77.4Gy in 43 fractions, 93% received 81Gy in 45 fractions. The findings indicate that high-dose IMRT is well tolerated and is associated with excellent long-term tumor-control outcomes in patients with localized high and very high-risk prostate cancer, with 91% of patients surviving at 5 years without biochemical relapse. The rates of long term G3 GU and GI toxicity were low at 8.7% and 0.4% respectively.

Retifanlimab: a breakthrough for the management of Merkel cell carcinoma

Merkel cell carcinoma (MCC) is a rare, highly metastatic cutaneous neuroendocrine cancer originating from specialized Merkel cells, which are responsible for touch sensation in the skin. It is characterized by a firm, rapidly expanding nodule on sun-exposed skin areas, especially the head and neck. It has a high mortality rate, with reported overall survival rates ranging from 14% for distant disease to 51% for local disease. In March 2023, retifanlimab (Zynyz) received accelerated U.S. Food and Drug Administration (FDA) approval for treating adults with metastatic or recurrent locally advanced MCC. This drug offers a first-line response against MCC by improving the body’s immune response against cancer cells. This article aims to provide updated guidelines on the properties, dosing, and mechanism of action while discussing its use for the management of adults.

Prostate Cancer in New York City: Impact of Neighborhood Level Social Determinants of Care

Social determinants of health may impact stage and aggressiveness of cancer presentation. As neighborhoods may influence adjacent neighborhoods across often porous and arbitrary borders, an analysis that measures the spatial impact of these social determinants provides a more holistic evaluation than an analysis that treats each neighborhood as independent and unrelated units. In this paper, we study the impact of sociodemographic and environmental characteristics of neighborhoods on cancer presentation in New York City, using both patient-level analysis and spatial autoregression on the New York State Public Access Cancer Epidemiology Data (NYSPACED) and the NYC Open neighborhood-level dataset. Two outcomes of interest were chosen: Presentation with high grade prostate cancer and presentation with distant disease. We performed logistic regression on individual patient level analysis. We created generalized cross sectional autoregressive spatial regression models to assess direct and indirect (via adjacent neighborhoods) impact of neighborhood level independent variables. We analyzed the following neighborhood level variables: 1) Percent population that was Black, 2) Percent population living in poverty, 3) Percent population obese based on self-reported height and weight, 4) Percent who report being current smokers, 5) Percent who report eating one or more servings of fruits and/or vegetables in the last day, and 6) annual average micrograms of fine particulate matter per cubic meter of air. We identified 95,749 patients diagnosed with prostate adenocarcinoma in New York City from 2001-2018. With reported Black race as the referent value, White patients were less likely to present with high grade disease (OR 0.92 [95% CI 0.89-0.95]). Similarly, self-identified White patients were also less likely to present with distant disease (vs. Black, OR 0.76 [95% CI 0.72-0.81]). Spatial autoregression models revealed no neighborhood level variables associated with direct or indirect impacts on presentation with high grade disease. However, there were several variables initially associated with distant disease presentation, including race, poverty, obesity, fruit and vegetable consumption, and air pollution. However, only neighborhood poverty and obesity levels continued to have significant direct impact on presentation with distant disease when included in the regression model with percent Black residents. In conclusion, we discovered a strong association between Race and poverty with the likelihood of presenting with advanced prostate cancer, at both the individual and neighborhood levels. Geographically targeted outreach to improve prostate cancer screening and access to care should be focused on Black men and neighborhoods with high levels of poverty.

Outcomes of Watch and Wait Following Total Neoadjuvant Therapy for Rectal Cancer

To evaluate the outcomes of patients with locally advanced rectal cancer who achieved a clinical complete response (cCR) after total neoadjuvant therapy and enrolled in a prospective watch and wait (WW) database. Consecutive patients with locally advanced rectal cancer who achieved cCR following total neoadjuvant therapy (long-course chemoradiotherapy plus systemic chemotherapy) and were enrolled in our institutional WW surveillance protocol from 2014 through 2022 with the intention of organ preservation. Patients with lack of follow up according to our institutional protocol were excluded. Primary outcomes included local tumor regrowth and distant metastatic disease recurrence. Thirty-three consecutive patients (48% male; median age 61 [33-77] years) with the diagnosis of locally advanced rectal adenocarcinoma were managed by a multidisciplinary team. All patients had Eastern Cooperative Oncology Group Performance Status score of 0 or 1 at time of rectal cancer diagnosis. Location of tumor included upper rectum (18%), middle rectum (40%), and lower rectum (42%). On initial staging magnetic resonance imaging, 4 (12%) patients had evidence of extramural venous invasion, 6 (18%) had a threatened mesorectal margin, and 4 (12%) had anal sphincter or levator ani tumor involvement. A majority (61%) received chemotherapy followed by long-course chemoradiotherapy. Only one patient had an unplanned break during radiotherapy. Local tumor regrowth was diagnosed in 4 (12%) patients and all underwent successful salvage surgery without additional local failures at a median follow-up of 19 [12-48] months. Two of these four patients remain disease-free at a median follow-up time of 12.5 months. Mean time to local tumor regrowth as first site of cancer recurrence was 33.5 [18-46] months. Distant metastatic disease as the first site of recurrence occurred two patients (6%). Mean time to distant metastatic disease as first site of recurrence was 27 months. Only one mortality occurred in the entire group at a median follow-up of 49 [8-102] months. Organ preservation after total neoadjuvant therapy for locally advanced rectal cancer yields excellent outcomes with low local and distant relapse rates. Structured surveillance protocols and multidisciplinary care are essential for success.

Prospective Evaluation of MRI-Based Endoluminal Brachytherapy with Novel Applicator for Anorectal Cancer

To present results of patients treated on a prospective dose escalation trial of MRI-based endoluminal high dose rate (HDR) brachytherapy (BT) and concurrent chemotherapy utilizing a novel double-balloon applicator for recurrent or inoperable rectal and anal cancer. A total of 15 patients were enrolled on a prospective, institutional review board-approved dose escalation protocol evaluating endoluminal HDR-BT with concurrent chemotherapy. Inclusion criteria were histologically confirmed locally residual or recurrent cancer of the rectum or anus and prior pelvic external beam radiation therapy (EBRT). BT was delivered with a novel anorectal applicator consisting of an inner balloon, which supported 8 channels for the radioactive source, and a compliant outer balloon for optimal deformation against exophytic lesions. Applicator insertion and treatment delivery were performed under general anesthesia in 3 weekly sessions. MRI-based treatment planning was performed while under anesthesia during the first session only. Capecitabine (825 mg/m2 BID) was administered Monday-Friday on the weeks of BT. Efficacy and toxicity were evaluated by clinical assessment and MRI examinations at pre-defined intervals (3, 6, and 12 months for the first year) after the procedure. From 1/2015 to 4/2018 15 patients at a median age of 65 years (43-86) with recurrent or residual cancer (9 rectal, 6 anal) were enrolled and treated at the initial dose level of 15 Gy in 3 fractions (n = 6), the intermediate dose level of 18 Gy in 3 fractions (n = 3), and the highest dose level of 21 Gy in 3 fractions (n = 6). Treatment was delivered as planned for 14 patients; 1 patient was treated with a single-channel Bougie applicator for the third fraction due to the development of severe circumferential narrowing that prevented insertion of the endorectal applicator. On first MRI imaging post-BT, 7 patients had a complete response, 5 patients had a partial response, 1 patient had progressive disease, and 2 patients had indeterminate imaging. At a median follow up of 26 months (7-88), 10 patients (6 rectal and 4 anal) have developed a local recurrence (2 also with distant disease) which were treated with surgery (4), systemic therapy (1), or no known therapy (3). Acute (<6 months post-RT) grade 2 and 3 toxicities were observed in 1 (rectal bleeding) and 2 (anorectal pain) patients, respectively, and the only late grade 3 toxicity observed was rectal bleeding in 1 patient. Endoluminal HDR BT with MRI-based treatment planning and a novel double-balloon applicator was feasible up to a dose level of 21Gy in 3 fractions in patients with non-operable rectal or anal cancers and history of prior EBRT. The clinical efficacy and toxicity associated with this treatment should be more clearly defined with analyses of larger cohorts of patients.

Predictors of Poor Treatment Experience in Cervical Cancer Patients Receiving Definitive Chemoradiation and Brachytherapy Boost: A Prospective Study

Cervical cancer patients experience high overall symptom burden. Here, we analyzed patient reported outcomes (PROs) to identify disease, treatment, or patient-related characteristics that can predict poor treatment experience. Cervical cancer patients treated with definitive chemoradiation (CRT) at a single institution enrolled on a prospective trial evaluating PROs between 2021-2023 were included. Patients received PRO questionnaires at baseline (BL) and 2-7 days after final brachytherapy implant (post-BT). Data was collected using the EORTC-QLQ-C30, which is a validated metric scored on a 4-point Likert scale (1 = not at all, 2 = a little, 3 = quite a bit, 4 = very much). Poor treatment experience was defined as low physical function [score >2], significant overall symptom burden [> population mean], or substantial nausea/vomiting (N/V), diarrhea, pain, or fatigue [score >2] after BT. Potential predictors included age, menopause status, stage, radiation field size, BT modality (PDR vs HDR), marital status, high baseline financial toxicity [score >2], depression [score >2], worse social function [score >2] and poor emotional function [score >2]. Logistic regression modeling was performed and p<0.05 were considered significant. A total of 36 patients completed BL and post-BT PRO metrics. Median age was 42 (range, 18-85), 22% (n = 8) of patients had localized disease, 75% (n = 27) had regional disease, and 3% (n = 1) had distant disease. Low BL social function was associated with high symptom burden after BT (HR 12.5, 95% CI 2.3-68.2, p = 0.004), significant N/V (HR 19.0, 95% CI 1.9-191.0, p = 0.012), high rates of fatigue (HR 9.29, 95% CI 1.6-54.8, p = 0.014), and overall poor physical function after treatment (HR 5.67, 95% CI 1.1-30.1, p = 0.042). High BL financial toxicity was predictive of elevated symptom burden after BT (HR 12.0, 95% CI 2.2-66.0, p = 0.004) and substantial fatigue (HR 7.33, 95% CI 1.5-36.7, p = 0.015). Significant depression at BL was also associated with high rates of N/V (HR 9.78, 95% CI 1.4-66.9, p = 0.02). Patient age, menopausal status, disease stage, radiation field size, BT modality, and marital status were not significantly predictive for symptom burden or physical function after treatment. Patients with poor baseline social function, high financial toxicity, and depression are at risk for increased symptom burden. Screening for these factors may provide an opportunity to intervene early and improve patient treatment experience.

Survival Outcomes for Oligometastatic vs. Polymetastatic Extensive-Stage Small Cell Lung Cancer Following Consolidative Thoracic Radiotherapy

For patients with limited metastatic burden, metastasis-directed radiotherapy has been shown to be associated with improved OS for certain types of cancer. However, these prior trials did not include patients with ES-SCLC. It is not yet clear if patients with oligometastatic ES-SCLC have improved outcomes over polymetastatic ES-SCLC after cTRT. We identified patients treated with cTRT for ES-SCLC in 2013-2020 at a single institution. Oligometastatic disease was defined at the time of diagnosis as three or fewer organs with distant disease, and with each organ having three or fewer metastatic lesions. All other patients were considered polymetastatic. The Kaplan-Meier estimator, log-rank test, and multivariable Cox proportional hazards regression were used to compare OS, progression-free survival (PFS), local recurrence-free survival (LRFS), and new metastasis-free survival (NMFS) between oligometastatic and polymetastatic ES-SCLC patients undergoing cTRT. Among 70 included patients, 36 were defined as oligometastatic. All patients received platinum-doublet chemotherapy and cT. Immunotherapy was given in 7 (19.4%) oligometastatic patients and 5 (14.7%) polymetastatic patients (p = 0.56). Median follow-up time was 38.2 months. Multivariable Cox regression analysis showed that oligometastatic disease (vs. polymetastatic disease) at diagnosis was associated with improved OS (hazard ratio [HR] 0.44, 95% CI 0.25-0.78, p = 0.005, 1-year OS 86.1% vs. 46.9%, 2-year OS 47.1% vs. 15.1%). PFS, LRFS, and NMFS were not significantly different between the cohorts. Among oligometastatic patients, pleural involvement (HR 2.44, 95% CI 1.02-5.83, p = 0.046) and lung involvement (HR 4.93, 95% CI 1.02-23.9, p = 0.047) were associated with inferior OS. Among the 26 of 36 (72.2%) oligometastatic patients with neither pleural nor bilateral lung involvement, 1-year OS was 88.5% and 2-year OS was 58.3%. We observed that oligometastatic ES-SCLC patients treated with cTRT (especially those without pleural or bilateral lung involvement) have superior OS than those with polymetastatic disease. We encourage enrollment on the NRG LU007/RAPTOR randomized trial to determine the impact of complete or incomplete consolidative RT to up to 5 sites in ES-SCLC, especially in those with oligometastatic disease.

Correlation of Post-Treatment Biopsy and Fluorodeoxyglucose PET/CT Findings Following Definitive Chemotherapy and Radiation for Cervical Cancer

Concurrent chemotherapy and external beam radiation with brachytherapy boost is considered standard of care for treatment of locally advanced cervical cancer. Post treatment surveillance fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) imaging is recommended 3-6 months after completion of therapy. Persistent FDG avidity is commonly observed at the cervix on surveillance scans, indeterminate for residual malignancy versus post treatment inflammatory change. To better understand the clinical significance of residual hypermetabolic activity, we performed an analysis of surveillance FDG-PET/CT images, correlating findings with post treatment cervical biopsy results after completion of therapy. The medical records of all patients treated with definitive chemotherapy and radiation for locally advanced (FIGO IB3 to IVA) cervical cancer at a single academic medical center between 2017 and 2022 were reviewed. Patients were treated with curative intent using a combination of pelvic external beam radiation with concurrent cisplatin chemotherapy followed by intracavitary or combined intracavitary/interstitial brachytherapy boost. Patients underwent FDG-PET/CT imaging at 3-6 months upon completion of therapy, followed by biopsy either for suspected residual disease or equivocal findings on physical exam or FDG-PET/CT scans. Biopsies were obtained within 100 days of FDG-PET/CT imaging (median, 14 days). Twenty-three patients met inclusion criteria. One patient was excluded from analysis due to lack of FDG avidity on her pre-treatment FDG-PET/CT. Among the 22 evaluable scans, median pre-treatment FDG- PET/CT SUVmax of the cervix was 16.3 (range, 4.9-55). Median post-treatment SUVmax was 4.4 (range, 2.1-7.4). Median change in SUVmax from pre-treatment to post-treatment was 11.8 (range, 1.1 to 50.6). Twenty patients had a post-treatment SUVmax of greater than 3. Among post treatment scans, eight showed no residual uptake; two showed uptakes equal to the liver; eleven showed uptakes moderately higher than liver; and one showed uptake markedly increased relative to liver. None of the biopsy specimens showed evidence of residual malignancy, instead showing fibroinflammatory necrosis and reactive changes. None of the patients developed clinical evidence of disease progression at the cervix within one year of treatment completion. Residual hypermetabolic activity at the cervix is common following definitive chemotherapy and radiation for cervical cancer. This is unlikely to represent residual viable malignancy. Post treatment FDG-PET/CT imaging remains valuable for detecting locoregional or distant disease progression/persistence following therapy.

Outcomes and after Hyperfractionated, Accelerated Reirradiation for Recurrent Anal Squamous Cell Carcinoma

Abdominoperineal resection (APR) is the standard salvage treatment for recurrent or persistent squamous cell carcinoma of the anus (SCCA). However, reirradiation (reRT) can be used preoperatively or for those who are not candidates for surgery. Using a single institutional database, patients were identified who underwent reRT for SCCA from 2003 to 2022. Response to reRT and outcomes after reRT were recorded. Variables analyzed included age at reRT, sex, reason for reRT (recurrent SCCA vs new SCCA after pelvic radiation for a different malignancy), interval between initial radiation and reRT, reRT dose, concurrent chemotherapy, receipt of APR and the presence of distant metastases at the time of reRT. Cox Proportional Hazard Model was used; multivariable analysis for all factors with a univariate P-value <0.1 on univariable analysis. A total of 42 patients received reRT, which consisted of 1.5 Gray (Gy) twice daily fractions with ≥6-hour interval to a total dose ranging 30Gy to 54Gy (median [IQR] 39Gy [39-42Gy]. Thirty-eight patients (90.5%) received concurrent chemotherapy; most often with weekly cisplatin and 5-fluorouracil (N = 23, 54.8%). Median [IQR] follow-up after reRT was 11.4 months [4.9-40.8 months]. Median [IQR] initial radiation dose was 54Gy [54-58Gy], and median [IQR] interval between initial radiation and reRT was 3.6 years [2.1-6.0 years]. For 8 patients (19.1%), the initial radiation was given for a different pelvic malignancy prior to being diagnosed with SCCA. Four of these patients received brachytherapy alone or in conjunction with external beam. For the remaining 34 patients, the initial radiation was for SCCA and the reRT was for recurrent SCCA either in the anal canal (N = 23, 67.6%) or regional nodes (N = 11, 32.3%). Four patients (9.5%) had distant disease at the time of reRT. Eleven patients (26.2%) had planned APR after preoperative reRT; 1 patient had a pathologic complete response (pCR), 2 patients had a near pCR (<5% viable cancer). Twenty-nine patients (69.0%) were treated with reRT alone; 15 (51.7%) attained a clinical CR. Two patients (4.8%) were treated with palliative intent and response was not assessed. Median local recurrence free survival (LRFS) was 9.9 months; 2- and 3-year LRFS were both 41%. Median distant metastasis free survival (DMFS) was 11.8 months; 2- and 3-year DMFS were 38% and 34%, respectively. Median overall survival (OS) was 40.5 months; 2- and 3-year OS were 54% and 51%, respectively. On multivariable analysis, only the presence of distant disease at the time of reRT was significantly associated with worse LRFS (HR (95% CI) 4.14 (1.34-12.81); P = .014), worse DMFS (4.06 (1.37-12.06); P = .012) and worse OS (5.73 (1.57-20.9); P = .008). ReRT is an option for patients presenting with either recurrent SCCA or new SCCA after prior pelvic radiation for a different malignancy. ReRT can be given prior to planned salvage APR or alone for patients who are not surgical candidates with an approximate 50% cCR rate.

Impact of Outside Referral and Dental Extractions on Package Time with Postoperative Radiation Therapy for Head and Neck Cancer

Patients with squamous cell carcinoma of head and neck (HNSCC) often receive post-operative radiotherapy (PORT) following surgical cancer removal. It has been shown that a total package time between surgery and completion of PORT of 100 days or less is correlated with lower rates of local and distant recurrence, and longer survival. However, limiting the package time to 100 days can be challenging, as adjuvant RT typically takes 6-7 weeks, leaving 8 weeks or less between surgery and the start of radiation. In this study, we investigate the impact of outside facility referral and dental extractions, both hypothesized to prolong the total treatment package time, with secondary detriment to relapse free survival (RFS) and overall survival (OS). We conducted a retrospective chart review on patients with HNSCC treated at our facility. Inclusion criteria were: HNSCC treated with surgery and PORT within the last five years, age 18 or older upon receiving surgery, and completion of radiation. Patients were excluded from analysis if they had distant metastatic disease at the time of presentation, had received prior radiation to the cancer site, or died during treatment. We then calculated average values for package time and time to recurrence and performed Kaplan-Meier analysis for survival. We performed statistical hypothesis testing via t-test for comparing package time as a continuous variable and via chi-square test for categorical variables. Of 148 patients with HNSCC treated at our facility, 94 met eligibility criteria. 35% of patients experienced local or distant recurrence and 21% of patients died. The median package time was 89.5 days, with 76% of patients achieving a package time of 100 days or less. 44% of patients received PORT at our facility (in-house), and these patients had a shorter package time (85 days vs 101 days, p = 0.0004) and higher likelihood of completion within 100 days (88% vs 66%, p = 0.01). 33% of patients received dental extractions, and this did not affect package time (97 days vs 93 days, p = 0.57) or likelihood of completion within 100 days (74% vs 76%, p = 0.83). A package time of 100 days or less was not associated with significantly lower rates of recurrence (31% vs 48%, p = 0.14) or death (23% vs 17%, p = 0.6), although recurrence was numerically higher with prolonged package times. A Kaplan-Meier analysis was performed to study patient survival over time, and a package time under 100 days was not associated with a change in RFS (p = 0.4) or OS (p = 0.7). In this study, we identified that outside facility referrals for PORT, but not dental extractions, prolong treatment package times. We also saw no effect of package time on RFS or OS, although there was limited variation of package time in this analysis, so our findings do not necessarily contradict previous studies. These results suggest that patients requesting outside facility referrals for PORT may benefit from a streamlined program that expedites the referral process.

Long-Term Survival Outcome for Metastatic Nasopharyngeal Carcinoma Patients Receiving Radiation to Primary and Metastatic Sites with Palliative Chemotherapy

A total of 6% - 8% of NPC patients were initial diagnosed as distant metastatic disease. The median overall survival (OS) is only 10-15 months with palliative chemotherapy for these patients. A phase III study showed that palliative chemotherapy combined with radical radiotherapy to primary site could be a newly effective treatment method for metastatic NPC. Another phase 2, RCT found that the patients who had the solid tumors with 1-5 metastases received standard palliative care plus stereotactic body radiation therapy (SABR), and the 5-year OS were improved to 42.3%. Nevertheless, there was few studies focus on the radiation to both primary site and metastatic lesions. Therefore, we aimed to investigate the potential clinical benefits for initial diagnosed metastatic NPC patients with radiation to both primary site and distant metastatic lesions plus palliative chemotherapy. Metastatic NPC patients treated with radiation to both primary site and distant metastatic lesions plus palliative chemotherapy were retrospectively collected in our hospital from May 2008 to May 2022. For treatment group, all patients underwent IGRT according to ICRU reports 50 and 62. The prescribed dose for primary site: GTVT: ≥66Gy, GTVn: ≥66Gy, CTV1: 60-66Gy, CTV2 54-60Gy, CTVln 50-54Gy. And the prescribed dose for distant metastatic lesions was more than 30Gy. For the control group, the patients treated with palliative chemotherapy were selected by propensity score matching from our hospital. The regimen for palliative chemotherapy was cisplatin-based chemotherapy every three weeks (100mg/m2 D1) for both groups. Kaplan-Meier method was used to analyze the OS. Cox regression model was used for multivariate analysis. A total of 54 metastatic NPC patients with radiation to both primary site and distant metastatic lesions were retrospectively included in the treatment group, and another 54 patients were selected as the control group. The median follow-up time was 52 months. In the treatment group, the median age was 52 years (37-82), male (68%), female (32%), the main metastatic sites were bone (36 cases, 66%), lung (18 cases, 33%) and liver (10 cases, 18%). There were 23 oligometastasis cases and 31 cases. 3-year and 5-year OS in the treatment group were both dramatically improved than control group (63.2% vs 50.6%, p<0.05; 49.6% vs 38.9%, p<0.05). Multivariate analysis showed that T stage, liver metastatic lesion and oligometastases were the independent prognostic factors for them. Palliative chemotherapy combined with radiation to primary sites and distant metastatic lesions might improve the OS for initial diagnosed distant metastatic NPC patients. More prospective clinical trials were needed to confirm it further.

Randomized Trial of Five or Two MRI-guided Adaptive Radiotherapy Treatments for Prostate Cancer (FORT)

The objective of this randomized clinical trial is to demonstrate that 2 treatments of real-time MRI-guided radiotherapy (RT) does not significantly increase patient-reported GI and GU symptoms compared to 5 treatments of RT 2 years after treatment completion (24 months). Key Eligibility Criteria: Inclusion Criteria 1. Men aged > 18 with histologically confirmed low or intermediate risk prostate cancer per NCCN guidelines. 2. ECOG 0 - 1 3. IPSS < 18 4. Ability to receive MRI-guided radiotherapy. 5. Ability to complete the Expanded Prostate Cancer Index Composite (EPIC) questionnaire. Exclusion Criteria 1. Prior history of receiving pelvic RT. 2. Patient with history of IBD. 3. Hip replacements. 4. History of bladder neck or urethral stricture. 5. TURP < 8 weeks prior to RT 6. Metastatic (pelvic nodal or distant) disease on CT, Bone, and/or PSMA PET scan. Study Design/Endpoints: This is a randomized phase II non-inferiority trial comparing 2 fractions of ultrahypofractionated RT (25 Gy total with optional PSMA/MRI boost to 28 Gy) versus 5 fractions of ultra-hypofractionated RT (37.5 Gy total with optional PSMA/MRI boost to 45 Gy) in the definitive setting for prostate cancer. Subjects will be stratified based on pre-specified stratification factors and randomized 1:1 to receive 2 or 5 fractions using permuted block randomization. The primary endpoint is the change in patient-reported GI and GU symptoms as measured by EPIC at 2 years from end of treatment. Secondary endpoints will include both the safety endpoints including change in GI and GU symptoms at 3, 6, 12 and 60 months from end of treatment, and multiple efficacy endpoints including time to progression, prostate cancer specific survival and overall survival. The sample size is calculated based on a non-inferiority design. The non-inferiority margins are set to be a change score of 6 points for the GI symptoms and 5 points for the GU symptoms. The standard deviations of the change scores are assumed to be 13.2 for the GI symptoms and 10.5 for the GU symptoms based on estimates generated in RTOG 0415 trial. This level of change in scores are deemed as clinically meaningful. For example, 6 points of change score for GI symptoms corresponds to two symptoms worsening by 1 level (i.e., loose stools and frequency of bowel movements change from "no problem" to "very small problem") or one of the symptoms worsening by 2 levels (i.e., loose stool change from "no problem" to "small problem"). A sample size of 122 with 61 in each arm will ensure 80% power for GI endpoint and 83% power for GU endpoint to detect non-inferiority using a one-sided two-sample t-test at the significance level of 0.05. Adjusting for a projected 10% EPIC/non-compliance rate, 136 patients (68 per arm) will be randomized. Stratification Factors: Patients will be stratified according to baseline EPIC bowel and urinary domain scores and country of treatment. Enrollment: Twenty patients. To be determined. To be determined.

Very APBI in 1 or 2 Days: Late Toxicity and Early Oncological Outcomes of the GEC-ESTRO Cohort

To analyze late toxicity after very accelerated partial breast irradiation (VAPBI) for low-risk breast cancer. In this retrospective observational international multicenter study (HDH F20220713143949) from 7 European centers, patients with low-risk breast cancer underwent lumpectomy + adjuvant VAPBI based on high-dose rate (HDR) multicatheter interstitial brachytherapy (MIB). VAPBI was performed with 4 (4 × 6.2 Gy/2 d), 3 (3 × 7.45 Gy/2 d) or 1 fraction (1 × 16 Gy or 1 × 18 Gy/1 d). Primary endpoint was late toxicity. Secondary endpoints were oncological outcome based on cumulative incidence of breast cancer local relapse (LR) and distant metastasis disease (DMD) and cause-specific (CSS) and overall (OS) survival. Prognostic factors for late toxicity were analyzed. From 01/2012 to 06/2022, the GEC-ESTRO VAPBI cohort included 516 pts with an early breast cancer. Median follow-up was 42 months [95% CI = 39 - 44]. Median age was 71 years [40 - 100]. Median tumor size was 12 mm [1 - 46]. Tumor was mainly invasive ductal carcinoma (78%), pN0 (88.5%), with positive hormonal receptors (98.5%) and negative HER2 overexpression (96%). Patients underwent hormonal and chemo-therapy in 93.8% and 2.3% respectively. Catheter placement was performed peri or post-operatively in 50.2% and 49.8% respectively. Median time interval between surgery and VABPI was 10 days [6 - 65]. VAPBI delivered 1, 3 and 4 fractions for 205 pts (39.7%), 167 pts (32.4%) and 144 pts (28%) respectively. Median CTV was 40.7 cc [95% CI = 26.6 - 72], median V100%, V150%, D90% and Dose non-uniformity ratio (DNR) were 90.2% [95% CI = 84.1 - 97.2], 24.2% [95% CI = 18.9 - 31.6], 103.8% [95% CI = 100.1 - 107.4] and 0.28 [95% CI = 0.23 - 0.33] respectively, 211 late toxicity events were observed in 168 pts (32.6%). Fibrosis, dyschromia, pain and telangiectasia were observed in 26.7%, 7.9%, 7.2% and 0.4 respectively. Grade 2 and 3 late toxicities were observed in 7.2 and 0.6% respectively (no G4). Grade ≥2 late toxicity was observed in 8.1%, 16.7% and 3.7% after 1, 3 and 4 fractions, respectively (p = 0.004). CTV > 50 cc (p = 0.007) and V150 > 40% (p = 0.027) were prognostic factors for G≥2 late toxicity. Regarding oncological outcome, 4-year cumulative incidence of LR, RR and DMD were 2% [95% CI = 0 - 3], 1% [95% CI = 0 - 2] and 1% [95% CI = 0 - 2] respectively. CSS and OS were 98% [95% CI = 96 - 100] and 93% [95% CI = 90 - 96] respectively. No significant difference was observed in terms of oncological outcome between the 3-fractionation groups. VAPBI based on 1 or 2 days of HDR MIB represents an attractive de-escalation irradiation approach for low-risk breast cancer. Late toxicity profile appears acceptable while early oncological outcome shows excellent local control. Brachytherapy technique remains a key component of clinical outcome. Longer follow-up is warranted in order to confirm these encouraging preliminary results.

Is it the Type of Axillary Surgery or the Number of Removed Lymph Nodes That Increases the Risk of Breast Cancer Related Lymphedema (BCRL)? Results from a Prospective Screening Trial

Axillary surgery has been identified as the main risk factor for BCRL regardless the delivery of regional nodal radiation (RLNR). Yet it remains unknown if it is the type of axillary surgery or the number of removed lymph nodes (LN) that increases BCRL risks. Between 2008 and 2021, 3,350 patients (pts) who received surgery for breast cancer were enrolled in a lymphedema screening trial. Patients with bilateral breast cancer or without axillary surgery were excluded. Perometry was used to assess limb volume preoperatively in all patients. BCRL was defined as a ≥10% relative arm-volume increase arising >3 months postoperatively. The cohort was divided by axillary surgery type: axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB). Radiation was delivered using 3D conformal technique and RLNR was defined as the usage of anterior supraclavicular field. No hypofractionation was used and doses ranged between 50 and 50.4 Gy in 25-28 fractions. Multivariable Cox proportional hazard models compared the cumulative incidence of BCRL and local failure between different patient groups. After applying inclusion criteria, 2,623 pts were available with overall median follow-up s of 6.1 years. Of the entire cohort, 709 (27%) had ALND with a median of 16 LN removed, while 1,914 (73%) received SLNB only with a median of 2 LN removed. The median number of malignant LN and patients receiving RLNR was higher in ALND group compared to SLNB only group. Frequency distribution analysis showed that the main overlap between ALND and SLNB only groups happen in the range of 3-11 LN removed. Therefore, the primary analysis focused only on pts with 3-11 LN across both groups (n = 690: ALND n = 140, SLNB n = 550). The multivariable model adjusted for BMI, RLNR, age and breast surgery showed that in this group with 3-11 LN removed in both cohorts, ALND remained significantly associated with BCRL (HR: 4.2, p<0.0001). Separate analyses for the entire SLNB only group and ALND groups were conducted to evaluate if the BCRL risk increases per each removed LN within the same axillary surgery group. The multivariable analysis for SLNB only pts(N = 1,914) showed that for each LN removed the risk of BCRL did not increase significantly (HR:1.06, p = 0.3), similarly for ALND group (N = 709) for each LN removed (HR:1.02, p = 0.08). For pts with pathologic N2-N3 disease and clinical node negative without neoadjuvant chemotherapy receiving ALND, the number of LN removed did not significantly improve neither Local control (HR:1.02, p = 0.8) nor distant disease survival (HR:1.01, p = 0.6). ALND procedure per se is the main risk factor for BCRL not the number of LNs removed. For high-risk pts with >N2 disease, aggressive ALND did not improve tumor outcome. De-escalation with targeted axillary sampling followed by RLNR should be evaluated. Future lymphedema research should account for type of axillary surgery instead of number of LNs removed as a factor. (NCT01521741).

Proton Re-Irradiation with Concurrent Hyperthermia in Patients with Recurrent Breast Cancer

The aim of this study is to evaluate the safety and effectiveness of proton re-irradiation with concurrent hyperthermia in the treatment of recurrent breast cancer. We retrospectively identified patients previously treated with photon whole breast or chest wall irradiation for a primary breast cancer at our institution, who subsequently developed a histologically-confirmed locoregional recurrence or new ipsilateral primary breast cancer and underwent proton chest wall re-irradiation with concurrent hyperthermia as part of definitive treatment. Acute toxicity was evaluated once weekly while on-treatment and at 2 weeks and 3 months post-treatment. Toxicities were graded according to CTCAE v4.0. Fifteen patients received proton re-irradiation with concurrent superficial hyperthermia at our institution from August 2018 to December 2022. Median interval between radiation treatment courses was 7.7 years (range 1-30 years). Four patients (26%) had gross, unresected disease at the time of re-treatment. The median initial radiation dose, re-irradiation dose, and cumulative EQD2 was 60.4 Gy (50.6-61.2 Gy), 60 Gy (RBE) (45-66 Gy (RBE)), and 120 Gy (RBE) (103-126 Gy (RBE)), respectively. Patients received a median of 9 (3-14) concurrent hyperthermia treatments delivered twice weekly, and 13 patients (87%) received seven or more hyperthermia treatments. Median toxicity follow-up was 9 months (0-36 months). Acute grade 3 toxicities included two patients (13%) with grade 3 dermatitis, both of which resolved with conservative management within 3 months of treatment completion. Chronic grade 2 or higher toxicities included two grade 2 hyperpigmentation, one grade 3 induration, one grade 2 telangiectasia, and one grade 2 rib fracture. There were no grade 4-5 acute or late toxicities. There was one in-field local recurrence and one regional recurrence outside of the re-irradiation field. Both patients had gross, unresected disease at the time of re-irradiation. Two patients (13%) developed distant disease. Proton re-irradiation with concurrent hyperthermia is feasible and well-tolerated in the re-treatment of breast cancer. Further studies are warranted to determine long-term toxicity and oncologic outcomes.

Evaluation of Metastatic Potential in Esophageal and Gastroesophageal Junction (GEJ) Cancer with Adherence to Elective Nodal Volume Guidelines: A Retrospective Analysis of Elective Nodal Irradiation

In 2015, expert guidelines on esophageal/GEJ cancer contouring for intensity-modulated radiation therapy (IMRT) were published in IJROBP, which delineate recommended elective nodal basins (celiac, para-aortic, gastrohepatic ligament, supraclavicular) to be irradiated depending on the primary tumor location. We hypothesize that incomplete coverage of these areas increases the risk of the development of distant failures. Patients treated for non-metastatic esophageal or GEJ cancer with chemoradiotherapy pre-operatively or definitively from 2012 to 2021 were retrospectively identified from a single institution database. Radiation plans of eligible patients were then analyzed by tumor location. Plans were deemed guideline-compliant if radiation dose coverage, between 41.4 to 45 Gy, encompassed nodal basins recommended by the 2015 guidelines. The primary endpoint of this study was the overall rate of distant disease. Other endpoints included locoregional failures, defined as failures within the radiation field but outside of the primary tumor, and local failures within the gross tumor volume. Summary and descriptive statistics were used to define collected variables. Differences were measured using chi-square and Fisher's exact test for categorical variables and two-sided t-tests for continuous measures. Assessment of distant, locoregional, and local failures were assessed using univariate logistic regression with statistical significance at p < 0.05. With a median follow-up of 25.0 months, 37 patients, with a median age of 66, were included in the study. Most patients were male (94.6%) with cT3 (54.1%), cN0 (43.2%), moderately differentiated (47.1%) adenocarcinoma (75.7%) located at the GEJ (56.8%). The median radiation dose used was 50.4 Gy, with the majority of patients receiving concurrent carboplatin and paclitaxel (83.8%). Four patients received induction chemotherapy and 20 (55.6%) underwent esophagectomy. When examining guideline compliance, 17 (46.0%) radiation plans demonstrated adequate ENI. The most common improperly covered nodal basin was para-aortic (65.0%), followed by gastrohepatic (30.0%). No patients with sufficient ENI coverage (0/17) developed distant failure compared to 45.0% (9/20) with insufficient coverage (p = 0.001). There were inappreciable differences in locoregional or local failure rates between those with and without complete ENI. Patients with complete ENI were more likely to be of larger craniocaudal length (p = 0.007) or have N2 disease (p = 0.003). When examining other tumor characteristics (histologic subtype, location, HER2 status, esophagectomy rate) of patients with and without complete ENI, no further differences were noted. These results suggest that proper coverage of nodal basins, when indicated by expert guidelines, could improve distant metastasis. ENI analysis of previous prospective CRT studies for esophageal cancer could validate these findings.

Overall Survival Among Patients With De Novo Stage IV Metastatic and Distant Metastatic Recurrent Non–Small Cell Lung Cancer

Despite recent breakthroughs in therapy, advanced lung cancer still poses a therapeutic challenge. The survival profile of patients with metastatic lung cancer remains poorly understood by metastatic disease type (ie, de novo stage IV vs distant recurrence). To evaluate the association of metastatic disease type on overall survival (OS) among patients with non-small cell lung cancer (NSCLC) and to identify potential mechanisms underlying any survival difference. Cohort study of a national US population based at a tertiary referral center in the San Francisco Bay Area using participant data from the National Lung Screening Trial (NLST) who were enrolled between 2002 and 2004 and followed up for up to 7 years as the primary cohort and patient data from Stanford Healthcare (SHC) for diagnoses between 2009 and 2019 and followed up for up to 13 years as the validation cohort. Participants from NLST with de novo metastatic or distant recurrent NSCLC diagnoses were included. Data were analyzed from January 2021 to March 2023. De novo stage IV vs distant recurrent metastatic disease. OS after diagnosis of metastatic disease. The NLST and SHC cohort consisted of 660 and 180 participants, respectively (411 men [62.3%] vs 109 men [60.6%], 602 White participants [91.2%] vs 111 White participants [61.7%], and mean [SD] age of 66.8 [5.5] vs 71.4 [7.9] years at metastasis, respectively). Patients with distant recurrence showed significantly better OS than patients with de novo metastasis (adjusted hazard ratio [aHR], 0.72; 95% CI, 0.60-0.87; P < .001) in NLST, which was replicated in SHC (aHR, 0.64; 95% CI, 0.43-0.96; P = .03). In SHC, patients with de novo metastasis more frequently progressed to the bone (63 patients with de novo metastasis [52.5%] vs 19 patients with distant recurrence [31.7%]) or pleura (40 patients with de novo metastasis [33.3%] vs 8 patients with distant recurrence [13.3%]) than patients with distant recurrence and were primarily detected through symptoms (102 patients [85.0%]) as compared with posttreatment surveillance (47 patients [78.3%]) in the latter. The main finding remained consistent after further adjusting for metastasis sites and detection methods. In this cohort study, patients with distant recurrent NSCLC had significantly better OS than those with de novo disease, and the latter group was associated with characteristics that may affect overall survival. This finding can help inform future clinical trial designs to ensure a balance for baseline patient characteristics.

Hyperbaric oxygen therapy as a complementary treatment in neuroblastoma - a narrative review.

Neuroblastoma is the most frequently diagnosed cancer during the first year of life. This neoplasm originates from neural crest cells derived from the sympathetic nervous system, adrenal medulla, or paraspinal ganglia. The clinical presentation can vary from an asymptomatic mass to symptoms resulting from local invasion and/or spread of distant disease spread. The natural history of neuroblastoma is highly variable, ranging from relatively indolent biological behavior to a high-risk clinical phenotype with a dismal prognosis. Age, stage, and biological features are important prognostic risk stratification and treatment assignment prognostic factors. The multimodal therapy approach includes myeloablative chemotherapy, radiotherapy, immunotherapy, and aggressive surgical resection. Hyperbaric oxygen therapy (HBOT) has been proposed as a complementary measure to overcome tumor hypoxia, which is considered one of the hallmarks of this cancer treatment resistance. This article aims to review the relevant literature on the neuroblastoma pathophysiology, clinical presentation, and different biological and genetic profiles, and to discuss its management, focusing on HBOT.

The impact of intensified staging and combined therapies in locally advanced pancreatic cancer: a secondary analysis of prospective studies.

To investigate the use of comprehensive pre-treatment staging with multiple diagnostic modalities, including functional imaging and minimally invasive surgical procedures, in locally advanced pancreatic cancer (LAPC) patients. The primary objective was to detect occult metastatic disease using staging laparoscopy and 18FFDG-PET/CT scan. The study also evaluated treatment efficacy and outcomes in LAPC patients treated with combined therapies. This study was a secondary analysis of three prospective studies of chemoradiotherapy (CRT) with or without induction chemotherapy (IC). The inclusion period was from December 2009 until February 2023. An intensified pretreatment staging was conducted for all LAPC patients. Patients without distant disease at initial staging, with borderline resectable or unresectable LAPC, were enrolled in chemoradiotherapy combination protocols (CRT with or without IC). IC regimens included GemOx or FOLFIRINOX for four cycles, followed by concurrent CRT with gemcitabine. The primary endpoint was the detection of occult metastatic disease, and secondary objectives included resection rate, treatment toxicity, overall survival (OS), progression-free survival (PFS), local control (LC), and metastasis-free survival (MFS). Out of the 134 LAPC patients, 33.5% were identified with metastatic disease. Of these, 23.1% had a positive exploratory laparoscopy. Additionally, 13.4% were identified as having distant metastases by 18-FDG PET/CT. The median PFS for all patients who completed CRT was 14.3 months, and the median OS was 17.2 months. Resected patients after the combined therapies demonstrated significantly improved outcomes compared to non-resected patients (median PFS, 22.5mo vs. 9.5mo, P<0.001; median OS, 38.2mo vs. 13mo, P<0.001). Moreover, patients treated with IC followed by CRT showed significantly better outcomes compared to upfront CRT group (median PFS, 19mo vs. 9.9mo, P<0.001; median OS, 19.3mo vs. 14.6mo, P<0.001). At univariate logistic regression analysis, the adding of IC was the only predictor for resection rate (95% CI 0.12-1.02, P=0.05), and this data was confirmed at multivariate analysis (95% CI 0.09-0.98, P=0.04). Haematological and gastrointestinal toxicities were observed during treatment, with manageable adverse events. The use of comprehensive pre-treatment staging, including laparoscopy and 18F-FDG-PET/CT scan, is an effective approach in identifying occult metastatic disease in LAPC patients. Our findings offer valuable insights into accurate staging and treatment efficacy, providing evidence-based support for optimal management strategies in LAPC patients.

Redo Pelvic Surgery and Combined Metastectomy for Locally Recurrent Rectal Cancer with Known Oligometastatic Disease: A Multicentre Review.

Historically, surgical resection for patients with locally recurrent rectal cancer (LRRC) had been reserved for those without metastatic disease. 'Selective' patients with limited oligometastatic disease (OMD) (involving the liver and/or lung) are now increasingly being considered for resection, with favourable five-year survival rates. A retrospective analysis of consecutive patients undergoing multi-visceral pelvic resection of LRRC with their oligometastatic disease between 1 January 2015 and 31 August 2021 across four centres worldwide was performed. The data collected included disease characteristics, neoadjuvant therapy details, perioperative and oncological outcomes. Fourteen participants with a mean age of 59 years were included. There was a female preponderance (n = 9). Nine patients had liver metastases, four had lung metastases and one had both lung and liver disease. The mean number of metastatic tumours was 1.5 +/- 0.85. R0 margins were obtained in 71.4% (n = 10) and 100% (n = 14) of pelvic exenteration and oligometastatic disease surgeries, respectively. Mean lymph node yield was 11.6 +/- 6.9 nodes, with positive nodes being found in 28.6% (n = 4) of cases. A single major morbidity was reported, with no perioperative deaths. At follow-up, the median disease-free survival and overall survival were 12.3 months (IQR 4.5-17.5 months) and 25.9 months (IQR 6.2-39.7 months), respectively. Performing radical multi-visceral surgery for LRRC and distant oligometastatic disease appears to be feasible in appropriately selected patients that underwent good perioperative counselling.