Concurrent Platinum-based Chemotherapy Research Articles

Locally Advanced Cervical Cancer: Neoadjuvant Treatment versus Standard Radio-Chemotherapy-An Updated Meta-Analysis.

The treatment of choice for patients with locally advanced cervical cancer (LACC) is definitive concurrent radio chemotherapy which consists of external beam radiotherapy (EBRT) and concurrent platinum-based chemotherapy (CCRT), with the possible addition of brachytherapy (BT). However, the benefits of adjuvant surgery after neoadjuvant treatments remain a debated issue and a still open question in the literature. This meta-analysis aims to provide an updated view on the controversial topic, focusing on comparing surgery after any adjuvant treatment and standard treatment. Following the recommendations in the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement, the PubMed and Embase databases were systematically searched in April 2023 for early publications. No limitations on the country were applied. Only English articles were considered. The comparative studies containing data about disease-free survival (DFS) and/or overall survival (OS) were included in the meta-analysis. The CCRT + surgery group showed a significantly better DFS than CCRT (RR 0.69 [95% CI 0.58-0.81] p < 0.01) and a better OS (RR 0.70 [95% CI 0.55-0.89] p < 0.01). Nine studies comparing neoadjuvant chemotherapy (NACT) plus surgery and CCRT were also enrolled. The NACT + surgery group showed a significantly better DFS than CCRT (RR 0.66 [95% CI 0.45-0.97] p < 0.01) and a better OS (RR 0.56 [95% CI 0.38-0.83] p < 0.01). In the sub-analysis of three randomized control trials, the surgery group documented a non-significantly better DFS and OS than CCRT (OR 1.10 [95% CI 0.67-1.80] p = 0.72; I2 = 69% p = 0.72; OR 1.09 [95% CI 0.63-1.91] p = 0.75; I2 = 13% p = 0.32). The results provide updated findings about the efficacy of neoadjuvant treatments, indicating significantly improved DFS and OS in patients undergoing hysterectomy after CCRT or NACT compared with patients undergoing standard treatments.

Efficacy and Toxicity of Moderately Hypofractionated Radiation Therapy with Helical TomoTherapy Versus Conventional Radiation Therapy in Patients with Unresectable Stage III Non-Small Cell Lung Cancer Receiving Concurrent Chemotherapy: A Multicenter, Randomized Phase 3 Trial

PurposeThe standard treatment schedule for unresectable stage III non–small-cell lung cancer (NSCLC) is chemotherapy with concurrent radiotherapy (60 Gy delivered in 30 fractions), although moderately hypofractionated radiotherapy (Hypo-RT) has also been considered as an alternative strategy. This study aimed to compare the efficacy and toxicity of moderately Hypo-RT with helical TomoTherapy versus conventionally fractionated radiotherapy (Con-RT) in patients with unresectable stage III NSCLC receiving concurrent chemotherapy. Methods and MaterialsIn this randomized multicentre non-blinded phase III clinical trial, eligible patients were randomized at a 1:1 ratio to either the Hypo-RT group, (60 Gy in 20 fractions) or to the Con-RT group (60 Gy in 30 fractions). All patients received two cycles of concurrent platinum-based chemotherapy plus two cycles of consolidation therapy. The primary endpoint was 3-year overall survival (OS) in the intention-to-treat population. The secondary endpoints were progression-free survival (PFS) and treatment-related adverse events. ResultsA total of 146 patients were enrolled from July 27, 2018 to November 1, 2021. The median follow-up was 46 months. The 3-year OS rates in the Hypo-RT and the Con-RT groups were 58.4% and 38.4%, respectively (P = 0.02). The median OS from randomization was 41 months in the Hypo-RT group and 30 months in the Con-RT group (hazard ratio, 0.61; 95% confidence interval, 0.40–0.94; P = 0.02). There was no significant difference in the rates of grade ≥2 treatment-related adverse events between the two groups. ConclusionsModerately Hypo-RT using helical TomoTherapy may improve OS in patients with unresectable stage III NSCLC while maintaining toxicity rates. TRIAL REGISTRATION Chinese Clinical Trial RegistryChiCTR1800017367

Daily AI-Based Treatment Adaptation under Weekly Offline MR Guidance in Chemoradiotherapy for Cervical Cancer 1: The AIM-C1 Trial.

(1) Background: External beam radiotherapy (EBRT) and concurrent chemotherapy, followed by brachytherapy (BT), offer a standard of care for patients with locally advanced cervical carcinoma. Conventionally, large safety margins are required to compensate for organ movement, potentially increasing toxicity. Lately, daily high-quality cone beam CT (CBCT)-guided adaptive radiotherapy, aided by artificial intelligence (AI), became clinically available. Thus, online treatment plans can be adapted to the current position of the tumor and the adjacent organs at risk (OAR), while the patient is lying on the treatment couch. We sought to evaluate the potential of this new technology, including a weekly shuttle-based 3T-MRI scan in various treatment positions for tumor evaluation and for decreasing treatment-related side effects. (2) Methods: This is a prospective one-armed phase-II trial consisting of 40 patients with cervical carcinoma (FIGO IB-IIIC1) with an age ≥ 18 years and a Karnofsky performance score ≥ 70%. EBRT (45-50.4 Gy in 25-28 fractions with 55.0-58.8 Gy simultaneous integrated boosts to lymph node metastases) will be accompanied by weekly shuttle-based MRIs. Concurrent platinum-based chemotherapy will be given, followed by 28 Gy of BT (four fractions). The primary endpoint will be the occurrence of overall early bowel and bladder toxicity CTCAE grade 2 or higher (CTCAE v5.0). Secondary outcomes include clinical feasibility, quality of life, and imaging-based response assessment.

Radiation-Induced Sensorineural Hearing Loss and Potential Management

The cochlear apparatus is one of the major organs at risk when considering radiation therapy (RT) for brain, head, and neck tumors. Radiation oncologists currently consider mean dose constraints of <35 Gy for conventionally fractioned radiation therapy (RT), <4 Gy for single fraction stereotactic radiosurgery, and <17.1 or 25 Gy for 3- or 5-fraction stereotactic radiosurgery, respectively, as the standard of care. Indeed, dose adjustments are made in the setting of concurrent platinum-based chemotherapy or when prioritizing tumor coverage during treatment planning. Despite guidelines, in many patients, RT to the cochlea may still cause sensorineural hearing loss through progressive degeneration and ossification of the inner ear. There are several audiologic and otolaryngologic interventions for incident RT-induced hearing loss, including hearing aids, cochlear implants, or, in the context of vestibular schwannoma due to neurofibromatosis type 2, auditory brain stem implantation. Cochlear implants are the most effective at restoring hearing and improving quality of life for those with an intact cochlear nerve. An early multidisciplinary approach is essential to optimally manage RT-induced hearing loss, and this topic discussion serves as a guide for radiation oncologists on cochlear dosimetric considerations as well as how to address potential RT-induced adverse effects.

Expression of 3q Oncogene SEC62 Predicts Survival in Head and Neck Squamous Cell Carcinoma Patients Treated with Primary Chemoradiation.

Primary chemoradiotherapy (CRT) is an established treatment option for locally advanced head and neck squamous cell carcinomas (HNSCC) usually combining intensity modified radiotherapy with concurrent platinum-based chemotherapy. Though the majority of patients can be cured with this regimen, treatment response is highly heterogeneous and can hardly be predicted. SEC62 represents a metastasis stimulating oncogene that is frequently overexpressed in various cancer entities and is associated with poor outcome. Its role in HNSCC patients undergoing CRT has not been investigated so far. A total of 127 HNSCC patients treated with primary CRT were included in this study. The median follow-up was 5.4 years. Pretherapeutic tissue samples of the primary tumors were used for immunohistochemistry targeting SEC62. SEC62 expression, clinical and histopathological parameters, as well as patient outcome, were correlated in univariate and multivariate survival analyses. High SEC62 expression correlated with a significantly shorter overall survival (p = 0.015) and advanced lymph node metastases (p = 0.024). Further significant predictors of poor overall and progression-free survival included response to therapy (RECIST1.1), nodal status, distant metastases, tobacco consumption, recurrence of disease, and UICC stage. In a multivariate Cox hazard proportional regression analysis, only SEC62 expression (p = 0.046) and response to therapy (p < 0.0001) maintained statistical significance as independent predictors of the patients' overall survival. This study identified SEC62 as an independent prognostic biomarker in HNSCC patients treated with primary CRT. The role of SEC62 as a potential therapeutic target and its interaction with radiation-induced molecular alterations in head and neck cancer cells should further be investigated.

Thoracic Radiation Dose Fractionation Schedules for Limited-Stage Small Cell Lung Cancer: A Systematic Review and Network Meta-Analysis of Randomized Trials

The Intergroup randomized controlled trial (RCT) established 45 Gy in 30 fractions (F) twice-daily (BID) as the standard thoracic radiation therapy (TRT) regimen with concurrent platinum-based chemotherapy (PBC) for limited-stage small cell lung cancer (LS-SCLC) in 1999. Since then, several RCTs were conducted to investigate novel TRT dose fractionation schedules (DoFS). However, it is unclear which is the optimal DoFS. This study aimed to compare the efficacy and safety of various DoFS of TRT in LS-SCLC using 45 Gy in 30F BID as the reference comparator. We searched biomedical databases for eligible RCTs comparing at least two DoFS of TRT in LS-SCLC. The outcomes of interest were progression-free survival (PFS), overall survival (OS), treatment-related death, grade 3-5 pneumonitis and esophagitis. We employed GRADE approach to appraise the certainty of the evidence. Meta-analyses were performed using fixed effects frequentist network model. The ESMO-Magnitude of Clinical Benefit Score (MCBS) version 1.1 was used to judge the value of the novel DoFS. This study was registered with PROSPERO (CRD42022336338). We identified six RCTs including 2,111 patients and six DoFS (45 Gy in 25F once-daily (OD), 42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) that were compared with 45 Gy in 30F BID. There was high certainty evidence showing that 65 Gy in 26F OD (hazard ratio (HR), 0.67; 95% confidence interval (CI), 0.46-0.96) significantly improved PFS and 60 Gy in 40F BID (HR, 0.61; 95% CI, 0.41-0.91) significantly improved OS, compared to 45 Gy in 30F BID. There were no significant differences among the DoFS (42 Gy in 15F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for PFS and OS. Both 65 Gy in 26F OD and 60 Gy in 40F BID were scored GRADE A on the ESMO-MCBS. The odds of grade 3-5 pneumonitis may be lower with 65 Gy in 26F OD (odds ratio (OR), 0.71; 95% CI, 0.12-4.32; low certainty) and higher with 60 Gy in 40F BID (OR, 6.60; 95% CI, 0.34-129.66); very low certainty). There were no significant differences among the DoFs (42 Gy in 15F OD, 66 Gy in 33F OD, 60 Gy in 40F BID, 65 Gy in 26F OD and 70 Gy in 35F OD) for treatment-related deaths or grade 3-5 esophagitis. There was no evidence to suggest that there were significant differences among the newer DoFS for PFS and OS with 45 Gy in 30F BID as the reference. Both 65 Gy in 26F OD and 60 Gy in 40F BID were judged to provide clinically meaningful benefit based on ESMO-MCBS. Treatment with 65 Gy in 26F OD may be an option if once-daily treatment is preferred. Treatment with 60 Gy in 40F BD may be considered for select patients with excellent performance status.

Circulating Growth Differentiation Factor 15 as a Biomarker in Patients with Unresected Locally Advanced Non-Small Cell Lung Cancer Treated with Chemo-Radiotherapy with or without Metformin

Growth differentiation factor 15 (GDF15) is a member of the TGFβ family suggested to have prognostic value in cancer. Plasma GDF15 levels are elevated in humans during cellular stress, chronic diseases, and cancer and in response to cytotoxic (chemotherapy and radiation) or metabolic (metformin) therapies. Currently, the effect of combined metformin and cytotoxic treatment on circulating GDF15 is not known, and it is unclear whether GDF15 can serve as a biomarker in patients receiving such therapy. To examine this question, we analyzed circulating GDF15 levels in stage IIIA or IIIB NSCLC patients that participated in the randomized phase II clinical trial OCOG-ALMERA (NCT02115464). In OCOG-ALMERA patients were randomized to treatment with concurrent platinum-based chemotherapy and chest radiotherapy (60-66 Gy), with or without consolidation chemotherapy (CRT) or the same treatment plus metformin (2000mg/d). Dosimetric parameters and survival outcomes were collected by the trial. EDTA Plasma was collected from patients at baseline, 2 weeks into CRT treatment, at completion of CRT and 6 months after treatment initiation and assayed for GDF15 using an ELISA method. Statistical analyses were conducted to explore potential associations between plasma GDF15 with survival and dosimetric parameters. Fifteen patients from the metformin arm and 18 from the control arms provided EDTA plasma for this analysis. Average baseline GDF15 levels for all participants were elevated compared to those reported for healthy individuals. Baseline plasma GDF15 was statistically prognostic for RFS and OS (hazard ratio = 1.19, 95% CI = 1.06 to 1.34, p = 0.005). GDF15 levels increased during CRT treatment reaching the highest value at the end of cytotoxic therapy. Addition of metformin to CRT treatment was associated with further increase in circulating GDF15 (p<0.001). Plasma GDF15 levels at 2 weeks of CRT were positively correlated with size of the radiotherapy clinical target volume and volumes of esophagus and heart receiving high dose radiotherapy. This work suggests that GDF15 may be a promising prognostic marker to predict response to standard chemoradiation therapy in NSCLC. Future studies should aim to validate these results in larger datasets and examine whether GDF15 may have value as early biomarker of radiation toxicity in lung cancer patients.

Predictive Value of Dynamic Tumor Volume Changes in Stage III Non-Small Cell Lung Cancer Treated with Chemoradiation and Consolidative Immunotherapy

Concurrent chemoradiation (CRT) followed by Immunotherapy is standard of care in unresectable, locally advanced, non-small cell lung cancer (NSCLC). We hypothesize that on-treatment dynamic changes in tumor volume may predict oncologic outcome in Stage III NSCLC. Stage III NSCLC patients who were treated with definitive CRT of 60 Gy in 30 fractions over 6 weeks with concurrent platinum-based concurrent chemotherapy followed by consolidative immunotherapy were retrospectively reviewed. We manually delineated the gross tumor volumes (GTV) of patients on cone beam computed tomography (CBCT) acquired on day 1, 15, 29 and 43. GTV reduction was quantified as the percent difference in volume on each CBCT as compared to CBCT Day 1. Mid-treatment response (MTR) and End of treatment response (ETR) was defined at day 29 (at 40 Gy) and day 43 (at 60 Gy), respectively. Loco-regional control (LRC) and overall survival (OS) was evaluated by Kaplan-Meier analysis, with log-rank test for groups stratified as per treatment response. Multivariate Cox regression analysis was performed to identify additional prognostic factors. We evaluated 24 consecutively treated patients from 01/2016 to 08/2019, with a median follow-up of 30.5 months. Median age was 69 years (range 51-84). Adenocarcinoma histology was present in 58 % and squamous cell carcinoma in 42% patients. The tumor stage IIIA in 38% and Stage IIIB in 62% patients. All patients received definitive CRT with at least 2 cycles of immunotherapy (median 8 cycles). The median ETR at CBCT43 was 49.5% (range, 1%-84.7%). 1-year cumulative incidence of loco-regional failure (LRF) was 27% versus 10% in patients with ETR <49.5% as compared to patients with greater ETR (p = 0.31). The median MTR at CBCT29 was 32.7% (range, 1%-81%). 1-year cumulative incidence of LRF was 28% versus 9% in patients MTR <32.7% as compared to patients with higher response (p = 0.03). The 3-year actuarial LRC of all patients was 51% which was significantly better in higher MTR (70% vs 30%; p = 0.02, log-rank) as compared to lower MTR. The 3-year actuarial OS for all patients was 45% which was 54% in patients with higher MTR verses 37% in low responders (p = 0.09). On multivariate analysis, age and T-stage were significant factors associated with LRC. Histologic subtype showed no impact on our findings. Stage III NSCLC patients with approximately one-third (33%) reduction of GTV on mid-treatment CBCT during CRT have significantly improved LRC and a trend towards improved OS. This approach may justify early adaptive intensification of RT or application of additional therapies in patients with non-optimal response. Additional large prospective study of CBCT is needed to determine whether treatment can be tailored based on tumor response, to improve outcomes.

Impact of hemoglobin on survival of young women with cervical cancer treated with concurrent chemoradiotherapy.

e17529 Background: Cervical cancer is a global public health problem, with higher impact in many low-income and middle income countries. In Peru, cervical cancer is the leading cause of cancer deaths among women. The aim of this study is to investigate the prognostic factors affecting long-term survival in locally advanced cervical cancer young patients treated with concurrent chemoradiotherapy. Methods: This is a retrospective study of young women with locally advanced cervical cancer who underwent radiotherapy with concurrent platinum-based chemotherapy at the national cancer peruvian institute (INEN), from 2008 to 2012. The clinicopathological factors of all patients were collected. To explore the relationship between factors and prognosis, survival rates were estimated by the Kaplan–Meier method. Results: A total of 192 patients under 35 years old . Among all patients, 167 were diagnosed with SCC, 19 with AC, and 5 with ASC. Most of the patients were IIB and IIIB FIGO stage, 69% and 22% respectively. 38 cases had no metastatic lymph nodes and 42 cases were diagnosed of lymph node metastases, of which 30 were positive for pelvic lymph nodes only, and 12 were positive for para-aortic lymph nodes. We obtained pretreatment hemoglobin levels for all patients and found a median of 111 g/L, also we calculated the Prognostic nutritional index (PNI) with a median of 41.87 that correlates with a moderate to severe malnutrition in patients prior treatment. Response to chemoradiotherapy was not available in 13 patients, 136 achieved complete response, 30 patients with persistent disease and 12 with disease progression. Estimated median OS of all patients was 114.1 months [101.8-126.4] and median DFS was 112.3 months [98.9-125.7]. Exploratory analysis was performed to determine potential prognostic factors, only hemoglobin ≤ 100 g/L was statistically significant (p = 0.007). Conclusions: In young patients undergoing chemoradiation for cervical carcinoma, the hemoglobin prior treatment is prognostically significant.

Definitive High-Dose Radiotherapy for Primary Vulvar Cancer: The DRIVE Multicenter Cohort Study

<h3>Purpose/Objective(s)</h3> There is limited published data on definitive chemoradiation therapy for vulvar cancer. A retrospective multi-institutional cohort study was conducted to determine the efficacy, patterns of failure and long-term toxicity of high-dose radiation therapy (RT) for the primary treatment of vulvar carcinoma. <h3>Materials/Methods</h3> DRIVE (definitive radiation therapy for primary vulvar cancer) is a multicenter cohort study evaluating outcome for definitive high-dose conformal RT (dRT) for first line treatment of vulvar cancer. Treatment compliance, toxicity and patterns of failure were investigated. Actuarial locoregional control (LRC) and survival (OS) were estimated using Kaplan-Meier method and compared using log rank test. Herein, we present our preliminary results. <h3>Results</h3> In total, 48 patients [median (interquartile range) age, 57 (46-67) years] who received dRT between 2010 and 2020 were analyzed. Median follow-up was 28 (2–113) months. Cohort included 15 (31%) with stage I-II, and 33 (69%) patients with stage III-IV disease. Inguinal nodes alone were involved in 13 patients (27%); 19 (40%) had inguinal and/or pelvic node metastases. Elective surgical staging of groins was performed in 16 (33%) patients, of whom 7 had involved nodes. Intensity-modulated RT (IMRT) was used in 45 (94%) patients, and 3 (6%) received 3D-conformal RT. Median tumor dose was 64Gy (52-74.8Gy). Concurrent platinum-based chemotherapy was administered in 40 (83%) patients (1-8 cycles). Clinical complete response (CR) was achieved in 81.3% (39/48) patients at the primary site, and 84% (27/32) at involved nodes. Eight (16.7%) patients had persistent/recurrent disease following treatment, all within treatment volume; 5 (10%) patients developed distant metastasis. Actuarial 2 and 5-year LRC was 77.7% and 73%, respectively. Two and 5-year overall survival were 71% and 55%, respectively. On univariate analysis, determinants of inferior LRC were stage III/IV (p=0.04), non-IMRT technique (p=0.05) and <2 cycles of chemo (p=0.03). Treatment compliance included 90% (43 patients) completing planned treatment, 11/48 (23%) hospitalization, 6/48 (12.5%) blood transfusion, 12/48 (25%) with >5 days interruptions and median weight loss of 2.6Kg during RT. Of 40 evaluable patients, 25 (63%) developed significant vaginal stenosis. Vulvar necrosis was observed in 5 (10%) patients, all received ≥64Gy [2 treated with hyperbaric oxygen, 1 had musculocutaneous flap-reconstruction]. No acute/chronic grade 3 GI or GU toxicity, or any grade 5 toxicities were seen. <h3>Conclusion</h3> Definitive high-dose RT for vulvar cancer achieves high rates of local control, good compliance with acceptable dose dependent long-term toxicity. Use of IMRT does not result in increased geographic miss and was associated with improved locoregional control over existing prospective data from GOG 205 study.

Simultaneous or Sequential Boost to Clinically Involved Lymph Nodes in Cervical Cancer

<h3>Purpose/Objective(s)</h3> The optimal approach to metastatic lymph nodes (LNs) in locally advanced cervical cancer (LACC) is controversial. This study aimed to evaluate the efficacy and toxicity profile of dose escalation with simultaneous integrated (SIB) or sequential boost (SB) for clinically positive LNs in LACC. <h3>Materials/Methods</h3> The data of 43 patients who underwent chemoradiotherapy (CRT) with a SIB or SB dose to positive LNs between 2015 and 2021 for LACC were retrospectively analyzed. All patients were applied 50.4 Gy intensity-modulated radiotherapy (IMRT) or modulated volumetric arc therapy (VMAT) to the lymphatic and primary regions in 28 fractions with concurrent platinum-based chemotherapy followed by 28 Gy HDR intracavitary brachytherapy (BRT) in four fractions. Response evaluations were performed via magnetic resonance imaging (MRI) and positron emission tomography (PET)-CT on the third month. <h3>Results</h3> Median age was 53 years (range: 34-80 years). The FIGO stage was IIIC1 in 30 (70%), IIIC2 in 10 (23%), and IVA in three patients (7%), respectively. Pelvic CRT was applied to 25 patients (58%), and pelvic-paraaortic CRT was applied to 18 patients (41%). A total of 94 LNs were boosted. The median longest diameter of the LNs was 1.7 cm (range: 1–7 cm) and median volume was 2.5 cc (range: 0.6-21.5 cc). A SIB was applied in 24 (56%), SB in 13 (30%), and both in 6 patients (14%), respectively. Patients in the SIB group received a total dose of 56-64 Gy in 28 fractions. The patients with SB on the other hand received 56.4-60.4 Gy in 31-33 fractions and patients with SIB+SB received 60-66 Gy in 30-32 fractions. The dose from the BRT was also calculated to the LNs and the minimum dose to LNs from BRT was between 0-7.6 Gy (median 3.6 Gy). The maximum dose from BRT was as 0-9.7 Gy (median 4.8 Gy). Median follow-up (FU) was 21 months (range: 3-77 months). Following CRT, 41 (98%) patients had a complete response (CR) and one (2%) had a partial response (PR) in boosted LNs on MRI whereas 39 (98%) patients had a CR and one (2%) had a PR on PET/CT. Recurrence occurred in 12 patients during FU: one local recurrence (LR), two regional recurrence out of the RT field, seven distant metastases (DM), and two LR+DM. There was no recurrence in any of the 94 boosted LNs and the local control (LC) rate was 100%. The 1- and 2-year rate of overall survival was 89.5% and 82.3%, disease-free survival was 80% and 65.8%, locoregional recurrence-free survival was 84.6% and 70.5%, and DM-free survival rate was 80.4% and 69.9%, respectively. Treatment was well tolerated without any serious acute toxicity. Grade 3 late toxicity was observed in two patients (1-rectovaginal fistula, 1-ureteral stenosis). <h3>Conclusion</h3> Dose escalation with IMRT/VMAT yields an excellent LC rate for the involved LNs, even for very large ones, in LACC with a low toxicity profile. Routine LN dissection may not be necessary for patients with a LACC, but prospective randomized trials are needed to clarify this.

Surgical Resection and Intensity Modulated Proton Therapy for Esthesioneuroblastoma

<h3>Purpose/Objective(s)</h3> Esthesioneuroblastoma (ENB) is a rare locally aggressive neuroendocrine sinonasal malignancy commonly presenting with skull base and intracranial invasion, which is often managed using multimodality therapy with surgery and radiotherapy (RT). Advances in surgical techniques as well as RT have improved outcomes for these complex tumors. Proton therapy has dosimetric advantages over conventional X-ray based approaches and may further improve the therapeutic ratio. We report our early experience with intensity modulated proton therapy (IMPT) in the management of ENB. <h3>Materials/Methods</h3> We retrospectively reviewed treatment records of patients with ENB treated at our center with IMPT from 2015-2021. IMPT was delivered with a 2 to 5 field pencil-beam scanning plan, initially with single-field optimization, then multi-field optimization after 2018. All pathology was internally reviewed. Event outcomes were calculated from date of biopsy to time of locoregional recurrence or death. Survival statistics were calculated using the Kaplan-Meier (KM) method using a scientific 2-D graphing and statistics software. <h3>Results</h3> 15 patients were identified, median age 52 (range 32-78), gender (male 12, female 3), Kadish stage (B – 2; C – 12; D – 1), AJCC T classification (T3 – 3, T4b – 12), 2 had nodal metastasis at diagnosis, Hyams (grade 2 – 10; grade 3-4 – 5). Local disease extent included: anterior cranial fossa – 11, middle cranial fossa – 2, dura – 12, brain parenchyma 1, nasopharynx – 2, orbit – 6. The majority (n=14) were managed with surgical resection followed by postoperative RT, and one underwent primary chemoradiation. Surgery included bifrontal craniotomy + extended endoscopic resection (n=7) and extended endoscopic resection alone (n=7). IMPT was delivered in conventional fractionation (n=12) or hyperfractionated accelerated course (n=3), median dose 68 CGE (range 60-72), neck coverage (n=11). Four received concurrent platinum-based chemotherapy. At median follow up of 20 months (IQR 16-51), 2 patients have died, unrelated to disease progression. Three patients have recurred including 1 local, 1 regional, and 1 distant metastasis (out of field dural metastases). Both patients with locoregional recurrence have undergone surgical salvage and have no evidence of disease. IMPT was well tolerated with expected acute toxicities. One patient developed frontal lobe brain necrosis at 3 years post-treatment managed conservatively, and one underwent functional sinus surgery for sinus obstruction. No de novo high grade visual toxicity was observed. KM 2-year locoregional recurrence-free survival was 83% and OS 88%. <h3>Conclusion</h3> IMPT is feasible in ENB with early outcomes demonstrating excellent local control and favorable toxicity profile in this cohort of patients with very locally advanced disease. IMPT may allow for improved coverage of tumor volumes in close proximity to numerous critical structures. Additional follow up is needed to track long term disease control outcomes and late toxicities.

EP08.01-110 Trial in Progress: A Phase 2 Multicenter Study (IOV-LUN-202) of Autologous Tumor-infiltrating Lymphocyte (TIL) Cell Therapy (LN-145) in mNSCLC

Patients with mNSCLC without actionable driver mutations have limited treatment options after progression on concurrent or sequential front-line immune checkpoint inhibitors (ICI) and platinum-based chemotherapy ± bevacizumab. LN-145, an autologous TIL cell therapy, has demonstrated feasibility, safety, and an early signal of efficacy with a 21.4% objective response rate (ORR) in heavily pretreated patients with mNSCLC, including responders with PD-L1-negative tumors (Schoenfeld AJ, SITC 2021 [abs 458]).

Outcomes and prognostic factors in patients with locally advanced cervical cancer treated with concurrent chemoradiotherapy

BackgroundTo investigate the prognostic factors affecting long-term survival in locally advanced cervical cancer (LACC) patients treated with concurrent chemoradiotherapy (CCRT).MethodsWe retrospectively analyzed 192 naive LACC (stage IIB–IVA) patients who underwent intensity-modulated radiotherapy (IMRT) with concurrent platinum-based chemotherapy in Xiangya Hospital from January 2014 to June 2017. The clinicopathological factors of all patients were collected. To explore the relationship between factors and prognosis, survival rates were estimated by the Kaplan–Meier method. Univariate and multivariate Cox proportional hazards models were used to evaluate the effect of various factors on overall survival (OS) and progression-free survival (PFS). The nomogram and calibration curves were generated on the basis of survival analysis.ResultsThe median follow-up time was 39.5 months. There-year rates of OS and PFS were 89.1% and 82.8%. LACC patients with non-squamous cell carcinoma [NSCC, including adenocarcinoma or adenosquamous carcinoma (AC/ASC)], advanced stage (IIIA-IVA), initially positive lymph node (pelvic or para-aortic lymph node, PLN/PALN), and a lower pretreatment hemoglobin (HGB) level (< 126 g/L) had lower survival rates. In univariate analysis, patients with NSCC, advanced stage, PLN or PALN metastasis had worse OS. Patients with NSCC, advanced stage, PLN or PALN metastasis, and a lower pretreatment HGB level had worse PFS. In multivariate analysis, NSCC and PALN metastasis were independent prognostic parameters of OS. NSCC, PALN metastasis and a lower pretreatment HGB level were independent prognostic parameters of PFS.ConclusionsNSCC and PALN metastasis were poor prognostic factors of OS and PFS, a lower pretreatment HGB level was an independent prognostic factor of PFS in LACC patients treated with CCRT.

Early-stage vocal cord cancer treated with hypofractionated radiotherapy to the larynx with or without concurrent chemotherapy.

We report outcomes among patients with T2 and select T3 glottic squamous cell carcinoma (SCC) treated with radiotherapy. We reviewed T2 and T3 (only paraglottic space invasion) N0 M0 glottic SCC patients treated with curative-intent hypofractionated larynx radiotherapy, with or without concurrent systemic therapy. Of 71 patients, those who received concurrent chemotherapy (23/71; 32%) had worse prognostic factors, including impaired cord mobility (70% vs. 40%, p=0.02) and larger median gross tumor volume (3.0 vs. 1.6cm3 , p=0.003). Over a median follow-up of 3.8 years, 2-year local controlamong patients with impaired cord mobility appeared higher for those who received chemotherapy (88% vs. 61%, p=0.12), but the difference was not statistically significant. Acute and late toxicity rates were not higher among patients who received chemotherapy. The addition of concurrent platinum-based chemotherapy to hypofractionated larynx radiotherapy among patients with early-stage glottic SCC with impaired cord mobility appears safe and worthy of additional investigation.

A phase Ⅱ prospective trial of photobiomodulation therapy in limiting oral mucositis in the treatment of locally advanced head and neck cancer patients.

This study aimed to compare the historical incidence rate of severe oral mucositis (OM) in head and neck cancer patients undergoing definitive concurrent chemoradiation therapy (CRT) versus a prospective cohort of patients with locally advanced head and neck squamous cell carcinoma (HNSCC) treated with prophylactic photobiomodulation therapy (PBMT). This US-based, institutional, single-arm, phase Ⅱ prospective clinical trial was initiated in 50 patients (age ≥ 18 years, Karnofsky Performance Scale Index > 60, with locally advanced HNSCC (excluding oral cavity) receiving definitive or adjuvant radiation therapy (RT) with concurrent platinum-based chemotherapy (CT). PBMT was delivered three times per week throughout RT utilizing both an intraoral as well extraoral delivery system. Primary outcome measure was incidence of severe OM utilizing both the National Cancer Institute Common Toxicity Criteria, version 4.0 (NCI-CTCAE) Grade ≥3 and the World Health Organization Mucositis Grading Scale (WHO) Grade ≥3 versus historical controls; secondary outcome measures included time to onset of severe OM following therapy initiation. At baseline, all patients included in final analysis (N = 47) had OM Grade 0. Average RT and CT dose was (66.3 ± 5.1) Gy and (486.1 ± 106.8) mg/m2, respectively. Severe OM was observed in 11 of 47 patients (23%, confidence interval: 12, 38). OM toxicity grade trended upward during treatment, reaching a maximum at 7 weeks (WHO: 1.8 vs. NCI-CTCAE: 1.7). Subsequently, OM grade returned to baseline 3 months following completion of RT.The mean time toonset of severe OM was (35 ± 12) days. The mean time to resolution of severe OM was (37 ± 37) days. Compared to historical outcomes, PBMT aides in decreasing severe OM in patients with locally advanced HNSCC. PBMT represents a minimally invasive, prophylactic intervention to decrease OM as a major treatment-related side effect.

Abstract CT130: Trial in progress: A phase 2 multicenter study (IOV-LUN-202) of autologous tumor-infiltrating lymphocyte (TIL) cell therapy (LN-145) in patients with metastatic non-small cell lung cancer (mNSCLC)

Abstract Background: Patients with mNSCLC without actionable driver mutations have limited second-line (2L) options after progression on concurrent or sequential front-line immune checkpoint inhibitors (ICI) and platinum-based chemotherapy ± bevacizumab. Early clinical experience with LN-145, an autologous TIL cell therapy, in heavily pretreated patients with mNSCLC has demonstrated feasibility, safety, and a 21.4% objective response rate (ORR), including 2 of 6 responders with PD-L1-negative tumors (Schoenfeld AJ, SITC 2021 [abs 458]). Based on the results of this signal-finding study and to address an unmet medical need in 2L, we amended the ongoing IOV-LUN-202 study, evaluating LN-145 in patients with stage IV mNSCLC after confirmed disease progression on front-line standard-of-care treatment, including concurrent or sequential ICI + chemotherapy ± bevacizumab. Methods: IOV-LUN-202 (NCT04614103) is an open-label, nonrandomized, phase 2 study. Cohorts 1 (tumor proportion score [TPS] &amp;lt;1% prior to ICI use or no historical TPS) and 2 (TPS ≥1% prior to ICI use) are actively enrolling patients. Cohort 3 (any TPS) uses core biopsies for tumor procurement and a 16-day Gen 3 manufacturing process for patients unable to undergo surgical resection. A retreatment cohort (n not prespecified) will enroll prior responders to LN-145 or patients with unconfirmed progressive disease from cohorts 1-3. A total of approximately 95 patients is planned for cohorts 1-3. Key eligibility criteria include mNSCLC with no EGFR, ALK, or ROS1 genomic alterations, progressing after ≤2 prior lines of therapy (if concurrent ICI + chemotherapy; ≤3 prior lines if sequential), including targeted therapy in those with actionable mutations (eg, MET, HER2, RET, BRAF, KRAS); in those without actionable mutations, progression after 1 prior concurrent ICI + chemotherapy (≤2 prior lines if sequential); ≥1.5-cm lesion(s) for TIL generation; ≥1 remaining RECIST-measurable lesion(s) after tumor harvest; and ECOG PS of 0 or 1. Tumor harvest and TIL manufacturing can occur before or after confirmed progression. LN-145 is generated at centralized GMP facilities, and the final cryopreserved infusion product is shipped to the sites. Upon progression, patients receive a conditioning regimen of nonmyeloablative lymphodepletion with 2 doses of cyclophosphamide (60 mg/kg) and 5 doses of fludarabine (25 mg/m2), followed by one-time infusion of LN-145 (1-150 × 109 cells), and ≤6 doses of IL-2 (600,000 IU/kg). The primary endpoint is ORR per RECIST v1.1. Secondary endpoints include complete response rate, duration of response, disease control rate, progression-free survival, overall survival, and safety (incidence of Grade ≥3 treatment-emergent adverse events [AEs] and serious AEs). Citation Format: Jason Alan Chesney, Adam J. Schoenfeld, Trisha Wise-Draper, Ammar Sukari, Kai He, Friedrich Graf Finckenstein, Parameswaran Hari, Madan Jagasia, Selda Samakoglu, Ann Leighton-Swayze, Guang Chen, Yong Ki Hong. Trial in progress: A phase 2 multicenter study (IOV-LUN-202) of autologous tumor-infiltrating lymphocyte (TIL) cell therapy (LN-145) in patients with metastatic non-small cell lung cancer (mNSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr CT130.

Pattern of failure in inoperable stage III non-small cell lung cancer patients treated with chemoradiotherapy with/without immune checkpoint inhibition.

e20570 Background: We compared pattern of failure in patients treated with chemoradiotherapy (CRT) with concurrent and/or sequential Programmed Cell Death 1 (PD-1) or Ligand 1 (PD-L1) immune checkpoint inhibition (IO, immuno-oncology therapy) and CRT alone for inoperable stage III NSCLC. Methods: Prospective data of thirty nine consecutive patients who completed CRT-IO with sequential durvalumab (72%, 28 patients) or concurrent and sequential nivolumab (28%, 11 patients) and a sensitive propensity score matched (PSM adjusted for patients age, gender, T- and N-status, PTV, histology) cohort of 39 patients treated with CRT alone were analyzed. First site of failure was compared between the CRT-IO and the CRT alone subgroup. Results: All patients were treated with conventionally fractionated thoracic irradiation to a total dose of at least 60Gy (range: 60-66Gy), all patients received either sequential or simultaneous chemotherapy while 95% (74 patients; CRT-IO: 38/39; CRT alone: 36/39) received two cycles of concurrent platinum-based chemotherapy. Median follow-up for the entire cohort was 33.3 (range: 1.5-102.9) months; median overall survival (OS) was 34.9 (95%CI: 10.7-59.1) months (CRT-IO: not reached; CRT alone: 24.4, p = 0.003); median progression-free survival (PFS) was 13.6 (95% CI: 10.5-6.7) months (CRT-IO: 26.3; CRT alone: 8.3; p &lt; 0.001). At the time of evaluation 21 (53.8%) vs. 7 (17.9%) patients of the CRT-IO vs. CRT alone subgroup were progression free and alive (p = 0.003); 4 (10.3%) vs. 3 (7.7%) had brain metastases as first site of failure; 7 (17.9%) vs. 6 (15.4%) had ≤ 3 extracranial metastasis and 3 (7.7%) vs. 4 (10.3%) had multi-organ progression. Local-regional recurrence (LRR) as first site of failure was significantly less frequent in patients treated with CRT-IO vs. CRT alone, namely 3 (7.7%) vs. 12 (30.8%) patients (p = 0.001); median time to LRR was not reached vs. 15.0 (95%CI: 0.9-33.7) months. Conclusions: Pattern of failure differ significantly in patients treated with CRT-IO vs. CRT alone; CRT-IO patients are significantly less likely to develop a LRR. No differences in the prevalence of brain metastases as first site of failure could be detected.

Have We Made Progress in Early Stage Vocal Cord Cancer with Impaired Cord Mobility?

<h3>Purpose/Objective(s)</h3> The probability of cure after hypofractionated larynx radiotherapy (RT) decreases among patients with T2 glottic cancers with impaired cord mobility. The role of concurrent chemotherapy in this setting is unclear. We report outcomes of patients with T2 (and T3 based on paraglottic space invasion alone) N0 glottic squamous cell carcinoma (SCC) treated with curative-intent hypofractionated larynx RT with or without chemotherapy. <h3>Materials/Methods</h3> We retrospectively reviewed the medical records of all patients with AJCC 8^th edition stage T2-T3 N0 M0 SCC of the glottic larynx treated with curative intent at a single institution between 2000 and 2020. T3 patients were included if they were upstaged by paraglottic space invasion alone. All patients received hypofractionated RT (2.25 Gy/fraction) to the larynx to 63 - 65.25 Gy, with or without concurrent systemic therapy, and had at least 6 months of follow-up. Disease control and survival outcomes were calculated by the Kaplan-Meier method, and we used descriptive analysis to compare prognostic factors since more robust statistics were limited by sample size. <h3>Results</h3> The study population included 71 patients with a median follow-up time of 3.8 (range, 0.1 – 17.2) years. Major 2-year outcomes (95% CI) were as follows: local control, 74% (62% - 83%); regional control, 92% (83% - 97%); laryngectomy-free survival, 70% (58% - 80%); and overall survival, 82% (71% - 90%). Among the 23 patients who received systemic therapy (92% received weekly cisplatin or carboplatin), a greater proportion had impaired mobility (70% vs. 40%, p=0.02), larger median gross tumor volume (3.0 vs 1.6 cc, p=0.003), and subglottic extension (61% vs. 25%, p=0.008). Despite their worse prognostic factors, patients with impaired cord mobility who received chemotherapy experienced better local control and avoided total laryngectomy, without increased toxicity (see Table). One patient (4%) treated with chemotherapy required gastrostomy tube and tracheostomy during RT (both removed within 1 year). All but 6 late grade 3+ adverse events occurred after salvage laryngectomy for local recurrence. There were only 2 isolated regional relapses despite limited use of elective nodal RT (n=2). <h3>Conclusion</h3> The addition of concurrent platinum-based chemotherapy to hypofractionated larynx RT among patients with early-stage glottic SCC with impaired cord mobility appears safe, effective, and worthy of additional investigation.

Management of Nasopharyngeal Carcinoma in Elderly Patients

Nasopharyngeal cancer (NPC) is one of the most difficult cancers in the head and neck region due to the complex geometry of the tumour and the surrounding critical organs. High-dose radical radiotherapy with or without concurrent platinum-based chemotherapy is the primary treatment modality. Around 10%–15% of NPC patients have their diagnosis at age after 70. The management of NPC in elderly patients is particularly challenging as they encompass a broad range of patient phenotypes and are often prone to treatment-related toxicities. Chronologic age alone is insufficient to decide on the management plan. Comprehensive geriatric assessment with evaluation on patients’ functional status, mental condition, estimated life expectancy, comorbidities, risks and benefits of the treatment, patients’ preference, and family support is essential. In addition, little data from randomized controlled trials are available to guide treatment decisions in elderly patients with NPC. In deciding which treatment strategy would be suitable for an individual elderly patient, we reviewed the literature and reviewed the analysis of primary studies, reviews, and guidelines on management of NPC. This review also summarises the current evidence for NPC management in elderly adults from early to late stage of disease.