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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors.

ABSTRACT: In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. We find that ENI increases local, distant, and metastatic tumor growth. Multi-compartmental analysis of the primary/distant tumor, the DLNs, and the blood shows that ENI decreases the immune response systemically. Additionally, we find that ENI decreases antigen-specific T cells and epitope spreading. Treating the primary tumor with radiation and immunotherapy, however, fails to reduce regional recurrence, but this is reversed by either concurrent sentinel lymph node resection or irradiation. Our data support using lymphatic sparing radiation therapy for head and neck cancer.

SUBMITTER: Darragh LB

PROVIDER: S-EPMC9668826 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors.

Darragh Laurel B LB Gadwa Jacob J Pham Tiffany T TT Van Court Benjamin B Neupert Brooke B Olimpo Nicholas A NA Nguyen Khoa K Nguyen Diemmy D Knitz Michael W MW Hoen Maureen M Corbo Sophia S Joshi Molishree M Zhuang Yonghua Y Amann Maria M Wang Xiao-Jing XJ Dow Steven S Kedl Ross M RM Samedi Von V Boss Mary-Keara MK Karam Sana D SD

Nature communications 20221116 1

In the setting of conventional radiation therapy, even when combined with immunotherapy, head and neck cancer often recurs locally and regionally. Elective nodal irradiation (ENI) is commonly employed to decrease regional recurrence. Given our developing understanding that immune cells are radio-sensitive, and that T cell priming occurs in the draining lymph nodes (DLNs), we hypothesize that radiation therapy directed at the primary tumor only will increase the effectiveness of immunotherapies. ...[more]

PMID: 36385142

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Project description:BACKGROUND:The majority of patients with head and neck squamous cell carcinoma (HNSCC) receive bilateral elective nodal irradiation (ENI), in order to reduce the risk of regional failure. Bilateral ENI, as compared to unilateral ENI, is associated with higher incidence of acute and late radiation-induced toxicity with subsequent deterioration of quality of life. Increasing evidence that the incidence of contralateral regional failure (cRF) in lateralized HNSCC is very low (< 10%) suggests that it can be justified to treat selected patients unilaterally. This trial aims to minimize the proportion of patients that undergo bilateral ENI, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation. METHODS:In this one-armed, single-center prospective trial, patients with primary T1-4 N0-2b HNSCC of the oral cavity, oropharynx, larynx (except T1 glottic) or hypopharynx, not extending beyond the midline and planned for primary (chemo) radiotherapy, are eligible. After 99mTc-nanocolloid tracer injection in and around the tumor, lymphatic drainage is visualized using SPECT/CT. In case of contralateral lymph drainage, a contralateral sentinel node procedure is performed on the same day. Patients without contralateral lymph drainage, and patients with contralateral drainage but without pathologic involvement of any removed contralateral sentinel nodes, receive unilateral ENI. Only when tumor cells are found in a contralateral sentinel node the patient will be treated with bilateral ENI. The primary endpoint is cumulative incidence of cRF at 1 and 2 years after treatment. Secondary endpoints are radiation-related toxicity and quality of life. The removed lymph nodes will be studied to determine the prevalence of occult metastatic disease in contralateral sentinel nodes. DISCUSSION:This single-center prospective trial aims to reduce the incidence and duration of radiation-related toxicities and improve quality of life of HNSCC patients, by using lymph drainage mapping by SPECT/CT to select patients with a minimal risk of contralateral nodal failure for unilateral elective nodal irradiation. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT03968679, date of registration: May 30, 2019.

Project description:BackgroundOral cavity (OC), oropharyngeal (OP), hypopharyngeal (HP), and laryngeal (LA) squamous cell carcinoma (SCC) have a high incidence of regional lymph node metastasis (LNM). Elective irradiation for clinically node-negative neck is routinely administered to treat lymph nodes harboring occult metastasis. However, the optimal elective irradiation schemes are still inconclusive. In this study, we aimed to establish individualized elective irradiation schemes for the ipsilateral and contralateral node-negative neck of these four types of cancer.MethodsFrom July 2005 to December 2018, 793 patients with OC-SCC, 464 with OP-SCC, 413 with HP-SCC, and 645 with LA-SCC were recruited retrospectively. Based on the actual incidence of LNM and the tumor characteristics, risk factors for contralateral LNM, as well as node level coverage schemes for elective irradiation, were determined using logistic regression analysis. Additionally, we developed a publicly available online tool to facilitate the widespread clinical use of these schemes.ResultsFor the ipsilateral node-negative neck, elective irradiation at levels I-III for OC-SCC and levels II-IVa for OP-, HP- and LA-SCC are generally recommended. In addition, level VIIa should be included in patients with OP-SCC. Multivariate analyses revealed that posterior hypopharyngeal wall and post-cricoid region involvement were independently associated with level VIIa metastasis in HP-SCC (all P < 0.05). For the contralateral node-negative neck, multivariate analyses revealed that ipsilateral N2b2-N3, tumors with body midline involvement, and degree of tumor invasion were the independent factors for contralateral LNM (all P < 0.05). In patients who require contralateral neck irradiation, levels I-II are recommended for OC-SCC, and additional level III is recommended for patients with ipsilateral N3 disease. Levels II-III are recommended for OP-, HP-, and LA-SCC, and additional level IVa is recommended for patients with advanced T or ipsilateral N classifications. Furthermore, additional level VIIa is recommended only for OP-SCC with T4 and ipsilateral N3 disease.ConclusionBased on our findings, we suggest that individualized and computer-aided elective irradiation schemes could reduce irradiation volumes in OC-, OP- and HP-SCC patients, as compared to current guidelines, and could thus positively impact the patients' quality of life after radiotherapy.

Project description:BACKGROUND:To assess the comparative efficacy and safety of elective nodal irradiation (ENI) and involved-field irradiation (IFI) in patients with esophageal cancer (EC) receiving neoadjuvant chemoradiotherapy plus surgery (nCRTS). MATERIAL AND METHODS:PubMed, Embase, Cochrane Library, Web of Science and major meetings were searched for randomized controlled trials (RCTs) that compared at least two of the following treatment regimens: nCRTS, neoadjuvant chemotherapy plus surgery (nCTS), and surgery (S) alone. Overall survival (OS) was the primary outcomes of interest, reported as hazard ratio (HR) and 95% confidence intervals (CIs). A Bayesian network meta-analysis was performed to compare all regimens simultaneously. RESULTS:Twenty-nine RCTs with a total of 5212 patients were included in the meta-analysis. Both nCRTS adopting ENI (nCRTS-ENI) (HR = 0.63, 95% CI: 0.48-0.83) and nCRTS adopting IFI (nCRTS-IFI) (HR = 0.75, 95% CI: 0.66-0.86) significantly improved OS compared to S alone. No significant differences in OS, locoregional recurrence, distant metastases, R0 resection and postoperative mortality were observed between nCRTS-ENI and nCRTS-IFI. In subgroup analyses, nCRTS-IFI showed a significant OS advantage over nCTS (HR = 0.78, 95% CI: 0.63-0.96) and S alone (HR = 0.50, 95% CI: 0.38-0.68) for esophagus squamous cell carcinoma (ESCC), but nCRTS-ENI did not; nCRTS-ENI using three-dimensional radiotherapy (3D-RT) resulted in an improved OS compared to that with 2D-RT (HR = 0.58, 95% CI: 0.34-0.99). Based on treatment ranking in term of OS, nCRTS-IFI (0.90) and nCRTS-ENI (0.96) was ranked the most effective treatment for ESCC and esophagus adenocarcinoma (EAC), respectively. CONCLUSION:Either adopting ENI or IFI, nCRTS is likely to be the optimal treatment for resectable EC, and nCRTS-IFI and nCRTS-ENI seem to be more effective for patients with ESCC and EAC, respectively. Future head to head comparison trials are needed to confirm these findings.

Project description:BackgroundThe patterns of nodal relapse in submandibular gland carcinoma (SMGC) patients treated with postoperative radiotherapy (PORT) remain unclear. This study aims to investigate the nodal failure patterns and the utility of elective nodal irradiation (ENI) in SMGC patients undergoing PORT.MethodsWe retrospectively enrolled 65 SMGC patients who underwent PORT between 2000 and 2014. The nodal failure sites in relation to irradiation fields and pathological parameters were analyzed. ENI regions were categorized into three bilateral echelons (first, levels I-II; second, level III; and third, levels IV-V). Extended ENI was defined as coverage of at least the immediately adjacent uninvolved echelons bilaterally; otherwise, limited ENI was administered.ResultsThirty patients (46%) were stage III-IV, and 18 (28%) were pN+. Neck irradiation included limited (72%) and extended ENI (28%). With a median follow-up of 79 months, 11 patients (17%) developed nodal failures (ipsilateral, N = 6; contralateral, N = 7), 7 (64%) of whom relapsed in the adjacent uninvolved echelons. We identified pN+ (P = 0.030), extranodal extension (ENE, P = 0.002), pT3-4 (P = 0.021), and lymphovascular invasion (LVI, P = 0.004) as significant predictors of contralateral neck recurrence. Extended ENI significantly improved regional control (RC) in patients with pN+ (P = 0.003), ENE (P = 0.022), pT3-4 (P = 0.044), and LVI (P = 0.014), and improved disease-free survival (DFS) in patients with pN+ (P = 0.034). For patients with ≥2 coincident adverse factors, extended ENI significantly increased RC (P < 0.001), distant metastasis-free survival (P = 0.019), and DFS (P = 0.007); conversely, no nodal recurrence was observed in patients without these adverse factors, even when only the involved echelon was irradiated.ConclusionsNodal failure is not uncommon in SMGC patients treated with PORT if pN+, ENE, pT3-4, and LVI are present. Extended ENI should be considered, particularly in patients with multiple pathological adverse factors.

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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors.

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Elective nodal irradiation mitigates local and systemic immunity generated by combination radiation and immunotherapy in head and neck tumors.

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