Integrating systemic therapy into larynx preservation: Lessons from 3 decades of progress.

Systemic therapy with or without local intervention for oligometastatic oesophageal squamous cell carcinoma (ESO-Shanghai 13): an open-label, randomised, phase 2 trial

To evaluate the therapeutic effects, larynx preservation and adverse events of non-surgical combined treatments for laryngeal organ preservation in locally advanced laryngeal squamous cell carcinomas(SCCs). Forty-six patients with locally advanced laryngeal carcinoma (T2-4, N0-N3) were treated individually with non-surgical combined treatments for larynx preservation (LP). These treatments included concurrent chemoradiotherapy (CCRT)(±epidermal growth factor receptor (EGFR) inhibitor), induction chemotherapy (ICT) followed by CCRT(± EGFR inhibitor), or concurrent radiotherapy and EGFR inhibitor. Radiation therapy was given to a total dose of 60-70 Gy. The Kaplan-Meier method was used to determine the overall survival. Side-effects were evaluated with the established Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. The average follow-up time was 31.8 months (range 6-95 months). All patients completed the planned radiotherapy without treatment breaks, and 45(97.8%) of 46 patients completed the planned chemotherapy.The 3-year and 5-year overall survival rates were 87.3%and 67.2%, respectively.The 5-year larynx preservation rate was 100.0%. The 3-year and 5-year progression free survival rates were 95.1% and 87.7%, respectively. The most common acute side effect in grade 3 was oropharyngeal mucositis. After treatment, tracheotomy was still required in 2 patients with glottis cancer for laryngeal edema or stenosis. No patient depended on a percutaneous gastrostomy and experienced speech impairment. Patients with locally advanced laryngeal cancer can be offered non-surgical combined treatments for laryngeal preservation and the high quality of life, showing a higher laryngeal preservation survival rate with minimal toxicities.

Efficacy of non-surgical larynx-preservation comprehensive treatment in advanced laryngeal carcinoma.

Supracricoid partial laryngectomy (SCPL) is an essential technique in the armamentarium of modern laryngeal organ preservation surgery. OBJECTIVE, DESIGN, SETTING: Retrospective case series to review the oncologic outcomes following SCPL in a large US-based cohort treated by a single surgeon in a tertiary-care university hospital. A total of 96 consecutive patients with primary or recurrent squamous cell carcinoma of the larynx undergoing SCPL from 1992 to 2010. Supracricoid partial laryngectomy surgery. Five-year local control and laryngeal preservation, using the Kaplan-Meier method. There were 54 primary laryngeal carcinomas and 42 previously treated with radiation to the larynx; 23% were supraglottic or transglottic tumors (n = 22). The overall 5-year local control rate for the series was 94%. For T2 and T3 primary tumors, the 5-year local control was 100% and 96%, respectively. In patients previously treated with radiation, the 5-year local control was 89%, with an 89% laryngeal preservation rate. Among stage III or IV primary laryngeal tumors for which concurrent chemoradiation was a treatment alternative, the 5-year local and locoregional control was 96% and 83%, respectively, and the 5-year larynx preservation was 91%. Ultimate local control was achieved for all patients in the series. A significant postoperative complication occurred in 19% (n = 18) and 1 anesthesia-related perioperative death occurred. No total laryngectomies were performed for laryngeal dysfunction. This series demonstrates excellent local control for both primary and recurrent laryngeal cancers, with functional larynx preservation. In appropriately staged and selected patients with T2 or T3 primary laryngeal cancer or laryngeal cancer following prior radiation treatment, SCPL should be considered as a treatment alternative to non-surgical treatment or total laryngectomy.

To investigate the treatment outcome, laryngeal preservation and side-effect in locally advanced hypopharyngeal carcinoma treated with combined Hilical tomotherapy (HT) or intensity-modulated radiotherapy (IMRT) and chemotherapy and/or EGFR inhibitor (Cetuximab or Nimotuzumab). A total of 68 patients (20 cases with T1-2N1-3M0 and 48 cases with T3-4N1-3M0) with locally advanced hypopharyngeal cancer were treated individualy with non-surgical combined modality treatments including induction chemotherapy followed by concurrent chemoradiotherapy, induction chemotherapy followed by concurrent radiotherapy and EGFR inhibitor, concurrent chemoradiotherapy and EGFR inhibitor, and concurrent radiotherapy and EGFR inhibitor. HT was used in 40 patients and IMRT in 28 patients. Side-effects were evaluated with the established Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 criteria. The average follow-up time was 25.7 months (range 3-69 months). All patients completed the planned radiotherapy without treatment breaks, and 66 (97.0%) of 68 patients completed the planned chemotherapy. The 2-year and 3-year overall survival rates were 78.8% and 64.7% respectively, with an organ preservation rate of 84.2%. The most common side-effect greater than or equal to grade 3 was oropharyngeal mucositis. No patient dependent on a percutaneous gastrostomy and tracheostomy tube. Hypopharyngeal carcinoma can be treated with non-surgical combined modality treatment including HT or IMRT, with a high laryngeal organ preservation rate and minimal toxicities.

Objective: To evaluate the efficacy of systemic therapy on psychiatric disorders in adulthood. Methods: This meta-analysis integrates results of 37 randomized controlled trials (RCT) of therapy with an explicit systemic focus on adults with psychiatric disorders. Studies were identified through systematic searches in electronic databases and cross-referencing. Results: On average, systemic therapy had stronger short-term (g = .51) and long-term (g = .55) efficacies than control groups without alternative treatment and stronger short-term effects than alternative active treatments (g = .25). In addition, efficacy of systemic therapy was similar to those of other bona fide psychotherapies. Individuals receiving systemic therapy plus medication showed stronger improvements at posttest (g = .71) and follow-up (g = .87) than those receiving only medication. Illness-specific analyses showed positive short-term efficacy of systemic therapy on eating disorders, mood disorders, obsessive–compulsive disorders, schizophrenia, and somatoform disorders. At follow-up, efficacy of systemic therapy was only found on eating disorders, mood disorders, and schizophrenia. In addition, systemic therapy had lower dropout rates than alternative treatments. For certain comparisons, effect sizes were moderated by participant age, study quality, and year of publication. Conclusions: We conclude that the present meta-analysis found some evidence for the efficacy of systemic therapy on five disorders, but the number of available RCT is still limited. More research is needed on systemic therapy of other disorders, such as anxiety disorders and substance use disorders.

ObjectiveTo review the available evidence and make recommendations regarding use of systemically administered drugs in combination or in sequence with radiation (RT) and/or surgery for cure and/or organ preservation in patients with locally advanced nonmetastatic (Stage III to IVB) squamous cell carcinoma of the head and neck (LASCCHN).MethodRecognizing the Meta-analysis of Chemotherapy in Head and Neck Cancer (MACH-NC) group reports have de facto guided practice since 2000, we searched for systematic reviews in the MEDLINE, EMBASE and Cochrane Database of Systematic Reviews published from January 2000 to February 2015 in reference to 4 research questions. A search was also conducted for randomized trials (RCTs) up to February 2015 not included in the meta-analyses.ResultThe MACH-NC reports, 5 additional meta-analyses, and 30 RCTs not included by MACH-NC were identified. For chemotherapy, MACH-NC findings showing improved overall survival with concomitant chemoRT did not require modification. High-dose cisplatin was most commonly studied. We confirmed this benefit with cisplatin monotherapy in patients treated with with postoperative concurrent chemoRT. Other than cetuximab, no targeted agents and radiosensitizers studied in RCTs were shown effective. TPF induction chemotherapy was superior to PF for tumor response and larynx preservation but not survival. Larynx preservation was reported with both CRT and induction chemotherapy approaches.ConclusionChemoRT with cisplatin at least 40 mg/m2 per week given as radical or postoperative adjuvant remains a standard treatment approach for LASCCHN that improves overall survival but increases toxicity. 5-FU plus platinum is supported by less data but may be a reasonable alternative for patients unsuitable for cisplatin. Of note, stratification of outcomes by HPV-status was not available but outcomes for oropharynx cancer appeared similar to other subsites in chemoRT RCTs. No RCTs have yet demonstrated superiority or non-inferiority of cetuximab-RT to CRT. In view of this, cetuximab-RT is suggested only for patients not candidates for CRT. Taxane-based triplet induction chemotherapy is superior to doublets for rapid tumour downsizing and for larynx preservation, but does not improve overall survival and should be used with primary G-CSF prophylaxis. Further investigation of induction approaches for larynx preservation may be warranted.

Multidisciplinary Management of Laryngeal Carcinoma

The efficacy of systemic antineoplastic therapy on recurrent World Health Organization (WHO) grades II and III meningiomas is unclear. We performed a retrospective multicenter analysis of serial cranial MRI in patients with recurrent WHO II and III meningiomas treated with antineoplastic systemic therapies. Growth rates for tumor volume and diameter, as well as change rates for edema size, were calculated for all lesions. We identified a total of 34 patients (23 atypical, 11 anaplastic meningiomas) with a total of 57 meningioma lesions who had been treated at 6 European institutions. Systemic therapies included bevacizumab, cytotoxic chemotherapy, somatostatin analogues, and tyrosine kinase inhibitors. Overall, tumor growth rates decreased during systemic therapy by 51% for tumor diameter and 14% for tumor volume growth rates compared with the period before initiation of systemic therapy. The most pronounced decrease in meningioma growth rates during systemic therapy was evident in patients treated with bevacizumab, with a reduction of 80% in diameter and 59% in volume growth. Furthermore, a decrease in size of peritumoral edema after initiation of systemic therapy was exclusively observed in patients treated with bevacizumab (-107%). Our data indicate that systemic therapy may inhibit growth of recurrent WHO grades II and III meningiomas to some extent. In our small cohort, bevacizumab had the most pronounced inhibitory effect on tumor growth, as well as some anti-edematous activity. Prospective studies are needed to better define the role of medical therapies in this tumor type.

Background: The incidence of central nervous system (CNS) metastases in breast cancer is increasing. While local treatments such as surgery and radiation remain standard, systemic therapies have shown promise in HER2-positive disease. However, data on the efficacy of systemic therapy in HER2-low breast cancer with CNS involvement remain limited. This study describes outcomes of upfront systemic therapy in HER2-low breast cancer patients with CNS metastases treated at a single institution. Methods: We retrospectively reviewed breast cancer patients with CNS metastases treated at Henry Ford Health between Jan 2014 and July 2024. HER2-low status was defined as: HER2 immunohistochemistry 1+, or 2+ with negative fluorescent in situ hybridization (FISH). Eligible patients received no concurrent local CNS therapy; prior local treatment was permitted if unrelated to the studied lesions. CNS responses were to be assessed using the Response Assessment in Neuro-Oncology for brain metastases (RANO-BM) or the modified RANO-LM (leptomeningeal metastases) criteria. Results: Sixteen HER2-low patients were included. The median age was 56 years (range, 38-93); 63% (n = 10) were African American. Most (75%) had hormone receptor-positive disease, and 53% presented with de novo metastatic disease. Thirteen patients (81%) had HER2 IHC 1+, and only three had HER2 IHC 2+/FISH-negative disease. The majority (88%) had parenchymal CNS metastases; one patient had leptomeningeal disease, and one had both. Eight patients (50%) had prior CNS metastases, and 38% received local therapy before study inclusion. Notably, a significant proportion of patients (88%) had non-measurable disease by RANO-BM criteria (lesions <10 mm), with 69% having lesions smaller than 5 mm. Systemic therapies for the CNS disease included cytotoxic chemotherapy in seven patients (44%), trastuzumab deruxtecan (T-DXd) in four (25%), abemaciclib in two (13%), other CDK4/6 inhibitors in two (13%), and sacituzumab govitecan in one (6%). Commonly utilized chemotherapy included taxanes (paclitaxel or nab-paclitaxel) in 4 of 7 patients. In the 16 patients, the overall response rate (ORR) was 31.3%, the disease control rate (DCR) was 56.3%, the median duration of response (DOR) was 7 months, and the median progression-free survival (PFS) was 2 months. In a comparison cohort of HER2-positive patients (n=17), ORR was 53%, DCR was significantly higher at 94% (p=0.017), with similar DOR (5 months), and numerically longer PFS (3 months, p=0.351). Outcomes among the African American patients (n=10) mirrored the overall HER2-low group, with ORR 30%, DCR 50%, DOR 5 months, and PFS 1 month. Notably, the patients with HER2 IHC 2+ tumors (n=3; all HR+) experienced higher benefit (ORR 67%, DCR 100%) with no disease progression at last follow-up. HER2-low patients treated with T-DXd (n=4) demonstrated a DCR of 75%, with only one progression. Chemotherapy yielded a poor ORR of 29%, though two patients achieved complete CNS responses with taxane-based regimens. Conclusion: This “real-world” experience highlights modest intracranial activity of systemic therapy in HER2-low breast cancer with CNS metastases. Although response rates were lower than in HER2-positive counterparts, HER2 2+ tumors and patients treated with T-DXd showed encouraging outcomes. These findings support the need for prospective studies focusing on HER2-low CNS disease and suggest T-DXd as a promising therapeutic option, even in the absence of concurrent local treatment. Additionally, our study underscores a unique challenge in the management of breast cancer and brain metastases: CNS lesions are often smaller than the >10 mm threshold typically required for clinical trial eligibility, necessitating special attention and adapted approaches for response assessment. Citation Format: B. Ghimire, L. Rogers, M. Girgis. Efficacy of systemic therapy in HER2-low breast cancer with CNS metastases: a “real-world” experience [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-05-28.

Introduction: Melanoma brain metastasis (MBM) affects nearly 50% of patients with advanced melanoma. Despite progress in systemic therapies, particularly immune checkpoint inhibitors, intracranial responses remain highly variable. The CD40/CD40L axis and its pleiotropic effects on the anti-tumoral immune response has the potential to improve MBM treatment. Our aim was to investigate whether the timing of MBM seeding, in a two-site mouse model of MBM, impacts the intracranial efficacy of anti-CD40 agonism (aCD40). Methods: 2 x 105 B16F1-cOVA murine melanoma cells were subcutaneously (s.c.) injected in the right flank in C57BL/6 mice (5F, 5M). After 3 days, 1 x 105 B16F1-cOVA cells were intracerebrally (i.c.) injected into the right striatum under stereotaxic guidance (early MBM’ cohort). A separate cohort of C57BL/6 mice (5F, 5M) had s.c. injection of B16F1-cOVA cells, followed by an i.c. injection of B16F1-cOVA cells after 5 days (‘late MBM’ cohort). In both experimental cohorts, the mice were randomly allocated to receive either an aCD40 antibody or an isotype IgG antibody (control) intraperitoneally on days 4 (D4) and 7 (D7) post-i.c. injection (D0). S.c. tumor volume and survival data were serially collected. Separately, tumor-bearing mice treated with either aCD40 or IgG (n = 4 per early/late MBM groups) were euthanized day 9 (D9) post-i.c. injection and tissues (blood, brain tumor [BT], and flank tumor [FT]) were collected for immune profiling by spectral flow cytometry. Results: The early MBM cohort showed a significant s.c. tumor response to aCD40 therapy with a mean D9:D4 s.c. tumor volume ratio of 2.81 (SD±2.05) vs 16.51 (±13.10) in the IgG group (unpaired t-test; p=0.0497). The late MBM cohort showed no significant difference in s.c. tumor response between aCD40 or IgG (D9:D4 ratio 1.52±1.00 vs 1.20±0.83; p=0.5999). Survival increased in early MBM following aCD40 vs IgG (median 20 days vs 13 days; logrank test, p=0.0078), which was not replicated in late MBM (median 21 days vs 19 days; p=0.7717). Systemic aCD40 led to reduced circulating B cells, most expressing CD11b, and increased monocytes, compared to IgG treatment. In the BT, there were higher infiltration of CD8 T cells (normalized to microglia), including OVA+ CD8 T cells, and CD4 T cells in early MBM treated with aCD40 vs IgG. Systemic aCD40 induced more infiltrating SIRP1a+ cDC2 cells than XCR1+ cDC1 cells and vice versa in the IgG group, in both the BT and FLT. Meanwhile, infiltrating B cells were predominantly CD11b+ in aCD40 groups in the BT, regardless of MBM timing. Conclusion: Systemic aCD40 therapy improved survival of MBM-bearing mice, with a shorter interval between s.c. and i.c. implantation; an effect abrogated by later MBM seeding. Systemic aCD40 therapy induced specific changes in the BT infiltrative immune profile, which may explain the distinct response between the early and late BM cohorts. These findings have implications on the experimental modelling of MBM and provide insight into variability of MBM response to immunomodulating therapies. Citation Format: Vinton W. T. Cheng, Victoria R. Breza, Beata Chertok, Natasha D. Sheybani, Timothy N. J. Bullock, Richard J. Price. Timing of melanoma brain metastasis seeding dictates the immunomodulatory effect and efficacy of systemic anti-CD40 agonist therapy [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Tumor-body Interactions: The Roles of Micro- and Macroenvironment in Cancer; 2024 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(22_Suppl):Abstract nr C030.

Systemic (family) therapy is a widely used psychotherapy approach. However, most systematic efficacy reviews have focused solely on "family-based treatment" rather than on the theoretic orientation "systemic therapy." We systematically review trials on the efficacy of systemic therapy for the treatment of childhood and adolescent externalizing disorders. All randomized (or matched) controlled trials (RCT) evaluating systemic/systems-oriented therapy in various forms (family, individual, group, multi-family group therapy) with child or adolescent index patients (0-17years) suffering from mental disorders were identified by data base searches and cross-references. Inclusion criteria were as follows: index patient diagnosed with a DSM- or ICD-listed mental disorder, and trial published in any language up to the end of 2011. The RCTs were analyzed for their research methodology, interventions applied, and results (postintervention; follow-up). A total of 47 trials from the United States, Europe, and China, published in English, German, and Mandarin, were identified. A total of 42 of them showed systemic therapy to be efficacious for the treatment of attention deficit hyperactivity disorders, conduct disorders, and substance use disorders. Results were stable across follow-up periods of up to 14years. There is a sound evidence base for the efficacy of systemic therapy for children and adolescents (and their families) diagnosed with externalizing disorders.

As survival of patients with central nervous system (CNS) metastases from breast cancer is poor and incidence rates are increasing, there is a growing need for better treatment strategies. In the current study, the efficacy of local and systemic therapies was analyzed in breast cancer patients with CNS metastases. Medical records from breast cancer patients with brain and/or leptomeningeal metastases (LM) treated at a tertiary referral center and a teaching hospital between 2010 and 2020 were retrospectively studied. Main outcomes of interest were overall survival (OS) and CNS progression free survival. Analyses were performed among patients with brain metastases (BM) and patients with LM, for the different systemic and local therapies for CNS metastases, and for subgroups based on breast cancer subtypes. We identified 155 patients, 97 with BM and 58 with LM. Median OS was 15.9months for patients with BM and 1.5months for patients with LM. Median OS was significantly longer for HER2-positive patients with BM (22.8months) vs triple negative (8.4months) and hormone receptor positive/HER2-negative (5.9months) (P < 0.001). Patients with BM receiving both local and systemic therapy also had a longer median OS (21.8months), compared to the other three subgroups (local therapy only: 9.9months, systemic therapy only: 4.3months, no therapy: 0.5months, P < 0.001). No significant difference in OS was observed between different systemic treatment regimens. Breast cancer patients with BM show longest median OS when the subtype is HER2-positive and when they are treated with both local and systemic therapy.

The Southwest Oncology Group (SWOG)1931 trial, also known as PROBE (ClinicalTrials.gov Identifier: NCT04510597) is a phase III study evaluating the role of cytoreductive nephrectomy (CN) in metastatic renal cell cancer (RCC). Kidney cancer presenting with synchronous metastases has demonstrated shorter survival outcome compared to the patients relapsing with metastases after nephrectomy. Previously, CN has been associated with survival improvement when interferon-based systemic therapy was used. In the setting of antivascular therapy sunitinib, a prospective randomized clinical trial demonstrated no benefit of CN. Immune checkpoint-based combination therapy has now become the standard-of-care in the frontline setting for RCC. The role of nephrectomy or primary resection has not been evaluated in the setting of immune checkpoint-based systemic therapy. The sequence and optimal timing of nephrectomy is also not established. The PROBE study design attempts to answer the question whether CN has an impact on overall survival outcomes in RCC within the context of immune checkpoint-based combination regimens. The study requires starting with systemic therapy; any one of the FDA approved immunotherapy-based regimens at the time the study was activated are permitted. The disease status and response are evaluated at 9–12 weeks of therapy and then consented patients are randomized 1:1 to receive CN or to continue systemic therapy. The patients who have rapid disease progression are considered ineligible for randomization as they need a switch in systemic therapy. Both groups should continue systemic therapy as long as they are tolerating the treatment and continuing to derive clinical benefit. Quality-of-life, tumor genomic testing, microbiome, radiomics and circulating tumor DNA assessments as predictive biomarkers are planned as study correlatives. The study hypothesis is that CN will improve OS in synchronous metastatic RCC when surgery is performed after starting systemic immune checkpoint-based combination therapy. A potential mechanism leading to improved survival is the broader antigen spread and higher neoantigen load enabled by the primary tumor enhancing the efficacy of the immune therapy. CN after initial systemic therapy would help select the patient subset most likely to benefit and will potentially enable eradication of immune resistant clones within the primary tumor.

Major research objectives