Narrative review of stereotactic body radiation therapy combined with tyrosine kinase inhibitors for oligometastatic EGFR-mutated non-small cell lung cancer: present and future developments.

Background and Objective: A significant number of individuals diagnosed with non-small cell lung cancer (NSCLC) have distant metastases, and the concept of oligometastatic NSCLC has shown promise in achieving a cure. Stereotactic body radiation therapy (SBRT) is currently considered a viable treatment option for a limited number of tumor metastases. It has also been demonstrated that third-generation tyrosine kinase inhibitors (TKIs) are effective in extending the survival of patients with epidermal growth factor receptor (EGFR)-mutated NSCLC. Hence, the combination of SBRT with third-generation TKIs holds the potential to enhance treatment efficacy in patients with oligometastatic EGFR-mutated NSCLC. This review aimed to assess the possibility of combining SBRT with TKIs as an optimum treatment option for patients with oligometastatic EGFR-mutated NSCLC. Methods: We performed a narrative review by searching the PubMed, Web of Science, Elsevier and ClinicalTrials.gov databases for articles published in the English language from January 2009 to February 2024 and by reviewing the bibliographies of key references to identify important literature related to combining SBRT with third-generation TKIs in oligometastatic EGFR-mutated NSCLC. Key Content and Findings: This review aimed to assess the viability of combining SBRT and EGFR-TKIs in oligometastatic EGFR-mutated NSCLC. Current clinical trials suggest that the combined therapies have better progression free survival (PFS) when using SBRT as either concurrent with EGFR-TKIs or consolidated with EGFR-TKIs. Furthermore, research with third-generation EGFR-TKIs and SBRT combinations has demonstrated tolerable toxicity levels without significant additional adverse effects as compared to prior therapies. However, further clinical trials are required to establish its effectiveness. Conclusions: The combined approach of SBRT and TKIs can effectively impede the progression of oligometastatic NSCLC in patients harboring EGFR mutations and, most notably, can prolong progression-free survival rates. However, the feasibility of combining SBRT with third-generation TKIs in clinical trials remains unclear.

Immunotherapy for head and neck cancer: where do we go from here?

Tweetable abstract Immunotherapy for head and neck cancer shows promising new directions - and challenges ahead. What can we learn from recent trials to improve patient selection and optimize combination therapy?

Definitive Radiation Therapy for Medically Inoperable Endometrial Carcinoma.

Purpose: Upfront radiation therapy consisting of brachytherapy with or without external beam radiation therapy is considered standard of care for patients with endometrial carcinoma who are unable to undergo surgical intervention. This study evaluated the cancer-free survival (CFS), cancer-specific survival (CSS), and overall survival (OS) of patients with endometrial carcinoma managed with definitive-intent radiation therapy. Methods and Materials: This was a single-institution retrospective analysis of medically inoperable patients with biopsy-proven endometrial carcinoma managed with up-front, definitive radiation therapy at UMass Memorial Medical Center between May 2010 and October 2021. A total of 55 cases were included for analysis. Patients were stratified as having low-risk endometrial carcinoma (LREC; uterine-confined grade 1-2 endometrioid adenocarcinoma) or high-risk endometrial carcinoma (HREC; stage III/IV and/or grade 3 endometrioid carcinoma, or any stage serous or clear cell carcinoma or carcinosarcoma). The CFS, CSS, OS, and grade ≥3 toxic effects were reported for patients with LREC and HREC. Results: The median age was 66 years (range, 42-86 years), and the median follow-up was 44 months (range, 4-135 months). Twelve patients (22%) were diagnosed with HREC. Six patients (11%) were treated with high-dose-rate brachytherapy alone and 49 patients (89%) were treated with high-dose-rate brachytherapy and external beam radiation therapy. Twelve patients (22%) were treated with radiation and chemotherapy. The 2-year CFS was 82% for patients with LREC and 80% for patients with HREC (log rank P = .0654). The 2-year CSS was 100% for both LREC and HREC patients. The 2-year OS was 92% for LREC and 80% for HREC (log P = .0064). There were no acute grade ≥3 toxic effects. There were 3 late grade ≥3 toxic effects owing to endometrial bleeding and gastrointestinal adverse effects. Conclusions: For medically inoperable patients with endometrial carcinoma, up-front radiation therapy provided excellent CFS, CSS, and OS. The CSS and OS were higher in patients with LREC than in those with HREC. Toxic effects were limited in both cohorts.

Radiotherapy and Immunotherapy Combinations for Lung Cancer.

PURPOSE OF REVIEW: Positive results from recent immunotherapy trials of non-small cell lung cancer (NSCLC) have coincided with a greater appreciation for the impact of radiation therapy (RT) on tumor immunity. Here, we summarize key clinical findings and ongoing efforts to combine immunotherapy and RT for the treatment of NSCLC. RECENT FINDINGS: The role of immunotherapy for NSCLC has expanded significantly following the pivotal approvals of nivolumab and pembrolizumab for metastatic NSCLC, maintenance durvalumab in unresectable stage III NSCLC, and atezolizumab for metastatic NSCLC. Several small early-phase trials have demonstrated the ability of RT to elicit clinically significant tumor immunity. These positive findings support current trial efforts combining RT with immunotherapy for NSCLC. Recently initiated trials of RT and immunotherapy hold significant promise in expanding the therapeutic options for NSCLC. Optimization of therapy will require careful patient selection to yield meaningful improvements in clinical outcomes.

Radiation unlocks the therapeutic potential of immune checkpoint blockers in lung cancer patients.

CTLA4 blockers have limited activity in patients with chemorefractory lung cancer. Recent clinical data demonstrate that radiation therapy combined with CTLA4 blockers enables disease control in a sizeable fraction of these patients, correlating with increased circulating levels of type I interferon and dynamic changes in the peripheral T cell repertoire.

Radiation therapy to enhance tumor immunotherapy: a novel application for an established modality.

Purpose: The aim of this review is to highlight key evidence supporting the effect of radiation therapy on tumor immunity. Conclusions: Recent findings in both the preclinical and clinical settings have provided convincing evidence of the ability of radiation therapy to influence tumor-directed immune responses, and have offered critical insights into the underlying mechanisms. Not only does radiation therapy convert the tumor microenvironment to promote robust tumor immunity, but it also enhances the generation of neoantigens and neoepitopes. Radiation therapy also shapes the TCR repertoire of CD8+ T cells in conjunction with immune checkpoint blockade. In conclusion, a high priority should be placed on developing rational strategies to integrate radiation therapy with immunotherapy in the clinical setting, with an emphasis on careful patient selection and identifying important correlative endpoints.

Generating antitumor immunity by targeted radiation therapy: Role of dose and fractionation.

Accumulating evidence supports the role of radiation therapy in the induction of antitumor immunity. With recent advancements in stereotactic radiation therapy, there is increasing appreciation that, when combined with immune checkpoint blockade, the type of radiation dose and fractionation regimen selected may both influence local tumor control and also affect the generation of immune responses that are important for systemic control. Although a broad range of radiation dose and fractionation schema have been tested in both the preclinical and clinical settings, recent preclinical evidence suggests the existence of a dose per fraction threshold beyond which radiation becomes less effective in generating tumor immune responses. Such a threshold seems to be tumor dependent, probably reflecting different genetic mutations of cancer. In this review we discuss the key preclinical and clinical evidence relating to radiation dose and fractionation considerations. Future clinical trials should focus on identifying optimal radiation dose and fractionation schedules, which may depend on the clinical context.

The Integration of Radiotherapy with Immunotherapy for the Treatment of Non-Small Cell Lung Cancer.

Five-year survival rates for non-small cell lung cancer (NSCLC) range from 14% to 49% for stage I to stage IIIA disease, and are <5% for stage IIIB/IV disease. Improvements have been made in the outcomes of patients with NSCLC due to advancements in radiotherapy (RT) techniques, the use of concurrent chemotherapy with RT, and the emergence of immunotherapy as first- and second-line treatment in the metastatic setting. RT remains the mainstay treatment in patients with inoperable early-stage NSCLC and is given concurrently or sequentially with chemotherapy in patients with locally advanced unresectable disease. There is emerging evidence that RT not only provides local tumor control but also may influence systemic control. Multiple preclinical studies have demonstrated that RT induces immunomodulatory effects in the local tumor microenvironment, supporting a synergistic combination approach with immunotherapy to improve systemic control. Immunotherapy options that could be combined with RT include programmed cell death-1/programmed cell death ligand-1 blockers, as well as investigational agents such as OX-40 agonists, toll-like receptor agonists, indoleamine 2,3-dioxygenase-1 inhibitors, and cytokines. Here, we describe the rationale for the integration of RT and immunotherapy in patients with NSCLC, present safety and efficacy data that support this combination strategy, review planned and ongoing studies, and highlight unanswered questions and future research needs.

Radiotherapy and checkpoint inhibitors: a winning new combination?

Immune checkpoint blockade has recently emerged as an important therapeutic approach to the management of malignancies across multiple disease settings. Concomitantly, there has been an increasing appreciation for the role of radiotherapy in eliciting and promoting tumor-directed immune responses. In this review, we discuss the clinical evidence to date on combinations of radiotherapy with immune checkpoint inhibitors, both from the standpoint of safety and efficacy. We highlight important but yet-unanswered questions for this combination approach, as well as their implications for future prospective studies.

First Report of NRG Oncology/Radiation Therapy Oncology Group 0622: A Phase 2 Trial of Samarium-153 Followed by Salvage Prostatic Fossa Irradiation in High-Risk Clinically Nonmetastatic Prostate Cancer After Radical Prostatectomy.

PURPOSE: To investigate the utility of 153Sm lexidronam (Quadramet) in the setting of men with prostate cancer status post radical prostatectomy who develop biochemical failure with no clinical evidence of osseous metastases. PATIENTS AND METHODS: Trial NRG Oncology RTOG 0622 is a single-arm phase 2 trial that enrolled men with pT2-T4, N0-1, M0 prostate cancer status post radical prostatectomy, who meet at least 1 of these biochemical failure criteria: (1) prostate-specific antigen (PSA) > 1.0 ng/mL; (2) PSA > 0.2 ng/mL if Gleason score 9 to 10; or (3) PSA > 0.2 ng/mL if N1. Patients received 153Sm (2.0 mCi/kg intravenously × 1) followed by salvage external beam radiation therapy (EBRT) to the prostatic fossa (64.8-70.2 Gy in 1.8-Gy daily fractions). No androgen deprivation therapy was allowed. The primary objective was PSA response within 12 weeks of receiving 153Sm. The secondary objectives were to: (1) assess the completion rate for the regimen of 153Sm and EBRT; (2) evaluate the hematologic toxicity and other adverse events (AEs) at 12 and 24 weeks; and (3) determine the freedom from progression rate at 2 years. RESULTS: A total of 60 enrolled eligible patients were included in this analysis. Median follow-up was 3.97 years. A PSA response was achieved in 7 of 52 evaluable patients (13.5%), compared with the 25% hypothesized. The 2-year freedom from progression rate was 25.5% (95% confidence interval 14.4%-36.7%), and the biochemical failure rate was 64.4% (95% CI 50.5%-75.2%). Samarium-153 was well tolerated, with 16 (of 60) grade 3 to 4 hematologic AEs and no grade 5 hematologic AEs. Radiation therapy was also well tolerated, with no grade 3 to 5 acute radiation therapy-related AEs and 1 grade 3 to 4 and no grade 5 late radiation therapy-related AEs. CONCLUSIONS: Trial NRG Oncology RTOG 0622 did not meet its primary endpoint of PSA response, although the regimen of 153Sm and salvage EBRT was well tolerated. Although the toxicity profile supports study of 153Sm in high-risk disease, it may not be beneficial in men receiving EBRT.

Treatment strategies in low-volume metastatic castration-resistant prostate cancer.

PURPOSE OF REVIEW: There are currently limited data to guide the optimal management of patients with low-volume metastatic castration-resistant prostate cancer (mCRPC). In this review, we critically assess the most relevant clinical data, and discuss opportunities for advancing therapeutic options in this patient population. RECENT FINDINGS: Over the past decade, treatment options for mCRPC have expanded beyond taxanes to include abiraterone/prednisone, enzalutamide, sipuleucel-T, and radium-223. However, only a subset of patients in the landmark phase 3 studies would meet criteria consistent with low-volume mCRPC, and optimal treatment approach for this patient population is unclear. There is emerging evidence that mCRPC patients who harbor low-volume or indolent disease may derive the most benefit from immunotherapy. Whereas prospective data are lacking, stereotactic body radiation appears to be well tolerated and effective for local control of metastases in oligometastatic CRPC. SUMMARY: Prospective studies are needed to establish optimal therapeutic approaches in carefully selected low-volume mCRPC patients. Advances in functional imaging and molecular profiling should provide opportunities to optimize patient selection for effective treatment strategies.

Postoperative Radiation After Radical Prostatectomy.

A total of 3 randomized clinical trials have demonstrated a significant clinical benefit with adjuvant radiation in patients with high-risk prostate cancer after radical prostatectomy, with each showing improved biochemical control outcomes, and one trial (SWOG 8794) also demonstrating increased overall survival. How broadly these results have informed clinical practice has evolved over time, given the widespread availability of ultrasensitive prostate-specific antigen level testing and increased awareness that the high-risk patients are not a uniform cohort. In this review, we discuss the evidence from published and ongoing trials as well as current controversies, focusing on unanswered questions such as when postoperative radiation should be offered and whether the inclusion of androgen-deprivation therapy improves clinical outcomes. The emerging interest in genomic prediction tools and the enhanced sensitivity of novel imaging modalities should offer strategies to improve patient selection, which would help to identify men who may benefit from postoperative radiation while avoiding unnecessary treatment and toxicities in other men.

Myeloid-Derived Suppressor Cells as an Immune Parameter in Patients with Concurrent Sunitinib and Stereotactic Body Radiotherapy.

PURPOSE: The clinical effects of sunitinib on human myeloid-derived suppressor cell (MDSC) subsets and correlation of the T-cell-mediated immune responses and clinical outcomes in patients with oligometastases treated by stereotactic body radiotherapy (SBRT) have been evaluated. EXPERIMENTAL DESIGN: The numbers of granulocytic and monocytic MDSC subsets, effector T cells, and regulatory T cells in the peripheral blood were evaluated pre- and post-sunitinib treatment and concurrent with SBRT. Correlations between MDSC, Treg, and T-cell responses and clinical outcomes were analyzed. RESULTS: Patients with oligometastases of various cancer types had elevated granulocytic MDSC and certain subsets of monocytic MDSC population. Sunitinib treatment resulted in a significant reduction in monocytic MDSC, phosphorylated STAT3, and arginase levels in monocytic MDSC (CD33(+)CD14(+)CD16(+)), and an increase in T-cell proliferative activity in cancer patients. Interestingly, the effects of sunitinib on reducing the accumulation and immune-suppressive function of MDSC were significantly correlated with Treg reduction, in responders but not in nonresponding patients. SBRT synergized the therapeutic effects of sunitinib, especially as related to decreased numbers of monocytic MDSC, Treg, and B cells, and augmented Tbet expression in primary CD4 and CD8 T cells. These effects were not observed in patients receiving radiation therapy alone. Most interestingly, the responders, defined by sunitinib-mediated reduction in CD33(+)CD11b(+) myeloid cell populations, tend to exhibit improved progression-free survival and cause-specific survival. CONCLUSIONS: Sunitinib treatment increased the efficacy of SBRT in patients with oligometastases by reversing MDSC and Treg-mediated immune suppression and may enhance cancer immune therapy to prevent tumor recurrence post-SBRT.

Tolerability, toxicity, and temporal implications of transoral robotic surgery (TORS) on adjuvant radiation therapy in carcinoma of the head and neck.

OBJECTIVES: Overall treatment package time (from surgery to radiotherapy [RT] completion) > 100 days can portend poor outcomes in head and neck cancer. Faster postoperative recovery seen with transoral robotic surgery may decrease treatment duration and toxicity for adjuvant RT and chemoradiation. METHODS: We retrospectively reviewed all patients treated with transoral robotic surgery (n = 124) and adjuvant RT and chemoradiation (n = 33) at our institution for head and neck cancer from April 2007 to December 2011 to determine treatment duration, acute toxicity, and long-term percutaneous gastric tube rates. RESULTS: The median overall treatment time was 86 days and from surgery to RT start was 41 days; median RT duration was 44 days. No wound breakdown or infection occurred during or after RT. Two-year actuarial locoregional control, distant metastasis-free survival, and overall survival rates were 93%, 96%, and 97%, respectively. CONCLUSIONS: Adjuvant RT after transoral robotic surgery for head and neck cancer can be completed safely and in a timely fashion. Longer follow-up and a larger cohort will be needed to determine if this regimen is more effective than traditional surgery followed by adjuvant RT.

Epidemiology of head and neck squamous cell cancer among HIV-infected patients.

BACKGROUND: HIV-infected individuals have a higher incidence of head and neck cancer (HNC). METHODS: Case series of 94 HIV-infected HNC patients (HIV-HNC) at 6 tertiary care referral centers in the US between 1991 and 2011. Clinical and risk factor data were abstracted from the medical record. Risk factors for survival were analyzed using Cox proportional hazard models. Human papillomavirus (HPV) and p16 testing was performed in 46 tumors. Findings were compared with Surveillance Epidemiology and End Results HNC (US-HNC) data. RESULTS: This study represents the largest HIV-HNC series reported to date. HIV-HNC cases were more likely than US-HNC to be male (91% vs. 68%), younger (median age, 50 vs. 62 years), nonwhite (49% vs. 18%), and current smokers (61% vs. 18%). Median HIV-HNC survival was not appreciably lower than US-HNC survival (63 vs. 61 months). At diagnosis, most cases were currently on highly active antiretroviral therapy (77%) but had detectable HIV viremia (99%), and median CD4 was 300 cells per microliter (interquartile range = 167-500). HPV was detected in 30% of HIV-HNC and 64% of HIV-oropharyngeal cases. Median survival was significantly lower among those with CD4 counts ≤200 than >200 cells per microliter at diagnosis (16.1 vs. 72.8 months, P < 0.001). In multivariate analysis, poorer survival was associated with CD4 <100 cells per microliter [adjusted hazard ratio (aHR) = 3.09, 95% confidence interval (CI): 1.15 to 8.30], larynx/hypopharynx site (aHR = 3.54, 95% CI: 1.34 to 9.35), and current tobacco use (aHR = 2.54, 95% CI: 0.96 to 6.76). CONCLUSIONS: Risk factors for the development of HNC in patients with HIV infection are similar to the general population, including both HPV-related and tobacco/alcohol-related HNC.

Association of early PSA failure time with increased distant metastasis and decreased survival in prostate brachytherapy patients.

BACKGROUND AND PURPOSE: We investigated whether earlier PSA failure following prostate brachytherapy is associated with increased rates of distant metastases (DM), prostate cancer-specific mortality (PCSM), and overall mortality. MATERIALS AND METHODS: We retrospectively analyzed 2818 patients who underwent brachytherapy ± external beam radiation therapy (EBRT) ± androgen deprivation therapy (ADT). With median follow-up of 5.52 years, 264 patients experienced PSA failure at a median time of 3.25 years. Patients were stratified to early vs. late PSA failures at cutoffs of 1.5 years, 3 years, or 5 years, and tested in univariate/multivariate analyses for freedom from DM, cause-specific survival (CSS), and overall survival (OS). RESULTS: Among patients with PSA failures, 69 (26%) patients experienced DM, 47 (18%) PCSM, and 56 (21%) deaths from other causes. Patients with rapid PSA failures demonstrated increased rates of DM, PCSM, and overall mortality, despite higher total BED and longer ADT. In multivariate analysis with a PSA failure interval <3 years, the hazard ratio (HR) for DM was 3.92 (95% CI: 2.34-6.55; p=0.000); HR for PCSM was 2.79 (95% CI: 1.45-5.38; p=0.002); and HR for overall mortality was 2.28 (95% CI: 1.50-3.48; p=0.000). CONCLUSION: Early PSA failure following radiation is a poor prognostic factor, as it is associated with increased DM, PCSM, and overall mortality.

Phase II trial of concurrent sunitinib and image-guided radiotherapy for oligometastases.

BACKGROUND: Preclinical data suggest that sunitinib enhances the efficacy of radiotherapy. We tested the combination of sunitinib and hypofractionated image-guided radiotherapy (IGRT) in a cohort of patients with historically incurable distant metastases. METHODS: Twenty five patients with oligometastases, defined as 1-5 sites of active disease on whole body imaging, were enrolled in a phase II trial from 2/08 to 9/10. The most common tumor types treated were head and neck, liver, lung, kidney and prostate cancers. Patients were treated with the recommended phase II dose of 37.5 mg daily sunitinib (days 1-28) and IGRT 50 Gy (days 8-12 and 15-19). Maintenance sunitinib was used in 33% of patients. Median follow up was 17.5 months (range, 0.7 to 37.4 months). RESULTS: The 18-month local control, distant control, progression-free survival (PFS) and overall survival (OS) were 75%, 52%, 56% and 71%, respectively. At last follow-up, 11 (44%) patients were alive without evidence of disease, 7 (28%) were alive with distant metastases, 3 (12%) were dead from distant metastases, 3 (12%) were dead from comorbid illness, and 1 (4%) was dead from treatment-related toxicities. The incidence of acute grade ≥ 3 toxicities was 28%, most commonly myelosuppression, bleeding and abnormal liver function tests. CONCLUSIONS: Concurrent sunitinib and IGRT achieves major clinical responses in a subset of patients with oligometastases. TRIAL REGISTRATION: ClinicalTrials.gov NCT00463060.

γ-H2AX kinetics as a novel approach to high content screening for small molecule radiosensitizers.

BACKGROUND: Persistence of γ-H2AX after ionizing radiation (IR) or drug therapy is a robust reporter of unrepaired DNA double strand breaks in treated cells. METHODS: DU-145 prostate cancer cells were treated with a chemical library ±IR and assayed for persistence of γ-H2AX using an automated 96-well immunocytochemistry assay at 4 hours after treatment. Hits that resulted in persistence of γ-H2AX foci were tested for effects on cell survival. The molecular targets of hits were validated by molecular, genetic and biochemical assays and in vivo activity was tested in a validated Drosophila cancer model. RESULTS: We identified 2 compounds, MS0019266 and MS0017509, which markedly increased persistence of γ-H2AX, apoptosis and radiosensitization in DU-145 cells. Chemical evaluation demonstrated that both compounds exhibited structurally similar and biochemical assays confirmed that these compounds inhibit ribonucleotide reductase. DNA microarray analysis and immunoblotting demonstrates that MS0019266 significantly decreased polo-like kinase 1 gene and protein expression. MS0019266 demonstrated in vivo antitumor activity without significant whole organism toxicity. CONCLUSIONS: MS0019266 and MS0017509 are promising compounds that may be candidates for further development as radiosensitizing compounds as inhibitors of ribonucleotide reductase.