Perioperative and oncologic outcomes of pulmonary resection for synchronous oligometastatic non-small cell lung cancer: Evidence for surgery in advanced disease.

OBJECTIVES: Recent randomized trials have demonstrated a survival advantage with the use of local consolidative therapy in oligometastatic non-small cell lung cancer; however, the indications for and outcomes after pulmonary resection as a component of local consolidative therapy remain ill defined. We sought to characterize the perioperative and long-term survival outcomes among patients with resected oligometastatic non-small cell lung cancer. METHODS: Patients presenting to a single center (2000-2017) with oligometastatic non-small cell lung cancer (≤3 synchronous metastases, intrathoracic nodal disease counted as a single site) who underwent resection of the primary tumor were retrospectively identified. Charts were reviewed, and demographic, clinical, pathologic, oncologic, and survival outcomes were recorded. Survival outcomes were analyzed from the date of surgery. RESULTS: A total of 52 patients met inclusion criteria, among whom most (38, 73.1%) were ever smokers, had nonsquamous tumors (48, 92.3%), had no intrathoracic nodal disease (33, 63.5%), and had 1 to 2 sites of metastases (49, 94.2%). The majority (41, 78.9%) received systemic therapy, predominantly in the neoadjuvant setting (24/41, 58.5%). After resection, there were no 30- or 90-day deaths. After a median follow-up of 94.6 months (95% CI, 69.0-139.1), 37 patients (71.2%) progressed and 38 patients (73.1%) died. Median postoperative progression-free survival and overall survival were 9.4 (5.5-11.6) months and 51.7 (22.3-65.3) months, respectively. CONCLUSIONS: Pulmonary resection as a means of maximum locoregional control in oligometastatic non-small cell lung cancer is feasible and safe, and may be associated with durable long-term survival benefits. The frequency of systemic postoperative progression highlights an urgent need to characterize perioperative and oncologic outcomes after pulmonary resection in the current era of novel systemic therapies.

Stereotactic ablative radiotherapy with or without immunotherapy for early-stage or isolated lung parenchymal recurrent node-negative non-small-cell lung cancer: an open-label, randomised, phase 2 trial.

BACKGROUND: Stereotactic ablative radiotherapy (SABR) is the standard treatment for medically inoperable early-stage non-small-cell lung cancer (NSCLC), but regional or distant relapses, or both, are common. Immunotherapy reduces recurrence and improves survival in people with stage III NSCLC after chemoradiotherapy, but its utility in stage I and II cases is unclear. We therefore conducted a randomised phase 2 trial of SABR alone compared with SABR with immunotherapy (I-SABR) for people with early-stage NSCLC. METHODS: We did an open-label, randomised, phase 2 trial comparing SABR to I-SABR, conducted at three different hospitals in TX, USA. People aged 18 years or older with histologically proven treatment-naive stage IA-IB (tumour size ≤4 cm, N0M0), stage IIA (tumour size ≤5 cm, N0M0), or stage IIB (tumour size >5 cm and ≤7 cm, N0M0) as per the American Joint Committee on Cancer version 8 staging system or isolated parenchymal recurrences (tumour size ≤7 cm) NSCLC (TanyNanyM0 before definitive surgery or chemoradiotherapy) were included in this trial. Participants were randomly assigned (1:1; using the Pocock & Simon method) to receive SABR with or without four cycles of nivolumab (480 mg, once every 4 weeks, with the first dose on the same day as, or within 36 h after, the first SABR fraction). This trial was unmasked. The primary endpoint was 4-year event-free survival (local, regional, or distant recurrence; second primary lung cancer; or death). Analyses were both intention to treat (ITT) and per protocol. This trial is registered with ClinicalTrials.gov (NCT03110978) and is closed to enrolment. FINDINGS: From June 30, 2017, to March 22, 2022, 156 participants were randomly assigned, and 141 participants received assigned therapy. At a median 33 months' follow-up, I-SABR significantly improved 4-year event-free survival from 53% (95% CI 42-67%) with SABR to 77% (66-91%; per-protocol population, hazard ratio [HR] 0·38; 95% CI 0·19-0·75; p=0·0056; ITT population, HR 0·42; 95% CI 0·22-0·80; p=0·0080). There were no grade 3 or higher adverse events associated with SABR. In the I-SABR group, ten participants (15%) had grade 3 immunologial adverse events related to nivolumab; none had grade 3 pneumonitis or grade 4 or higher toxicity. INTERPRETATION: Compared with SABR alone, I-SABR significantly improved event-free survival at 4 years in people with early-stage treatment-naive or lung parenchymal recurrent node-negative NSCLC, with tolerable toxicity. I-SABR could be a treatment option in these participants, but further confirmation from a number of currently accruing phase 3 trials is required. FUNDING: Bristol-Myers Squibb and MD Anderson Cancer Center Alliance, National Cancer Institute at the National Institutes of Health through Cancer Center Core Support Grant and Clinical and Translational Science Award to The University of Texas MD Anderson Cancer Center.

Efficacy and clinicogenomic correlates of response to immune checkpoint inhibitors alone or with chemotherapy in non-small cell lung cancer.

The role of combination chemotherapy with immune checkpoint inhibitors (ICI) (ICI-chemo) over ICI monotherapy (ICI-mono) in non-small cell lung cancer (NSCLC) remains underexplored. In this retrospective study of 1133 NSCLC patients, treatment with ICI-mono vs ICI-chemo associate with higher rates of early progression, but similar long-term progression-free and overall survival. Sequential vs concurrent ICI and chemotherapy have similar long-term survival, suggesting no synergism from combination therapy. Integrative modeling identified PD-L1, disease burden (Stage IVb; liver metastases), and STK11 and JAK2 alterations as features associate with a higher likelihood of early progression on ICI-mono. CDKN2A alterations associate with worse long-term outcomes in ICI-chemo patients. These results are validated in independent external (n = 89) and internal (n = 393) cohorts. This real-world study suggests that ICI-chemo may protect against early progression but does not influence overall survival, and nominates features that identify those patients at risk for early progression who may maximally benefit from ICI-chemo.

Benchmarking Outcomes for Molecularly Characterized Synchronous Oligometastatic Non-Small-Cell Lung Cancer Reveals EGFR Mutations to Be Associated With Longer Overall Survival.

PURPOSE: Local consolidative therapy (LCT) for patients with synchronous oligometastatic non-small-cell lung cancer is an evolving treatment strategy, but outcomes following LCT stratified by genetic mutations have not been reported. We sought to identify genomic associations with overall survival (OS) and progression-free survival (PFS) for these patients. METHODS: We identified all patients presenting between 2000 and 2017 with stage IV non-small-cell lung cancer and ≤ 3 synchronous metastatic sites. Patients were grouped according to mutational statuses. Primary outcomes included OS and PFS following initial diagnosis. RESULTS: Of 194 included patients, 121 received comprehensive LCT to all sites of disease with either surgery or radiation. TP53 mutations were identified in 40 of 78 (55%), KRAS in 32 of 95 (34%), EGFR in 24 of 109 (22%), and STK11 in nine of 77 (12%). At median follow-up of 96 months, median OS and PFS were 26 (95% CI, 23 to 31) months and 11 (95% CI, 9 to 13) months, respectively. On multivariable analysis, patients with EGFR mutations had lower mortality risk (hazard ratio [HR], 0.53; 95% CI, 0.29 to 0.98; P = .044) compared with wild-type patients, and patients with STK11 mutations had higher risk of progression or mortality (HR, 2.32; 95% CI, 1.12 to 4.79; P = .023) compared with wild-type patients. TP53 and KRAS mutations were not associated with OS or PFS. Among 71 patients with known EGFR mutational status who received comprehensive LCT, EGFR mutations were associated with lower mortality compared with wild-type (HR, 0.45; 95% CI, 0.22 to 0.94; P = .032). CONCLUSION: When compared with wild-type patients, those with EGFR and STK11 mutations had longer OS and shorter PFS, respectively. EGFR mutations were associated with longer OS among oligometastatic patients treated with comprehensive LCT in addition to systemic therapy.

Effect of dexamethasone on dyspnoea in patients with cancer (ABCD): a parallel-group, double-blind, randomised, controlled trial.

BACKGROUND: Systemic corticosteroids are commonly prescribed for palliation of dyspnoea in patients with cancer, despite scarce evidence to support their use. We aimed to assess the effect of high-dose dexamethasone versus placebo on cancer-related dyspnoea. METHODS: The parallel-group, double-blind, randomised, controlled ABCD (Alleviating Breathlessness in Cancer Patients with Dexamethasone) trial was done at the at the University of Texas MD Anderson Cancer Center and the general oncology clinic at Lyndon B Johnson General Hospital (both in Houston, TX, USA). Ambulatory patients with cancer, aged 18 years or older, and with an average dyspnoea intensity score on an 11-point numerical rating scale (NRS; 0=none, 10=worst) over the past week of 4 or higher were randomly assigned (2:1) to receive dexamethasone 8 mg orally every 12 h for 7 days followed by 4 mg orally every 12 h for 7 days, or matching placebo capsules for 14 days. Pharmacists did permuted block randomisation with a block size of six, and patients were stratified by baseline dyspnoea score (4-6 vs 7-10) and study site. Patients, research staff, and clinicians were masked to group assignment. The primary outcome was change in dyspnoea NRS intensity over the past 24 h from baseline to day 7 (±2 days). Analyses were done by modified intention-to-treat (ie, including all patients who were randomly assigned and started the study treatment, regardless of whether they completed the study). Enrolment was stopped after the second preplanned interim analysis, when the futility criterion was met. This study is registered with ClinicalTrials.gov (NCT03367156) and is now completed. FINDINGS: Between Jan 11, 2018, and April 23, 2021, we screened 2867 patients, enrolled 149 patients, and randomly assigned 128 to dexamethasone (n=85) or placebo (n=43). The mean change in dyspnoea NRS intensity from baseline to day 7 (±2 days) was -1·6 (95% CI -2·0 to -1·2) in the dexamethasone group and -1·6 (-2·3 to -0·9) in the placebo group, with no significant between-group difference (mean 0 [95% CI -0·8 to 0·7]; p=0·48). The most common all-cause grade 3-4 adverse events were infections (nine [11%] of 85 patients in the dexamethasone group vs three [7%] of 43 in the placebo group), insomnia (seven [8%] vs one [2%]), and neuropsychiatric symptoms (three [4%] vs none [0%]). Serious adverse events, all resulting in hospital admissions, were reported in 24 (28%) of 85 patients in the dexamethasone group and in three (7%) of 43 patients in the placebo group. No treatment-related deaths occurred in either group. INTERPRETATION: High-dose dexamethasone did not improve dyspnoea in patients with cancer more effectively than placebo and was associated with a higher frequency of adverse events. These data suggest that dexamethasone should not be routinely given to unselected patients with cancer for palliation of dyspnoea. FUNDING: US National Cancer Institute.

Current status and application of proton therapy for esophageal cancer.

Esophageal cancer remains one of the leading causes of death from cancer across the world despite advances in multimodality therapy. Although early-stage disease can often be treated surgically, the current state of the art for locally advanced disease is concurrent chemoradiation, followed by surgery whenever possible. The uniform midline tumor location puts a strong importance on the need for precise delivery of radiation that would minimize dose to the heart and lungs, and the biophysical properties of proton beam makes this modality potential ideal for esophageal cancer treatment. This review covers the current state of knowledge of proton therapy for esophageal cancer, focusing on published retrospective single- and multi-institutional clinical studies, and emerging data from prospective clinical trials, that support the benefit of protons vs photon-based radiation in reducing postoperative complications, cardiac toxicity, and severe radiation induced immune suppression, which may improve survival outcomes for patients. In addition, we discuss the incorporation of immunotherapy to the curative management of esophageal cancers in the not-too-distant future. However, there is still a lack of high-level evidence to support proton therapy in the treatment of esophageal cancer, and proton therapy has its limitations in clinical application. It is expected to see the results of future large-scale randomized clinical trials and the continuous improvement of proton radiotherapy technology.

Increased biologically effective dose (BED) to the primary tumor is associated with improved survival in patients with oligometastatic NSCLC.

PURPOSE: Local consolidative therapy (LCT) for oligometastatic non-small cell lung cancer (NSCLC) is an evolving treatment paradigm. We investigated whether the biologically effective dose (BED) of consolidative radiation therapy (RT) to the primary tumor predicted for improved local control, progression-free survival (PFS), and overall survival (OS) among NSCLC patients presenting with oligometastatic disease. MATERIALS AND METHODS: Patients presenting to a single institution (2000-2017) with stage IV NSCLC, ≤3 synchronous metastatic lesions at diagnosis, and treated with RT to the primary tumor were identified. Univariate and multivariable Cox proportional-hazards regression modeling were performed to identify factors associated with local recurrence-free survival (LRFS), PFS, and OS. RESULTS: One hundred twenty-four patients were identified meeting our inclusion criteria. With a median follow-up of 55.1 months, median PFS and OS for the entire cohort were 11.0 months and 25.3 months, respectively. The median BED (α/ß = 10) of RT to the primary tumor was 74.3 Gy. On univariate analysis, increased BED to the primary tumor predicted for improved PFS (p < 0.001) and LRFS (p = 0.01), with a median PFS of 8.5 vs 12.8 months and median LRFS of 23.4 vs 58.4 months between patients treated with BED < 75 Gy and ≥75 Gy, respectively. Increased BED to the primary tumor was also associated with significantly improved OS (p = 0.02); patients treated with a BED of <75 Gy demonstrated a median OS of 22.9 months vs 27.5 months if treated with BED ≥ 75 Gy. On multivariable analysis, primary site BED remained a significant predictor of OS (p = 0.02) and PFS (p = 0.002). CONCLUSIONS: We found that delivery of >75 Gy BED RT regimens to the primary lesion in patients with synchronous oligometastatic NSCLC is associated with improved local control, PFS, and OS. These data support results of recent prospective trials and other ongoing prospective efforts to characterize therapeutic benefits associated with this management strategy.

Assessment of Prognostic Value of High-Sensitivity Cardiac Troponin T for Early Prediction of Chemoradiation Therapy-Induced Cardiotoxicity in Patients with Non-Small Cell Lung Cancer: A Secondary Analysis of a Prospective Randomized Trial.

PURPOSE: Cardiotoxicities induced by cancer therapy can negatively affect quality of life and survival. We investigated whether high-sensitivity cardiac troponin T (hs-cTnT) levels could serve as biomarker for early detection of cardiac adverse events (CAEs) after chemoradiation therapy (CRT) for non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: This study included 225 patients who received concurrent platinum and taxane-doublet chemotherapy with thoracic radiation therapy to a total dose of 60 to 74 Gy for NSCLC. All patients were evaluated for CAEs; 190 patients also had serial hs-cTnT measurements. RESULTS: Grade ≥3 CAEs occurred in 24 patients (11%) at a median interval of 9 months after CRT. Pretreatment hs-cTnT levels were higher in men, in patients aged ≥64 years, and in patients with pre-existing heart disease or poor performance status (P < .05). hs-cTnT levels increased at 4 weeks during CRT (P < .05) and decreased after completion of CRT but did not return to pretreatment levels (P = .002). The change (Δ) in hs-cTnT levels during CRT correlated with mean heart dose (P = .0004), the heart volumes receiving 5 to 55 Gy (P < .05), and tumor location (P = .006). Risks of severe CAEs and mortality were significantly increased if the pretreatment hs-cTnT was >10 ng/L or the Δ during CRT was ≥5 ng/L. CONCLUSIONS: Elevation of hs-cTnT during CRT was radiation heart dose-dependent, and high hs-cTnT levels during the course of CRT were associated with CAEs and mortality. Routine monitoring of hs-cTnT could identify patients who are at high risk of CRT-induced CAEs early to guide modifications of cancer therapy and possible interventions to mitigate cardiotoxicity.

Single Institution Experience of Proton and Photon-based Postoperative Radiation Therapy for Non-small-cell Lung Cancer.

INTRODUCTION: Postoperative radiation therapy (PORT) for non-small-cell lung cancer remains controversial with studies showing no overall survival (OS) benefit in the setting of excessive cardiopulmonary toxicity. Proton beam therapy (PBT) can potentially reduce toxicity with improved organ-at-risk sparing. We evaluated outcomes of PORT patients treated with PBT and intensity-modulated radiation therapy (IMRT). MATERIALS AND METHODS: This is a retrospective review of 136 PORT patients (61 PBT, 75 IMRT) treated from 2003 to 2016. A Kaplan-Meier analysis was performed to assess oncologic outcomes. A Cox regression was conducted to identify associated factors. Total toxicity burden (TTB) was defined as grade ≥ 2 pneumonitis, cardiac, or esophageal toxicity. RESULTS: Median OS was 76 and 46 months for PBT and IMRT with corresponding 1- and 5-year OS of 85.3%, 50.9% and 89.3%, 37.2% (P = .38), respectively. V30 Gy heart (odds ratio [OR], 144.9; 95% confidence interval [CI], 2.91-7214; P = .013) and V5 Gy lung (OR, 15.8; 95% CI, 1.22-202.7; P = .03) were predictive of OS. Organ-at-risk sparing was improved with PBT versus IMRT; mean heart 2.0 versus 7.4 Gy (P < .01), V30 Gy heart 2.6% versus 10.7% (P < .01), mean lung 7.9 versus 10.4 Gy (P = .042), V5 Gy lung 23.4% versus 42.1% (P < .01), and V10 Gy lung 20.4% versus 29.6% (P < .01). TTB was reduced with PBT (OR, 0.35; 95% CI, 0.15-0.83; P = .017). Rates of cardiac toxicity were 14.7% IMRT and 4.9% PBT (P = .09). Rates of ≥ grade 2 pneumonitis were 17.0% IMRT and 4.9% PBT (P = .104). CONCLUSION: PBT improved cardiac and lung sparing and reduced toxicity compared with IMRT. Considering the impact of cardiopulmonary toxicity on PORT outcomes, PBT warrants prospective evaluation.

Postoperative Radiotherapy for Locally Advanced NSCLC: Implications for Shifting to Conformal, High-Risk Fields.

BACKGROUND: To examine the effect of radiotherapy field size on survival outcomes and patterns of recurrence in patients treated with postoperative radiotherapy (PORT) for non-small-cell lung cancer (NSCLC). METHODS: We retrospectively reviewed the records of 216 patients with T1-4 N1-2 NSCLC following surgery and PORT using whole mediastinum (WM) or high-risk (HR) nodal fields from 1998 to 2015. Survival rates were calculated using the Kaplan-Meier method. Univariate and multivariable analyses were conducted using Cox proportional hazards modeling for outcomes and logistic regression analysis for treatment toxicities. RESULTS: Median follow-up was 28 months (interquartile range [IQR] 13-75 months) and 38 months (IQR 19-73 months) for WM (n = 131) and HR (n = 84) groups, respectively. Overall survival (OS) was not significantly different between groups (median OS: HR 49 vs. WM 32 months; P = .08). There was no difference in progression-free survival (PFS), freedom from locoregional recurrence (LRR), or freedom from distant metastasis (P > .2 for all). Field size was not associated with OS, PFS, or LRR (P > .40 for all). LRR rates were 20% for HR and 26% for WM groups (P = .30). There was no significant difference in patterns of initial site of LRR between groups (P > .1). WM fields (OR 3.73, P = .001) and concurrent chemotherapy (odds ratio 3.62, P = .001) were associated with grade ≥2 toxicity. CONCLUSIONS: Locoregional control and survival rates were similar between PORT groups; an improved toxicity profile was observed in the HR group. Results from an ongoing prospective randomized clinical trial will provide further insight into the consequences of HR PORT fields.

Thoracic Radiation Oncology Clinical Trial Accrual and Reasons for Nonenrollment: Results of a Large, Prospective, Multiyear Analysis.

PURPOSE: Clinical trials are considered the gold standard in evidence-based medicine, yet few patients with cancer ultimately enroll. Here we examine patients screened for thoracic radiation oncology clinical trials to better understand enrollment trends. METHODS AND MATERIALS: A prospective database tracking screening and enrollment for patients referred for thoracic radiation oncology consultation at our institution from 2016 to 2019 was evaluated. Proportional enrollment rates, patient and disease characteristics, self-reported socioeconomic factors, and reasons for ineligibility or nonenrollment across 17 radiation therapy trials were compared. RESULTS: Enrollment data on 2372 patients were available for analysis. Of these patients, 40.0% (949) were deemed "not eligible" (NE) for any trial or were unwilling to be further screened. Reasons for ineligibility included stage (44%), histology (13%), radiation therapy not indicated (12%), patient decision (7%), and enrollment in a competing medical or surgical oncology trial (5%). The remaining 60.0% (1423) were "potentially eligible" (PE) for one or more trials. Most had non-small cell lung cancer (71%) or esophageal cancer (16%), and there were significantly fewer stage IV PE (29%) versus NE (49%) patients (P < .0001). Of 2372 patients, 281 (11.9%) enrolled. Notable reasons for nonenrollment were inclusion and exclusion criteria (58%), patients declining enrollment (14%), and physician decision (5%). The proportion of white patients was higher in the PE versus NE group (82.5% vs 75.8%; P < .001). Additionally, white race (87.9% vs 81.2%; P = .008), English language preference (96.4% vs 92.9%; P = .032), and non-Hispanic/Latino ethnicity (94.0% vs 90.1%; P = .042) were significantly different in enrolled versus nonenrolled PE patients. CONCLUSIONS: Only 12% of patients screened for radiation therapy trials ultimately enrolled, and more than two-thirds had no trial available or were found ineligible. In addition, 19% of potential eligible patients did not enroll because the patient or physician declined. Future trials may benefit from pragmatic designs with more inclusive enrollment criteria and multidisciplinary engagement of referring providers.

Stereotactic body radiation therapy (SBRT) in the management of pulmonary spindle cell carcinoma.

A 69-year-old woman underwent routine screening with CT scan of the chest, which showed a new right upper lobe lesion. Interval increase in size of the right upper lobe nodule over 3 months, prompted a CT-guided biopsy of the lung that confirmed a diagnosis of malignant pulmonary spindle cell carcinoma (PSCC) with 90% programmed death ligand 1 expression. Positron emission tomography CT demonstrated localised stage IIA disease. Given histologically proven PSCC and the rapid growth of her tumour, curative radiation with stereotactic body radiation therapy (SBRT) to the right upper lobe primary tumour was planned as patient was deemed not to be a surgical candidate. Repeat imaging with a CT chest 2 months after SBRT demonstrated good local control of the primary disease in the right upper lobe despite rapidly advancing distant metastasis. The patient continues systemic therapy with pembrolizumab, to which she has shown good response.

Association of Medicaid Insurance With Survival Among Patients With Small Cell Lung Cancer.

Importance: Small cell lung cancer (SCLC) is an aggressive neoplasm requiring rapid access to subspecialized multidisciplinary care. For this reason, insurance coverage such as Medicaid may be associated with oncologic outcomes in this disproportionately economically vulnerable population. With Medicaid expansion under the Affordable Care Act, it is important to understand outcomes associated with Medicaid coverage among patients with SCLC. Objective: To determine the association of Medicaid coverage with survival compared with other insurance statuses. Design, Setting, and Participants: This cohort study included adult patients with limited-stage (LS) and extensive-stage (ES) SCLC in the US National Cancer Database from 2004 to 2013. Data were analyzed in January 2019. Main Outcomes and Measures: Patients were analyzed with respect to insurance status. Associations of insurance status with survival were interrogated with univariate analyses, multivariable analyses, and propensity score matching. Results: A total of 181 784 patients with SCLC (93 131 [51.2%] female; median [interquartile range] age; 67 [60-75] years for patients with LS-SCLC and 68 [60-75] years for patients with ES-SCLC) were identified, of whom 70 247 (38.6%) had LS-SCLC and 109 479 (60.2%) had ES-SCLC. On univariate analyses of patients with LS-SCLC, Medicaid coverage was not associated with a survival advantage compared with being uninsured (hazard ratio, 1.02; 95% CI, 0.96-1.08; P = .49). Likewise, on multivariable analyses of patients with ES-SCLC, compared with being uninsured, Medicaid coverage was not associated with a survival advantage (hazard ratio, 1.00; 95% CI, 0.96-1.03; P = .78). After propensity score matching, median survival was similar between the uninsured and Medicaid groups both among patients with LS-SCLC (14.4 vs 14.1 months; hazard ratio, 1.05; 95% CI, 0.98-1.12; P = .17) and those with ES-SCLC (6.3 vs 6.4 months; hazard ratio, 1.00; 95% CI, 0.96-1.04; P = .92). Conclusions and Relevance: Despite of billions of dollars in annual federal and state spending, Medicaid was not associated with improved survival in patients with SCLC compared with being uninsured in the US National Cancer Database. These findings suggest that there are substantial outcome inequalities for SCLC relevant to the policy debate on the Medicaid expansion under the Affordable Care Act.

Randomized Phase IIB Trial of Proton Beam Therapy Versus Intensity-Modulated Radiation Therapy for Locally Advanced Esophageal Cancer.

PURPOSE: Whether dosimetric advantages of proton beam therapy (PBT) translate to improved clinical outcomes compared with intensity-modulated radiation therapy (IMRT) remains unclear. This randomized trial compared total toxicity burden (TTB) and progression-free survival (PFS) between these modalities for esophageal cancer. METHODS: This phase IIB trial randomly assigned patients to PBT or IMRT (50.4 Gy), stratified for histology, resectability, induction chemotherapy, and stage. The prespecified coprimary end points were TTB and PFS. TTB, a composite score of 11 distinct adverse events (AEs), including common toxicities as well as postoperative complications (POCs) in operated patients, quantified the extent of AE severity experienced over the duration of 1 year following treatment. The trial was conducted using Bayesian group sequential design with three planned interim analyses at 33%, 50%, and 67% of expected accrual (adjusted for follow-up). RESULTS: This trial (commenced April 2012) was approved for closure and analysis upon activation of NRG-GI006 in March 2019, which occurred immediately prior to the planned 67% interim analysis. Altogether, 145 patients were randomly assigned (72 IMRT, 73 PBT), and 107 patients (61 IMRT, 46 PBT) were evaluable. Median follow-up was 44.1 months. Fifty-one patients (30 IMRT, 21 PBT) underwent esophagectomy; 80% of PBT was passive scattering. The posterior mean TTB was 2.3 times higher for IMRT (39.9; 95% highest posterior density interval, 26.2-54.9) than PBT (17.4; 10.5-25.0). The mean POC score was 7.6 times higher for IMRT (19.1; 7.3-32.3) versus PBT (2.5; 0.3-5.2). The posterior probability that mean TTB was lower for PBT compared with IMRT was 0.9989, which exceeded the trial's stopping boundary of 0.9942 at the 67% interim analysis. The 3-year PFS rate (50.8% v 51.2%) and 3-year overall survival rates (44.5% v 44.5%) were similar. CONCLUSION: For locally advanced esophageal cancer, PBT reduced the risk and severity of AEs compared with IMRT while maintaining similar PFS.

An improved method for analyzing and reporting patterns of in-field recurrence after stereotactic ablative radiotherapy in early-stage non-small cell lung cancer.

INTRODUCTION: Patterns of local, regional, and distant failure after stereotactic ablative radiotherapy (SABR) for early-stage non-small cell lung cancer (NSCLC) have been widely reported. However, reliable methods for analyzing causes of local failure are lacking. We describe a method for analyzing and reporting patterns of in-field recurrence after SABR, incorporating dosimetric parameters from initial treatment plan as well as geometric information from diagnostic images at recurrence. MATERIAL AND METHODS: Diagnostic CT images at recurrence were registered with initial treatment planning images and radiation dose by deformable image registration. Recurrent gross tumor volume (rGTV) and centroid (geometric center of rGTV) were delineated. In-field failure was classified as centroids originating within the original planning target volume. Dose-volume histograms for each rGTV were used to further classify in-field recurrences as central high-dose (dose to 95% of rGTV [rGTVD95%] ≥95% of dose prescribed to PTV) or peripheral high-dose (rGTVD95% <95% of dose prescribed to PTV). RESULTS: 634 patients received SABR from 2004 to 2014 with 48 local recurrences. 35 of these had evaluable images with 16 in-field recurrences: 9 central high-dose, 6 peripheral high-dose, and 1 had both. Time to and volume of recurrence were not statistically different between central versus peripheral high-dose recurrences. However mean rGTV dose, mean centroid dose, and rGTVD95% were higher for central versus peripheral high-dose recurrences. CONCLUSION: We report a standardized method for analysis and classification of in-field recurrence after SABR. There were more central as opposed to peripheral high-dose recurrences, suggesting biological rather than technical issues underlying majority of in-field failures.

Does Proton Therapy Offer Demonstrable Clinical Advantages for Treating Thoracic Tumors?

The finite range of proton beams in tissues offers unique dosimetric advantages that theoretically allow dose to the target to be escalated while minimizing exposure of surrounding tissues and thus minimizing radiation-induced toxicity. This theoretical advantage has led to widespread adoption of proton therapy around the world for a wide variety of tumors at different anatomical sites. Many treatment-planning comparisons have shown that proton therapy has substantial dosimetric advantages over conventional radiotherapy. However, given the significant difference in cost for proton vs conventional photon therapy, thorough investigation of the evidence of proton therapy's clinical benefits in terms of toxicity and survival is warranted. Some data from retrospective studies, single-arm prospective studies, and a very few randomized clinical trials comparing these modalities are beginning to emerge. In this review, we examine the available data with regard to proton therapy for thoracic malignancies. We begin by discussing the unique challenges involved in treating moving targets with significant tissue heterogeneity and the technologic efforts underway to overcome these challenges. We then discuss the rationale for minimizing normal tissue toxicity, particularly pulmonary, cardiac, and hematologic toxicity, within the context of previously unsuccessful attempts at dose escalation for lung and esophageal cancer. Finally, we explore strategies for accelerating the development of trials aimed at measuring meaningful clinical endpoints and for maximizing the value of proton therapy by personalizing its use for individual patients.

Preclinical rationale for combining radiation therapy and immunotherapy beyond checkpoint inhibitors (i.e., CART).

An increasing appreciation for the role of the immune system in targeting cancer cells over the last decade has led to the development of several immunomodulatory agents aimed at enhancing the systemic antitumor immune response. One such method is the use of T cells that are genetically engineered to express chimeric antigen receptors (CARs). The remarkable success of this approach in advanced hematologic malignancies has garnered much enthusiasm for using this novel tool in treating other cancers. However, multiple challenges have hampered the application of this therapy to a broader set of solid tumors, most notably lung cancer. Immunotherapy has already shown great success in lung cancer, and is now the first-line treatment in PD-L1 expressing metastatic disease. Given the mounting evidence that radiation therapy plays a crucial role in amplifying the immune response elicited by immunomodulatory agents, there is potential for radiation to help in overcoming some of these challenges. In this review, we describe the basic principles of CAR T cell therapy and examine its successes and challenges to date. We then discuss the preclinical and clinical data supporting the use of radiation with immunomodulatory agents with a focus on preclinical rationale for combining CAR T cells and radiation therapy in future experiments with a focus on lung cancer.

Macrophage-dependent tumor cell transendothelial migration is mediated by Notch1/MenaINV-initiated invadopodium formation.

The process of intravasation involving transendothelial migration is a key step in metastatic spread. How the triple cell complex composed of a macrophage, Mena over-expressing tumor cell and endothelial cell, called the tumor microenvironment of metastasis (TMEM), facilitates tumor cell transendothelial migration is not completely understood. Previous work has shown that the physical contact between a macrophage and tumor cell results in the formation of invadopodia, actin-rich matrix degrading protrusions, important for tumor cell invasion and transendothelial migration and tumor cell dissemination. Herein, we show that the macrophage-induced invadopodium is formed through a Notch1/MenaINV signaling pathway in the tumor cell upon macrophage contact. This heterotypic tumor cell - macrophage interaction results in the upregulation of MenaINV through the activation of MENA transcription. Notch1 and MenaINV expression are required for tumor cell transendothelial migration, a necessary step during intravasation. Inhibition of the Notch signaling pathway blocked macrophage-induced invadopodium formation in vitro and the dissemination of tumor cells from the primary tumor in vivo. Our findings indicate a novel role for Notch1 signaling in the regulation of MenaINV expression and transendothelial migration and provide mechanistic information essential to the use of therapeutic inhibitors of metastasis.

Awakening the immune system with radiation: Optimal dose and fractionation.

The importance of ionizing radiation has historically been limited to achieving local control of tumor cells. However, emerging evidence over the last decade suggests an increasingly important role for radiation in amplifying the antitumor immune response elicited by immunomodulatory agents. Combination of radiation with immunotherapy has been shown to elicit powerful systemic responses in several pre-clinical tumor models. Additionally, recent clinical observations support the use of radiation therapy for augmenting antitumor immunity in the metastatic setting. However, radiation dose and fractionation schedules for optimal synergy between radiotherapy and immunotherapy are not well defined. Here we review pre-clinical and clinical data relating to radiation dose and fractionation in the setting of immunotherapy and discuss optimal strategies for combining the two therapies.