Risk of subsequent primary cancers after carbon ion radiotherapy, photon radiotherapy, or surgery for localised prostate cancer: a propensity score-weighted, retrospective, cohort study.

BACKGROUND: The risk of subsequent primary cancers in patients with prostate cancer after treatment with photon radiotherapy is small in absolute numbers, but it is higher than that after surgical treatment. Carbon ion radiotherapy has a theoretically lower risk of inducing secondary malignancies than photon radiotherapy, but this risk has not been investigated in practice because of the low number of facilities offering such therapy worldwide and the limited data on long-term follow-up because the therapy has only been available since 1994. We aimed to analyse the risk of subsequent primary cancers after treatment with carbon ion radiotherapy in patients with localised prostate cancer and to compare it with that after photon radiotherapy or surgery in this setting. METHODS: In this retrospective cohort study, we reviewed records of patients who received carbon ion radiotherapy for prostate cancer between June 27, 1995, and July 10, 2012, at the National Institute of Radiological Sciences (NIRS) in Japan. We also retrieved the records of patients diagnosed and treated for prostate cancer between Jan 1, 1994, and Dec 31, 2012, from the Osaka Cancer Registry. Eligible patients had histologically confirmed localised prostate cancer and a minimum follow-up of at least 3 months; no age restrictions were applied. We excluded patients with metastasis, node-positive disease, or locally invasive (T4 stage) prostate cancer, those with previous or synchronous malignancies, and those who received previous radiotherapy or chemotherapy. We did a multivariable analysis to estimate predictors of subsequent cancers after carbon ion radiotherapy treatment. We also used propensity score inverse probability weighting to retrospectively compare the incidence of subsequent cancers in patients with localised prostate cancer treated with carbon beams, photon radiotherapy, or surgery. FINDINGS: Of 1580 patients who received carbon radiotherapy for prostate cancer at the NIRS, 1455 (92%) patients met the eligibility criteria. Of 38 594 patients with prostate cancer identified in the Osaka registry, 1983 (5%) patients treated with photon radiotherapy and 5948 (15%) treated with surgery were included. Median follow-up durations were 7·9 years (IQR 5·9-10·0) for patients who received carbon ion radiotherapy (after limiting the database to 10-year maximum follow-up), 5·7 years (4·5-6·4) for patients who received photon radiotherapy, and 6·0 years (5·0-8·6) for those who received surgery. 234 subsequent primary cancers were diagnosed in the carbon ion radiotherapy cohort; some patients developed several tumours. On multivariable analysis, age (p=0·0021 for 71-75 years vs ≤60 years; p=0·012 for >75 years vs ≤60 years) and smoking (p=0·0005) were associated with a higher risk of subsequent primary cancers in patients treated with carbon ion radiotherapy. In the propensity score-weighted analyses, carbon ion radiotherapy was associated with a lower risk of subsequent primary cancers than photon radiotherapy (hazard ratio [HR] 0·81 [95% CI 0·66-0·99]; p=0·038) or surgery (HR 0·80 [0·68-0·95]; p=0·0088), whereas photon radiotherapy was associated with a higher risk of subsequent primary cancers than surgery (HR 1·18 [1·02-1·36]; p=0·029). INTERPRETATION: Our analysis suggests that patients with localised prostate cancer treated with carbon ion radiotherapy appear to have a lower risk of subsequent primary cancers than those treated with photon radiotherapy. Although prospective evaluation with longer follow-up is warranted to support these results, our data supports a wider adoption of carbon ion radiotherapy for patients with expected long-term overall survival or those with poor outcomes after receiving conventional treatments. FUNDING: Research Project for Heavy Ions at the National Institute of Radiological Sciences (Japan).

A Phase I/II Study of Nab-Paclitaxel, Cisplatin, and Cetuximab With Concurrent Radiation Therapy for Locally Advanced Squamous Cell Cancer of the Head and Neck.

Nab-paclitaxel might impact efficacy of radiation for head and neck (H&N) cancer. Nab-paclitaxel, cisplatin, cetuximab, and radiation were evaluated in patients with locally advanced head and neck cancer in this phase I/II trial. Median follow-up was 24 months for 34 patients. The maximum tolerated dose of nab-paclitaxel was 20 mg/m2 with 20 mg/m2 cisplatin and 250 mg/m2 cetuximab. The 2-year progression-free survival (PFS) was 60% (95% confidence interval (CI) 0.42, 0.78), local control 71% (95% CI 0.55, 0.87), and overall survival 68% (95% CI 0.50, 0.86). This is the first study evaluating these agents with radiation in humans, with similar 2-year PFS as historic control.

Standard-dose versus high-dose conformal radiotherapy with concurrent and consolidation carboplatin plus paclitaxel with or without cetuximab for patients with stage IIIA or IIIB non-small-cell lung cancer (RTOG 0617): a randomised, two-by-two factorial phase 3 study.

BACKGROUND: We aimed to compare overall survival after standard-dose versus high-dose conformal radiotherapy with concurrent chemotherapy and the addition of cetuximab to concurrent chemoradiation for patients with inoperable stage III non-small-cell lung cancer. METHODS: In this open-label randomised, two-by-two factorial phase 3 study in 185 institutions in the USA and Canada, we enrolled patients (aged ≥ 18 years) with unresectable stage III non-small-cell lung cancer, a Zubrod performance status of 0-1, adequate pulmonary function, and no evidence of supraclavicular or contralateral hilar adenopathy. We randomly assigned (1:1:1:1) patients to receive either 60 Gy (standard dose), 74 Gy (high dose), 60 Gy plus cetuximab, or 74 Gy plus cetuximab. All patients also received concurrent chemotherapy with 45 mg/m(2) paclitaxel and carboplatin once a week (AUC 2); 2 weeks after chemoradiation, two cycles of consolidation chemotherapy separated by 3 weeks were given consisting of paclitaxel (200 mg/m(2)) and carboplatin (AUC 6). Randomisation was done with permuted block randomisation methods, stratified by radiotherapy technique, Zubrod performance status, use of PET during staging, and histology; treatment group assignments were not masked. Radiation dose was prescribed to the planning target volume and was given in 2 Gy daily fractions with either intensity-modulated radiation therapy or three-dimensional conformal radiation therapy. The use of four-dimensional CT and image-guided radiation therapy were encouraged but not necessary. For patients assigned to receive cetuximab, 400 mg/m(2) cetuximab was given on day 1 followed by weekly doses of 250 mg/m(2), and was continued through consolidation therapy. The primary endpoint was overall survival. All analyses were done by modified intention-to-treat. The study is registered with ClinicalTrials.gov, number NCT00533949. FINDINGS: Between Nov 27, 2007, and Nov 22, 2011, 166 patients were randomly assigned to receive standard-dose chemoradiotherapy, 121 to high-dose chemoradiotherapy, 147 to standard-dose chemoradiotherapy and cetuximab, and 110 to high-dose chemoradiotherapy and cetuximab. Median follow-up for the radiotherapy comparison was 22.9 months (IQR 27.5-33.3). Median overall survival was 28.7 months (95% CI 24.1-36.9) for patients who received standard-dose radiotherapy and 20.3 months (17.7-25.0) for those who received high-dose radiotherapy (hazard ratio [HR] 1.38, 95% CI 1.09-1.76; p=0.004). Median follow-up for the cetuximab comparison was 21.3 months (IQR 23.5-29.8). Median overall survival in patients who received cetuximab was 25.0 months (95% CI 20.2-30.5) compared with 24.0 months (19.8-28.6) in those who did not (HR 1.07, 95% CI 0.84-1.35; p=0.29). Both the radiation-dose and cetuximab results crossed protocol-specified futility boundaries. We recorded no statistical differences in grade 3 or worse toxic effects between radiotherapy groups. By contrast, the use of cetuximab was associated with a higher rate of grade 3 or worse toxic effects (205 [86%] of 237 vs 160 [70%] of 228 patients; p<0.0001). There were more treatment-related deaths in the high-dose chemoradiotherapy and cetuximab groups (radiotherapy comparison: eight vs three patients; cetuximab comparison: ten vs five patients). There were no differences in severe pulmonary events between treatment groups. Severe oesophagitis was more common in patients who received high-dose chemoradiotherapy than in those who received standard-dose treatment (43 [21%] of 207 patients vs 16 [7%] of 217 patients; p<0.0001). INTERPRETATION: 74 Gy radiation given in 2 Gy fractions with concurrent chemotherapy was not better than 60 Gy plus concurrent chemotherapy for patients with stage III non-small-cell lung cancer, and might be potentially harmful. Addition of cetuximab to concurrent chemoradiation and consolidation treatment provided no benefit in overall survival for these patients. FUNDING: National Cancer Institute and Bristol-Myers Squibb.

Stereotactic ablative body radiation therapy for tumors in the lung in octogenarians: a retrospective single institution study.

BACKGROUND: Treatment of cancer in the lung in octogenarians is limited by their health and functional status. Stereotactic ablative radiotherapy is an established noninvasive treatment option for medically inoperable patients, with a toxicity profile that may be more tolerable in elderly patients. METHODS: Patients more than 80 years old treated with stereotactic ablative radiotherapy for malignant tumors in the lung between January 2007 and August 2012 at a single institution were identified and retrospectively analyzed for toxicity and survival. RESULTS: Thirty patients were identified with a total of 32 lesions treated. Patients ranged in age from 80.8 to 90.7 years old (median 84.9) at the time of treatment. Twenty patients had ECOG performance status 0-1, and 10 had performance status 2-3. Stage distribution at treatment was: stage I (20 patients), stage III (1), stage IV (1), and 8 recurrent tumors. Patients were treated to a median total dose of 54 Gy in 3 fractions (range 20-60 Gy in 1 to 5 fractions). Median follow up was 13 months (range 2-60 months). Fifteen patients were still living at last review. There was one failure in field and one failure in the same lobe that was treated. One patient died with progressive regional disease, and four died of progressive metastatic disease. Three patients had late grade 3 pulmonary dyspnea with no grade 4 or 5 toxicities. One patient had late grade 2 pneumonitis, and 3 patients had late grade 1 pneumonitis. Three patients had grade 1 chest wall pain. CONCLUSIONS: Octogenarians tolerated ablative treatment with minimal toxicity. Stereotactic ablative body radiotherapy is an option to consider in treatment of elderly patients.

Vorinostat as a radiosensitizer for brain metastasis: a phase I clinical trial.

Perform a phase I study to evaluate the safety, and tolerability of vorinostat, an HDAC inhibitor, when combined with whole brain radiation treatment (WBRT) in patients with brain metastasis. A multi-institutional phase I clinical trial enrolled patients with a histological diagnosis of malignancy and radiographic evidence of brain metastasis. WBRT was 37.5 Gy in 2.5 Gy fractions delivered over 3 weeks. Vorinostat was administrated by mouth, once daily, Monday through Friday, concurrently with radiation treatment. The vorinostat dose was escalated from 200 to 400 mg daily using a 3+3 trial design. Seventeen patients were enrolled, 4 patients were excluded from the analysis due to either incorrect radiation dose (n = 1), or early treatment termination due to disease progression (n = 3). There were no treatment related grade 3 or higher toxicities in the 200 and 300 mg dose levels. In the 400 mg cohort there was a grade 3 pulmonary embolus and one death within 30 days of treatment. Both events were most likely related to disease progression rather than treatment; nonetheless, we conservatively classified the death as a dose limiting toxicity. We found Vorinostat administered with concurrent WBRT to be well tolerated to a dose of 300 mg once daily. This is the recommended dose for phase II study.

National Effort to Re-Establish Heavy Ion Cancer Therapy in the United States.

In this review, we attempt to make a case for the establishment of a limited number of heavy ion cancer research and treatment facilities in the United States. Based on the basic physics and biology research, conducted largely in Japan and Germany, and early phase clinical trials involving a relatively small number of patients, we believe that heavy ions have a considerably greater potential to enhance the therapeutic ratio for many cancer types compared to conventional X-ray and proton radiotherapy. Moreover, with ongoing technological developments and with research in physical, biological, immunological, and clinical aspects, it is quite plausible that cost effectiveness of radiotherapy with heavier ions can be substantially improved.

A How-To Compendium for GammaPod Treatments, Clinical Workflow, and Clinical Program at an Early Adopting Institution.

In 2019, our institution became the second in the world to go live with GammaPod (Xcision Medical Systems, LLC, Columbia, MD), a device dedicated for stereotactic radiation therapy of breast cancer, with breast immobilization, real-time imaging, and highly-conformal dosimetry. At our institution, GammaPod is used for 5-fraction adjuvant partial breast irradiation, single-fraction tumor cavity boost before whole-breast irradiation, single-fraction preoperative radiation, and (in poor surgical candidates), single-fraction definitive radiation. Here, we describe our workflow, observed procedure step times, and homegrown techniques for improved efficiency in our institutional experience of 93 patients treated between 2019 and 2021.

Phase II Trial of Stereotactic Ablative Radiation for Oligoprogressive Metastatic Kidney Cancer.

BACKGROUND: Patients with metastatic renal cell carcinoma (mRCC) treated with systemic therapy sometimes progress at limited sites.The best treatment approach for patients with oligoprogression remains unclear. OBJECTIVE: To determine the ability of stereotactic ablative radiation (SAbR) to extend ongoing systemic therapy in mRCC patients with oligoprogression. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase II clinical trial was conducted at a university medical center and county hospital, including 20 patients with mRCC on first- to fourth-line systemic therapy with three or fewer sites of progression (including new sites) involving ≤30% of all sites. INTERVENTION: SAbR to oligoprogressing metastases at outset and longitudinally, while radiated sites remain controlled and overall disease oligoprogressive. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary objective was to extend ongoing systemic therapy by >6 mo in >40% of patients. Secondary endpoints included overall survival, toxicity, and patient-reported quality of life. RESULTS AND LIMITATIONS: Twenty patients were enrolled. Upfront and sequential SAbR was administered to a total of 37 sites. The local control rate was 100%. At a median follow-up of 10.4 mo (interquartile range: 5.8-16.4), SAbR extended the duration of the ongoing systemic therapy by >6 mo in 14 patients (70%, 95% confidence interval [CI]: 49.9-90.1). The median time from SAbR to the onset of new systemic therapy or death was 11.1 mo (95% CI: 4.5-19.3). The median duration of SAbR-aided systemic therapy was 24.4 mo (95% CI: 15.3-42.2). Median overall survival was not reached. One patient developed grade 3 gastrointestinal toxicity possibly related to treatment. There was no significant decline in quality of life. Limitations include nonrandomized design and a small patient cohort. CONCLUSIONS: SAbR extended the duration of the ongoing systemic therapy for patients with oligoprogressive mRCC without undermining quality of life. These data support the evaluation of SAbR for oligoprogressive mRCC in a prospective randomized clinical trial. PATIENT SUMMARY: Patients with metastatic kidney cancer on systemic therapy but progressing at limited sites may benefit from focused radiation to progressive sites. Focused radiation was safe and effective, and extended the duration of the ongoing systemic therapy.

T Stage and Pretreatment Standardized Uptake Values Predict Tumor Recurrence With 5-Fraction SABR in Early-Stage Non-Small Cell Lung Cancer.

Purpose: Five-fraction stereotactic ablative radiotherapy (SABR) regimens are frequently used to treat centrally located early-stage non-small cell lung cancer or disease in the proximity of the chest wall as a means of optimizing tumor control and reducing treatment toxicity. However, increasing these SABR regimens to 5 fractions may reduce tumor control outcomes. We sought to identify the clinical parameters predictive of treatment failures with these 5-fraction courses. Methods: Ninety patients with T1-2 non-small cell lung cancer were treated with 50 or 60 Gy in 5 fractions. Failure over time was modeled using cumulative incidences of local, regional, or distant failure, with death as a competing risk. Cox proportional hazards analysis for incidences of failure was performed to control for patient variables. Results: Of 90 patients, 24 of 53 patients with T1 tumors and 19 of 37 patients with T2 tumors received 50 Gy SABR, and the other 47 patients received 60 Gy. Two-year overall survival and progression-free survival for the whole cohort were 75.8% and 59.3%, respectively. Total SABR dose (50 vs 60 Gy) did not influence survival nor failure rates at 2 and 5 years. Within 2 years of treatment, 7.8% of all patients developed local failure. For all patient and tumor characteristics evaluated, only T stage and pretreatment positron emission tomography standardized uptake values served as predictors of local, regional, and distant failure at 2 and 5 years posttreatment on univariate and multivariable analysis. Conclusions: Five-fraction SABR provides excellent in-field control. T2 and high fluorodeoxyglucose uptake tumors have increased failure rates, suggesting the potential need for adjuvant therapies, which are being assessed in randomized phase 3 trials.

Stereotactic Ablative Radiation for Systemic Therapy-naïve Oligometastatic Kidney Cancer.

BACKGROUND: Evidence-based guidelines for the management of systemic therapy-naïve oligometastatic renal cell carcinoma (RCC) are lacking. OBJECTIVE: To evaluate the potential of stereotactic ablative radiotherapy (SAbR) to provide longitudinal disease control while preserving quality of life (QOL) in patients with systemic therapy-naïve oligometastatic RCC. DESIGN, SETTING, AND PARTICIPANTS: RCC patients with three or fewer extracranial metastases were eligible. SAbR was administered longitudinally to all upfront and, as applicable, subsequent metastases. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: This prospective phase II single-arm trial was powered to achieve a primary objective of freedom from systemic therapy for >1 yr in >60% of patients (using the Clopper and Pearson methodology). Secondary endpoints included progression-free survival (PFS), defined as the time from first SAbR to progression not amenable to SAbR (local failure at SAbR-treated sites, new metastases not amenable to SAbR, more than three new metastases, or brain metastases); patient-reported QOL metrics; local control (LC) rates; toxicity; cancer-specific survival (CSS); and overall survival (OS). RESULTS AND LIMITATIONS: Twenty-three patients received SAbR to 33 initial and 57 total sites. The median follow-up was 21.7 mo (interquartile range 16.3-30.3). Exceeding the prespecified 60% benchmark, freedom from systemic therapy at 1 yr was 91.3% (95% confidence interval [CI]: 69.5, 97.8). One-year PFS was 82.6% (95% CI: 60.1, 93.1). QOL was largely unaffected. LC was 100%. There were no grade 3/4 toxicities, but there was one death due to immune-related colitis 3 mo after SAbR while on subsequent checkpoint inhibitor therapy, where a SAbR contribution could not be excluded. One-year OS was 95.7% (95% CI: 72.9, 99.4); one-year CSS was 100%. CONCLUSIONS: SAbR for oligometastatic RCC was associated with meaningful longitudinal disease control while preserving QOL. These data support further evaluation of SAbR for systemic therapy-naïve oligometastatic RCC. PATIENT SUMMARY: Sequential stereotactic radiation therapy can safely and effectively control metastatic kidney cancer with limited spread for over a year without compromising patients' quality of life.

SABR for High-Risk Prostate Cancer: A Prospective Multilevel MRI-Based Dose Escalation Trial.

PURPOSE: Radiation dose intensification improves outcome in men with high-risk prostate cancer (HR-PCa). A prospective trial was conducted to determine safety, feasibility, and maximal tolerated dose of multilevel magnetic resonance imaging (MRI)-based 5-fraction SABR in patients with HR-PCa. METHODS AND MATERIALS: This phase I clinical trial enrolled patients with HR-PCa with grade group ≥4, prostate-specific antigen (PSA) ≥20 ng/mL, or radiographic ≥T3, and well-defined prostatic lesions on multiparametric MRI (mpMRI) into 4 dose-escalation cohorts. The initial cohort received 47.5 Gy to the prostate, 50 Gy to mpMRI-defined intraprostatic lesion(s), and 22.5 Gy to pelvic lymph nodes in 5 fractions. Radiation doses were escalated for pelvic nodes to 25 Gy and mpMRI lesion(s) to 52.5 Gy and then 55 Gy. Escalation was performed sequentially according to rule-based trial design with 7 to 15 patients per cohort and a 90-day observation period. All men received peri-rectal hydrogel spacer, intraprostatic fiducial placement, and 2 years of androgen deprivation. The primary endpoint was maximal tolerated dose according to a 90-day acute dose-limiting toxicity (DLT) rate <33%. DLT was defined as National Cancer Institute Common Toxicity Criteria for Adverse Events ≥grade 3 treatment-related toxicity. Secondary outcomes included acute and delayed gastrointestinal (GI)/genitourinary (GU) toxicity graded with Common Toxicity Criteria for Adverse Events. RESULTS: Fifty-five of the 62 enrolled patients were included in the analysis. Dose was escalated through all 4 cohorts without observing any DLTs. Median overall follow-up was 18 months, with a median follow-up of 42, 24, 12, and 7.5 months for cohorts 1 to 4 respectively. Acute and late grade 2 GU toxicities were 25% and 20%, while GI were 13% and 7%, respectively. Late grade 3 GU and GI toxicities were 2% and 0%, respectively. CONCLUSIONS: SABR dose for HR-PCa was safely escalated with multilevel dose painting of 47.5 Gy to prostate, 55 Gy to mpMRI-defined intraprostatic lesions, and 25 Gy to pelvic nodal region in 5 fractions. Longer and ongoing follow-up will be required to assess late toxicity.

Cetuximab in combination therapy: from bench to clinic.

Cetuximab, a chimeric IgG(1) monoclonal antibody directed against the ligand-binding domain of the epidermal growth factor receptor, offers a paradigm for the combination of molecularly targeted therapies with cytotoxic agents. In preclinical models, the addition of cetuximab to chemotherapy or radiation therapy enhances antitumor activity. Proposed mechanisms include reducing tumor cell proliferation, angiogenesis, and DNA repair capacity; increasing apoptosis; and inducing cell cycle arrest at treatment-sensitive points. These effects may enhance and restore tumor sensitivity to cytotoxic therapies. In clinical trials, the addition of cetuximab to chemotherapy improves outcomes of patients who had previously failed such agents, as illustrated in irinotecan-resistant and oxaliplatin-refractory metastatic colorectal cancer. As initial therapy, the addition of cetuximab to chemotherapy extends survival in colorectal cancer, lung cancer, and head and neck cancer. Combining cetuximab with radiation therapy extends survival in locally advanced head and neck cancer. As predictive biomarkers are identified, it may become possible to select patients most likely to benefit from such combinations.

Stereotactic Ablative Radiation Therapy for Oligoprogressive Renal Cell Carcinoma.

PURPOSE: Oligoprogression, defined as limited sites of progression on systemic therapy, in patients with metastatic renal cell carcinoma (mRCC) is not uncommon, possibly because of inter- and intratumoral heterogeneity. We evaluated the effect of stereotactic ablative radiation therapy (SAbR) for longitudinal control of oligoprogressive mRCC. METHODS AND MATERIALS: Patients with extracranial mRCC were included in this retrospective analysis if they progressed in ≤3 sites on systemic therapy while demonstrating response/stability at other sites and received SAbR to all progressing sites without switching systemic therapy. Our primary endpoint was modified progression-free survival (mPFS), which we calculated from the start of SAbR to the start of a subsequent systemic therapy, death, or loss to follow-up. RESULTS: We identified 36 patients with a median follow-up of 20.4 months (interquartile range, 10.9-29.4). Forty-three sites were treated with SAbR with a median dose of 36 Gy (range, 18-50) in 3 fractions (range, 1-5). Median time to SAbR from the start of systemic therapy was 11.4 months (interquartile range, 6.1-17.1). Median mPFS was 9.2 months (95% confidence interval [CI], 5.9-13.2). Patients receiving SAbR while on immunotherapy exhibited a longer median mPFS (>28.4 months, log-rank P = .0001) than patients not on immunotherapy (9.2 months). Median overall survival from SAbR administration was 43.4 months (95% CI, 21.5-not Reached). The 1-year local control rate was 93% (95% CI, 78.7-97.5). Most SAbR-related toxicities were grade 1 to 2 (33% of patients), with one grade 5 hemoptysis event possibly related to SAbR or disease progression. CONCLUSIONS: SAbR has the potential to extend the the duration of current systemic therapy for selected patients with mRCC, preserving subsequent therapies for later administration possibly enabling longer treatment duration.

Outcome and Immune Correlates of a Phase II Trial of High-Dose Interleukin-2 and Stereotactic Ablative Radiotherapy for Metastatic Renal Cell Carcinoma.

PURPOSE: This phase II clinical trial evaluated whether the addition of stereotactic ablative radiotherapy (SAbR), which may promote tumor antigen presentation, improves the overall response rate (ORR) to high-dose IL2 (HD IL2) in metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: Patients with pathologic evidence of clear cell renal cell carcinoma (RCC) and radiographic evidence of metastasis were enrolled in this single-arm trial and were treated with SAbR, followed by HD IL2. ORR was assessed based on nonirradiated metastases. Secondary endpoints included overall survival (OS), progression-free survival (PFS), toxicity, and treatment-related tumor-specific immune response. Correlative studies involved whole-exome and transcriptome sequencing, T-cell receptor sequencing, cytokine analysis, and mass cytometry on patient samples. RESULTS: Thirty ethnically diverse mRCC patients were enrolled. A median of two metastases were treated with SAbR. Among 25 patients evaluable by RECIST v1.1, ORR was 16% with 8% complete responses. Median OS was 37 months. Treatment-related adverse events (AE) included 22 grade ≥3 events that were not dissimilar from HD IL2 alone. There were no grade 5 AEs. A correlation was observed between SAbR to lung metastases and improved PFS (P = 0.0165). Clinical benefit correlated with frameshift mutational load, mast cell tumor infiltration, decreased circulating tumor-associated T-cell clones, and T-cell clonal expansion. Higher regulatory/CD8+ T-cell ratios at baseline in the tumor and periphery correlated with no clinical benefit. CONCLUSIONS: Adding SAbR did not improve the response rate to HD IL2 in patients with mRCC in this study. Tissue analyses suggest a possible correlation between frameshift mutation load as well as tumor immune infiltrates and clinical outcomes.

Accelerated Hypofractionated Image-Guided vs Conventional Radiotherapy for Patients With Stage II/III Non-Small Cell Lung Cancer and Poor Performance Status: A Randomized Clinical Trial.

IMPORTANCE: A significant subset of patients with stage II/III non-small cell lung cancer (NSCLC) cannot receive standard concurrent chemoradiotherapy owing to the risk of toxic effects outweighing potential benefits. Without concurrent chemotherapy, however, the efficacy of conventional radiotherapy is reduced. OBJECTIVE: To determine whether hypofractionated image-guided radiotherapy (IGRT) would improve overall survival in patients with stage II/III NSCLC who could not receive concurrent chemoradiotherapy and therefore were traditionally relegated to receiving only conventionally fractionated radiotherapy (CFRT). DESIGN, SETTING, AND PARTICIPANTS: This nonblinded, phase 3 randomized clinical study enrolled 103 patients and analyzed 96 patients with stage II/III NSCLC and Zubrod performance status of at least 2, with greater than 10% weight loss in the previous 6 months, and/or who were ineligible for concurrent chemoradiotherapy after oncology consultation. Enrollment occurred at multiple US institutions. Patients were enrolled from November 13, 2012, to August 28, 2018, with a median follow-up of 8.7 (3.6-19.9) months. Data were analyzed from September 14, 2018, to April 11, 2021. INTERVENTIONS: Eligible patients were randomized to hypofractionated IGRT (60 Gy in 15 fractions) vs CFRT (60 Gy in 30 fractions). MAIN OUTCOMES AND MEASURES: The primary end point was 1-year overall survival. RESULTS: A total of 103 patients (96 of whom were analyzed [63 men (65.6%); mean (SD) age, 71.0 (10.2) years (range, 50-90 years)]) were randomized to hypofractionated IGRT (n = 50) or CFRT (n = 46) when a planned interim analysis suggested futility in reaching the primary end point, and the study was closed to further accrual. There was no statistically significant difference between the treatment groups for 1-year overall survival (37.7% [95% CI, 24.2%-51.0%] for hypofractionated IGRT vs 44.6% [95% CI, 29.9%-58.3%] for CFRT; P = .29). There were also no significant differences in median overall survival, progression-free survival, time to local failure, time to distant metastasis, and toxic effects of grade 3 or greater between the 2 treatment groups. CONCLUSIONS AND RELEVANCE: This phase 3 randomized clinical trial found that hypofractionated IGRT (60 Gy in 15 fractions) was not superior to CFRT (60 Gy in 30 fractions) for patients with stage II/III NSCLC ineligible for concurrent chemoradiotherapy. Further studies are needed to verify equivalence between these radiotherapy regimens. Regardless, for well-selected patients with NSCLC (ie, peripheral primary tumors and limited mediastinal/hilar adenopathy), the convenience of hypofractionated radiotherapy regimens may offer an appropriate treatment option. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01459497.

Higher Radiation Dose to the Immune Cells Correlates with Worse Tumor Control and Overall Survival in Patients with Stage III NSCLC: A Secondary Analysis of RTOG0617.

Background: We hypothesized that the Effective radiation Dose to the Immune Cells (EDIC) in circulating blood is a significant factor for the treatment outcome in patients with locally advanced non-small-cell lung cancer (NSCLC). Methods: This is a secondary study of a phase III trial, NRG/RTOG 0617, in patients with stage III NSCLC treated with radiation-based treatment. The EDIC was computed as equivalent uniform dose to the entire blood based on radiation doses to all blood-containing organs, with consideration of blood flow and fractionation effect. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS) and local progression-free survival (LPFS). The EDIC-survival relationship was analyzed with consideration of clinical significant factors. Results: A total of 456 patients were eligible. The median EDIC values were 5.6 Gy (range, 2.1-12.2 Gy) and 6.3 Gy (2.1-11.6 Gy) for the low- and high-dose groups, respectively. The EDIC was significantly associated with OS (hazard ratio [HR] = 1.12, p = 0.005) and LPFS (HR = 1.09, p = 0.02) but PFS (HR = 1.05, p = 0.17) after adjustment for tumor dose, gross tumor volume and other factors. OS decreased with an increasing EDIC in a non-linear pattern: the two-year OS decreased first with a slope of 8%/Gy when the EDIC < 6 Gy, remained relatively unchanged when the EDIC was 6-8 Gy, and followed by a further reduction with a slope of 12%/Gy when the EDIC > 8 Gy. Conclusions: The EDIC is a significant independent risk factor for poor OS and LPFS in RTOG 0617 patients with stage III NSCLC, suggesting that radiation dose to circulating immune cells is critical for tumor control. Organ at risk for the immune system should be considered during RT plan.

A phase II study of celecoxib in combination with paclitaxel, carboplatin, and radiotherapy for patients with inoperable stage IIIA/B non-small cell lung cancer.

PURPOSE: Cyclooxygenase (COX)-2 up-regulation plays an important role in the pathogenesis of lung cancer. Selective COX-2 inhibitors have promoted chemosensitivity and radiosensitivity of tumor cells in preclinical trials. EXPERIMENTAL DESIGN: In a single-institution phase II study, we sought to determine the effectiveness of concurrent chemoradiation given with celecoxib and examined biomarkers to predict response to COX-2 inhibition. RESULTS: Seventeen patients with stage IIIA or IIIB non-small cell lung cancer (NSCLC) were enrolled in the study. All received 400 mg celecoxib twice daily continuously while on trial in addition to concurrent chemoradiation therapy with paclitaxel and carboplatin. Celecoxib was continued until disease progression. The overall objective response rate was 42.9%, and the median overall survival time was 203 days. In contrast to nonresponders, those patients with complete and partial responses had a significant decrease in the level of urinary 11alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid (PGE-M), the major metabolite of prostaglandin E(2), after 1 week of celecoxib administration. Patients with very high levels of PGE-M before initiation of therapy also responded poorly to therapy. Serum vascular endothelial growth factor levels did not predict response or survival. CONCLUSION: The trial was terminated because it did not meet the predetermined goal of 80% overall response rate. In unselected patients, the addition of celecoxib to concurrent chemoradiotherapy with inoperable stage IIIA/B NSCLC does not improve survival. Urinary PGE-M is a promising biomarker for predicting response to COX-2 inhibition in NSCLC.

Stereotactic body radiation therapy for inoperable early stage lung cancer.

CONTEXT: Patients with early stage but medically inoperable lung cancer have a poor rate of primary tumor control (30%-40%) and a high rate of mortality (3-year survival, 20%-35%) with current management. OBJECTIVE: To evaluate the toxicity and efficacy of stereotactic body radiation therapy in a high-risk population of patients with early stage but medically inoperable lung cancer. DESIGN, SETTING, AND PATIENTS: Phase 2 North American multicenter study of patients aged 18 years or older with biopsy-proven peripheral T1-T2N0M0 non-small cell tumors (measuring <5 cm in diameter) and medical conditions precluding surgical treatment. The prescription dose was 18 Gy per fraction x 3 fractions (54 Gy total) with entire treatment lasting between 1(1/2) and 2 weeks. The study opened May 26, 2004, and closed October 13, 2006; data were analyzed through August 31, 2009. MAIN OUTCOME MEASURES: The primary end point was 2-year actuarial primary tumor control; secondary end points were disease-free survival (ie, primary tumor, involved lobe, regional, and disseminated recurrence), treatment-related toxicity, and overall survival. RESULTS: A total of 59 patients accrued, of which 55 were evaluable (44 patients with T1 tumors and 11 patients with T2 tumors) with a median follow-up of 34.4 months (range, 4.8-49.9 months). Only 1 patient had a primary tumor failure; the estimated 3-year primary tumor control rate was 97.6% (95% confidence interval [CI], 84.3%-99.7%). Three patients had recurrence within the involved lobe; the 3-year primary tumor and involved lobe (local) control rate was 90.6% (95% CI, 76.0%-96.5%). Two patients experienced regional failure; the local-regional control rate was 87.2% (95% CI, 71.0%-94.7%). Eleven patients experienced disseminated recurrence; the 3-year rate of disseminated failure was 22.1% (95% CI, 12.3%-37.8%). The rates for disease-free survival and overall survival at 3 years were 48.3% (95% CI, 34.4%-60.8%) and 55.8% (95% CI, 41.6%-67.9%), respectively. The median overall survival was 48.1 months (95% CI, 29.6 months to not reached). Protocol-specified treatment-related grade 3 adverse events were reported in 7 patients (12.7%; 95% CI, 9.6%-15.8%); grade 4 adverse events were reported in 2 patients (3.6%; 95% CI, 2.7%-4.5%). No grade 5 adverse events were reported. CONCLUSION: Patients with inoperable non-small cell lung cancer who received stereotactic body radiation therapy had a survival rate of 55.8% at 3 years, high rates of local tumor control, and moderate treatment-related morbidity.

Phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost for metastatic cancer.

BACKGROUND: Advanced radiotherapeutic treatment techniques limit the cognitive morbidity associated with whole-brain radiotherapy (WBRT) for brain metastasis through avoidance of hippocampal structures. However, achieving durable intracranial control remains challenging. METHODS: We conducted a single-institution single-arm phase II trial of hippocampal-sparing whole brain irradiation with simultaneous integrated boost (HSIB-WBRT) to metastatic deposits in adult patients with brain metastasis. Radiation therapy consisted of intensity-modulated radiation therapy delivering 20 Gy in 10 fractions over 2-2.5 weeks to the whole brain with a simultaneous integrated boost of 40 Gy in 10 fractions to metastatic lesions. Hippocampal regions were limited to 16 Gy. Cognitive performance and cancer outcomes were evaluated. RESULTS: A total of 50 patients, median age 60 years (interquartile range, 54-65), were enrolled. Median progression-free survival was 2.9 months (95% CI: 1.5-4.0) and overall survival was 9 months. As expected, poor survival and end-of-life considerations resulted in a high exclusion rate from cognitive testing. Nevertheless, mean decline in Hopkins Verbal Learning Test-Revised delayed recall (HVLT-R DR) at 3 months after HSIB-WBRT was only 10.6% (95% CI: -36.5‒15.3%). Cumulative incidence of local and intracranial failure with death as a competing risk was 8.8% (95% CI: 2.7‒19.6%) and 21.3% (95% CI: 10.7‒34.2%) at 1 year, respectively. Three grade 3 toxicities consisting of nausea, vomiting, and necrosis or headache were observed in 3 patients. Scores on the Multidimensional Fatigue Inventory 20 remained stable for evaluable patients at 3 months. CONCLUSIONS: HVLT-R DR after HSIB-WBRT was significantly improved compared with historical outcomes in patients treated with traditional WBRT, while achieving intracranial control similar to patients treated with WBRT plus stereotactic radiosurgery (SRS). This technique can be considered in select patients with multiple brain metastases who cannot otherwise receive SRS.

Long-Term Results of NRG Oncology RTOG 0617: Standard- Versus High-Dose Chemoradiotherapy With or Without Cetuximab for Unresectable Stage III Non-Small-Cell Lung Cancer.

PURPOSE: RTOG 0617 compared standard-dose (SD; 60 Gy) versus high-dose (HD; 74 Gy) radiation with concurrent chemotherapy and determined the efficacy of cetuximab for stage III non-small-cell lung cancer (NSCLC). METHODS: The study used a 2 × 2 factorial design with radiation dose as 1 factor and cetuximab as the other, with a primary end point of overall survival (OS). RESULTS: Median follow-up was 5.1 years. There were 3 grade 5 adverse events (AEs) in the SD arm and 9 in the HD arm. Treatment-related grade ≥3 dysphagia and esophagitis occurred in 3.2% and 5.0% of patients in the SD arm v 12.1% and 17.4% in the HD arm, respectively (P = .0005 and < .0001). There was no difference in pulmonary toxicity, with grade ≥3 AEs in 20.6% and 19.3%. Median OS was 28.7 v 20.3 months (P = .0072) in the SD and HD arms, respectively, 5-year OS and progression-free survival (PFS) rates were 32.1% and 23% and 18.3% and 13% (P = .055), respectively. Factors associated with improved OS on multivariable analysis were standard radiation dose, tumor location, institution accrual volume, esophagitis/dysphagia, planning target volume and heart V5. The use of cetuximab conferred no survival benefit at the expense of increased toxicity. The prior signal of benefit in patients with higher H scores was no longer apparent. The progression rate within 1 month of treatment completion in the SD arm was 4.6%. For comparison purposes, the resultant 2-year OS and PFS rates allowing for that dropout rate were 59.6% and 30.7%, respectively, in the SD arms. CONCLUSION: A 60-Gy radiation dose with concurrent chemotherapy should remain the standard of care, with the OS rate being among the highest reported in the literature for stage III NSCLC. Cetuximab had no effect on OS. The 2-year OS rates in the control arm are similar to the PACIFIC trial.