Introduction: As immunotherapy has improved distant metastasis-free survival (DMFS) in Non-Small Cell Lung Cancer (NSCLC), isolated locoregional recurrences have increased. However, management of locoregional recurrences can be challenging. We report our institutional experience with definitive intent re-irradiation using Intensity Modulated Proton Therapy (IMPT). Method: Retrospective cohort study of recurrent or second primary NSCLC or LS-SCLC treated with IMPT. Kaplan-Meier method and log-rank test were used for time-to-event analyses. Results: 22 patients were treated from 2019 to 2021. After first course of radiation (median 60 Gy, range 45-70 Gy), 45% received adjuvant immunotherapy. IMPT re-irradiation began a median of 28.2 months (8.8-172.9 months) after initial radiotherapy. The median IMPT dose was 60 GyE (44-60 GyE). 36% received concurrent chemotherapy with IMPT and 18% received immunotherapy after IMPT. The median patient’s IMPT lung mean dose was 5.3 GyE (0.9-13.9 GyE) and 5 patients had cumulative esophagus max dose >100 GyE with 1-year overall survival (OS) 68%, 1-year local control 80%, 1-year progression free survival 45%, and 1-year DMFS 60%. Higher IMPT (HR 1.4; 95% CI 1.1-1.7, p=0.01) and initial radiotherapy mean lung doses (HR 1.3; 95% CI 1.0-1.6, p=0.04) were associated with worse OS. Two patients developed Grade 3 pneumonitis or dermatitis, one patient developed Grade 2 pneumonitis, and seven patients developed Grade 1 toxicity. There were no Grade 4 or 5 toxicities. Discussion: Definitive IMPT re-irradiation for lung cancer can prolong disease control with limited toxicity, particularly in the immunotherapy era.
Background: We assessed locoregional control with omission of intentional primary site radiation after transoral robotic surgery (TORS) and quantified nontargeted primary site dose. Methods: Following Institutional Review Board (IRB) approval, patients treated with primary TORS resection for squamous cell carcinomas of the oropharynx were reviewed. Patients with cT1-2 tumors, >2 mm margins, in whom the surgeon resected the primary without revising specimen-driven margins, qualified for omission of primary site radiation. Results: From 2014 to 2019, 112 patients met criteria. Fifty-nine (52%) patients did not receive radiation targeting the primary site; of whom, 22 received no radiation. In this group, there were no local failures; mean age was 58 years and median follow-up was 25 months. Thirty-seven patients received adjuvant radiation targeting the neck, mean bystander dose to the primary site was 28.8 Gy (range, 13.3–50.6 Gy). Conclusion: In a 59 patient population, omission of radiation to the primary site after TORS resulted in no locoregional failures.
Purpose: Metallic implants have been correlated to local control failure for spinal sarcoma and chordoma patients due to the uncertainty of implant delineation from computed tomography (CT). Such uncertainty can compromise the proton Monte Carlo dose calculation (MCDC) accuracy. A component method is proposed to determine the dimension and volume of the implants from CT images. Methods: The proposed component method leverages the knowledge of surgical implants from medical supply vendors to predefine accurate contours for each implant component, including tulips, screw bodies, lockers, and rods. A retrospective patient study was conducted to demonstrate the feasibility of the method. The reference implant materials and samples were collected from patient medical records and vendors, Medtronic and NuVasive. Additional CT images with extensive features, such as extended Hounsfield units and various reconstruction diameters, were used to quantify the uncertainty of implant contours. Results: For in vivo patient implant estimation, the reference and the component method differences were 0.35, 0.17, and 0.04 cm3 for tulips, screw bodies, and rods, respectively. The discrepancies by a conventional threshold method were 5.46, 0.76, and 0.05 cm3, respectively. The mischaracterization of implant materials and dimensions can underdose the clinical target volume coverage by 20 cm3 for a patient with eight lumbar implants. The tulip dominates the dosimetry uncertainty as it can be made from titanium or cobalt–chromium alloys by different vendors. Conclusions: A component method was developed and demonstrated using phantom and patient studies with implants. The proposed method provides more accurate implant characterization for proton MCDC and can potentially enhance the treatment quality for proton therapy. The current proof-of-concept study is limited to the implant characterization for lumbar spine. Future investigations could be extended to cervical spine and dental implants for head-and-neck patients where tight margins are required to spare organs at risk.
Anti-programmed cell death protein 1 (PD-1) therapy is a standard of care in recurrent metastatic head and neck squamous cell carcinoma (RMHNSCC). Vascular endothelial growth factor inhibitors, including tyrosine kinase inhibitors, have immunomodulatory properties and have offered promising results when combined with anti-PD-1 agents. We conducted a phase 2, multicenter, single-arm trial of pembrolizumab and cabozantinib in patients with RMHNSCC who had Response Evaluation Criteria in Solid Tumors v.1.1 measurable disease and no contraindications to either agent. We assessed the primary end points of tolerability and overall response rate to the combination with secondary end points of progression-free survival and overall survival and performed correlative studies with PDL-1 and combined positive score, CD8+ T cell infiltration and tumor mutational burden. A total of 50 patients were screened and 36 were enrolled with 33 evaluable for response. The primary end point was met, with 17 out of 33 patients having a partial response (52%) and 13 (39%) stable disease with an overall clinical benefit rate of 91%. Median and 1-year overall survival were 22.3 months (95% confidence interval (CI) = 11.7–32.9) and 68.4% (95% CI = 45.1%–83.5%), respectively. Median and 1-year progression-free survival were 14.6 months (95% CI = 8.2–19.6) and 54% (95% CI = 31.5%–72%), respectively. Grade 3 or higher treatment-related adverse events included increased aspartate aminotransferase (n = 2, 5.6%). In 16 patients (44.4%), the dose of cabozantinib was reduced to 20 mg daily. The overall response rate correlated positively with baseline CD8+ T cell infiltration. There was no observed correlation between tumor mutational burden and clinical outcome. Pembrolizumab and cabozantinib were well tolerated and showed promising clinical activity in patients with RMHNSCC. Further investigation of similar combinations are needed in RMHNSCC. The trial is registered at ClinicalTrials.gov under registration no. NCT03468218.
With limited high-level evidence, we carried out a comparative effectiveness study for the effect of proton beam therapy (PBT) on overall survival compared to external-beam radiotherapy (EBRT) and brachytherapy (BT) among patients with localized prostate cancer using a national database. PBT was associated with a significant overall survival benefit compared to EBRT and had a similar performance as BT.
Background:
There are few comparative outcomes data regarding the therapeutic delivery of proton beam therapy (PBT) versus the more widely used photon-based external-beam radiation (EBRT) and brachytherapy (BT). We evaluated the impact of PBT on overall survival (OS) compared to EBRT or BT on patients with localized prostate cancer.
Patients and Methods:
The National Cancer Data Base (NCDB) was queried for 2004–2015. Men with clinical stage T1–3, N0, M0 prostate cancer treated with radiation, without surgery or chemotherapy, were included. OS, the primary clinical outcome, was fit by Cox proportional hazard model. Propensity score matching was implemented for covariate balance.
Results:
There were 276,880 eligible patients with a median follow-up of 80.9 months. A total of 4900 (1.8%) received PBT, while 158,111 (57.1%) received EBRT and 113,869 (41.1%) BT. Compared to EBRT and BT, PBT patients were younger and were less likely to be in the high-risk group. On multivariable analysis, compared to PBT, men had worse OS after EBRT (adjusted hazard ratio [HR] = 1.72; 95% confidence interval [CI], 1.51–1.96) or BT (adjusted HR = 1.38; 95% CI, 1.21–1.58). After propensity score matching, the OS benefit of PBT remained significant compared to EBRT (HR = 1.64; 95% CI, 1.32–2.04) but not BT (adjusted HR = 1.18; 95% CI, 0.93–1.48). The improvement in OS with PBT was most prominent in men ≤ 65 years old with low-risk disease compared to other subgroups (interaction P < .001).
Conclusion:
In this national data set, PBT was associated with a significant OS benefit compared to EBRT, and with outcomes similar to BT. These results remain to be validated by ongoing prospective trials.
Background: Tobacco and alcohol use are risk factors for Squamous Cell Carcinoma of the Head and Neck (SCCHN); however, there is growing recognition of HPV as a risk factor for SCCHN. HPV-related SCCHN is thought to affect mostly middle-aged individuals but as the US population ages, it is important to evaluate the change in incidence of HPV- and non-HPV-related SCCHN in individuals who are ≥65 years old. Methods: This was a retrospective study using data from a population-based cancer registry (SEER) to identify individuals ≥65 years old diagnosed with SCCHN between 2000 and 2016 also stratified by sex, race, and birth cohort. The subgroups of HPV-associated and non-HPV associated sites were analyzed independently. The incidence per year was calculated and joinpoint detection was used to identity significant changes in incidence trends and annual percent change (APC). Results: For HPV-associated sites from 2000 to 2016, there was an average annual rate of 10.8 per 100,000 individuals with an APC of 2.92% (p = <0.05). For HPV- and non-HPV-related SCCHN males had a higher annual rate compared to females, 54.5 versus 18.0 in non-HPV-related and 19.1 versus 4.4 in HPV-related sites. For non-HPV-related sites there was a decrease in APC across all stratified groups. For HPV-related sites there was an increase in APC across all stratified groups, especially males (APC 8.82% 2006–2016 p < 0.05) and White individuals (APC 8.19% 2006–2016 p < 0.05). When stratified by birth cohort, HPV-related SCCHN sites had a higher APC in ages 65–69 (8.38% p < 0.05) and 70–74 (8.54% p < 0.05). Conclusion: Among the population ≥65 years old from 2000 to 2016, the incidence rate for HPV-related SCCHN sites has increased across all stratified groups, especially in White individuals, males, and age groups 65–74. The incidence rate for non-HPV-related sites has decreased across all stratified groups during this time.
Purpose: Anal cancer affects a disproportionate percentage of persons infected with human immunodeficiency virus (HIV). We analyzed a cohort of patients with HIV and anal cancer who received modern radiation therapy (RT) and concurrent chemotherapy to assess whether certain factors are associated with poor oncologic outcomes. Patients and Methods: We performed a retrospective chart review of 75 consecutive patients with HIV infection and anal cancer who received definitive chemotherapy and RT from 2008 to 2018 at a single academic institution. Local recurrence, overall survival, changes in CD4 counts, and toxicities were investigated. Results: Most patients were male (92%) with large representation from Black patients (77%). The median pretreatment CD4 count was 280 cells/mm3, which was persistently lower at 6 and 12 months’ posttreatment, 87 cells/mm3 and 182 cells/mm3, respectively (P <.001). Most (92%) patients received intensity modulated RT; median dose was 54 Gy (Range, 46.8-59.4 Gy). At a median follow-up 5.4 years (Range, 4.37-6.21 years), 20 (27%) patients had disease recurrence and 10 (13%) had isolated local failures. Nine patients died due to progressive disease. In multivariable analysis, clinically node negative involvement was significantly associated with better overall survival (hazard ratio, 0.39; 95% confidence interval, 0.16-1.00, P =.049). Acute grade 2 and 3 skin toxicities were common, at 83% and 19%, respectively. Acute grade 2 and 3 gastrointestinal toxicities were 9% and 3%, respectively. Acute grade 3 hematologic toxicity was 20%, and one grade 5 toxicity was reported. Several late grade 3 toxicities persisted: gastrointestinal (24%), skin (17%), and hematologic (6%). Two late grade 5 toxicities were noted. Conclusions: Most patients with HIV and anal cancer did not experience local recurrence; however, acute and late toxicities were common. CD4 counts at 6 and 12 months’ posttreatment remained lower than pretreatment CD4 counts. Further attention to treatment of the HIV-infected population is needed.
Purpose: To evaluate the clinical outcomes and treatment related toxicities of charged particle-based re-irradiation (reRT; protons and carbon ions) for the definitive management of recurrent or second primary skull base and head and neck tumors. Materials and Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were applied for the conduct of this systematic review. Published work in English language evaluating the role of definitive charged particle therapies in the clinical setting of reRT for recurrent or second primary skull base and head and neck tumors were eligible for this analysis. Results: A total of 26 original studies (15 protons, 10 carbon ions, and 1 helium/neon studies) involving a total of 1, 118 patients (437 with protons, 670 with carbon ions, and 11 with helium/neon) treated with curative-intent charged particle reRT were included in this systematic review. All studies were retrospective in nature, and the majority of them (n=23, 88 %) were reported as single institution experiences (87% for protons, and 90% for carbon ion-based studies). The median proton therapy reRT dose was 64.5 Gy (RBE 1.1) (range, 50.0 - 75.6 Gy ), while the median carbon ion reRT dose was 53.8 Gy (RBE 2.5 - 3.0) (range, 44.8 - 60 Gy ). Induction and/or concurrent chemotherapy was administered to 232 (53%) of the patients that received a course of proton reRT, and 122 (18%) for carbon ion reRT patients. ReRT with protons achieved 2-year local control rates ranging from 50% to 86%, and 41% to 92% for carbon ion reRT. The 2-year overall survival rates for proton and carbon ion reRT ranged from 33% to 80%, and 50% to 86% respectively. Late ≥ G3 toxicities ranged from 0% to 37%, with brain necrosis, ototoxicity, visual deficits, and bleeding as the most common complications. Grade 5 toxicities for all treated patients occurred in 1.4% (n=16/1118) with fatal bleeding as the leading cause. Conclusions: Based on current data, curative intent skull base and head and neck reRT with charged particle radiotherapy is feasible and safe in well-selected cases, associated with comparable or potentially improved local control and toxicity rates compared to historical reRT studies using photon radiotherapy. Prospective multi-institutional studies reporting oncologic outcomes, toxicity, and dosimetric treatment planning data are warranted to further validate these findings and to improve the understanding of the clinical benefits of charged particle radiotherapy in the reRT setting.
Purpose: For patients with high-risk bladder cancer (pT3þ or Nþ), local regional failure remains a challenge after chemotherapy and cystectomy. An ongoing prospective phase 2 trial (NCT01954173) is examining the role of postoperative photon radiation therapy for high-risk patients using volumetric modulated arc therapy. Proton beam therapy (PBT) may be beneficial in this setting to reduce hematologic toxicity. We evaluated for dosimetric relationships with pelvic bone marrow (PBM) and changes in hematologic counts before and after pelvic radiation therapy and explored the potential of PBT treatment plans to achieve reductions in PBM dose. Materials and Methods: All enrolled patients were retrospectively analyzed after pelvic radiation per protocol with 50.4 to 55.8 Gy in 28 to 31 fractions. Comparative PBT plans were generated using pencil-beam scanning and a 3-beam multifield optimization technique. Changes in hematologic nadirs were assessed using paired t test. Correlation of mean nadirs and relative PBM dose levels were assessed using the Pearson correlation coefficient (CC). Results: Eighteen patients with a median age of 70 were analyzed. Mean cell count values after radiation therapy decreased compared with preradiation therapy values for white blood cells (WBCs), absolute neutrophil count (ANC), absolute lymphocyte count (all P,.001), and platelets (P ¼.03). Increased mean PBM dose was associated with lower nadirs in WBC (Pearson CC -0.593, P ¼.02), ANC (Pearson CC -0.597, P ¼.02), and hemoglobin (Pearson CC -0.506, P ¼.046), whereas the PBM V30 to V40 correlated with lower WBC (Pearson CC -0.512 to -0.618, P,.05), and V20 to V30 correlated with lower ANC (Pearson CC -0.569 to -0.598, P,.04). Comparative proton therapy plans decreased the mean PBM dose from 26.5 Gy to 16.1 Gy (P,.001) and had significant reductions in the volume of PBM receiving doses from 5 to 40 Gy (P,.001). Conclusion: Increased PBM mean dose and V20 to V40 were associated with lower hematologic nadirs. PBT plans reduced PBM dose and may be a valuable strategy to reduce the risk of hematologic toxicity in these patients.