The advent of proton beam therapy (PBT) has initiated a paradigm shift in the field of pediatric radiation oncology, with increasing promise to alleviate both short-term and long-term toxicities. ...Given the dramatic rise in proton therapy centers in the United States, a discussion of the quality of evidence supporting its use in pediatric cancers is warranted.
Proton radiotherapy appears to decrease the incidence and severity of late effects with the strongest evidence in pediatric brain tumor cohorts that shows benefits in neurocognitive, hearing, and endocrine outcomes. However, emerging data has shown that more conservative brainstem dose limits with protons compared with photons are required to limit brainstem toxicity; these modified recommendations have been incorporated into national cooperative group studies. Decreased toxicity in tumors outside of the CNS for PBT have also been reported in sarcomas, Hodgkin disease and neuroblastoma. Similarly, QoL outcomes are improved in brain tumor and other cohorts of patients treated with PBT.
The collective findings demonstrate improved understanding and refinement of PBT in pediatric cancers. Data on QOL, toxicity and disease outcomes with PBT should continue to be collected and reported in order to understand the full extent of the risks and benefits associated with PBT.
Background The adoption of immune checkpoint inhibitors (ICIs) has dramatically transformed the treatment of numerous cancers. Medicare is the largest payer in the US and pays for ...physician-administered drugs through its medical Part B benefit. The aim of this study was to describe trends in ICI utilization and corresponding government expenditures within the US Medicare population. Methods We analyzed Medicare data to describe trends in total number of claims, total annual expenditures, expenditures per patient, and expenditures per claim for ICIs from January 2014 to December 2019. Results From 2014 to 2019, utilization rates for each of the seven market approved ICIs in the US increased. Over this time period, total Medicare expenditure on ICIs increased 1916% from $285,506,498 to $5,755,319,571. Concurrently, overall Medicare Part B drug expenditure increased 57% from $23,679,547,748 to $37,271,080,631. Expenditures on ICIs accounted for 40% of the increase in total Medicare Part B drug spending over this time period. Conclusions The rapid increase in utilization of ICIs has accounted for a disproportionate share of government drug spending growth in the United States. Policymakers can potentially curb spending growth by linking payments to patient outcomes.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Wound care accounts for more than $6 billion of health expenditure in the United States annually. In addition, Medicare reimbursement per relative value unit has remained flat with respect to ...inflation over the past 20 years. Yet, physicians face increasing operating costs. The economic effects of declining inflation-adjusted Medicare physician reimbursement on the use of wound debridement procedures have yet to be elucidated. This study describes trends in Medicare reimbursement, utilization, and total Medicare expenditure for wound debridement procedures. Using Medicare claims data, we aggregated the volume of services and average Medicare reimbursement for wound debridement procedures over the calendar years 2012 to 2017. For each billing code, we estimated inflation-adjusted total Medicare expenditure by multiplying the average inflation-adjusted Medicare reimbursement by the aggregate volume of services. The average inflation-adjusted payment for wound debridement procedures decreased by 6% from 2012 to 2017. Over this time period, the utilization of wound care procedures increased 32%. Total inflation-adjusted annual Medicare expenditure on wound care increased 24% from 2012 to 2017. Therefore, despite declining physician reimbursement rates, total Medicare expenditure on wound debridement increased from 2012 to 2017. This increase in total Medicare expenditure was driven by higher utilization of wound debridement procedures.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and ...immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS HR = 0.60 (95%CI: 0.40-0.89,
= .01). Among other microbes,
was associated with the worst survival (HR = 3.88;
= .008), while
had the best survival (HR = 0.05;
= .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 (
< .001) and M2 macrophages (
= .035), while HPV+ tumors had more T regulatory cells (
< .001) and CD8+ T-cells (
< .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.
Cisplatin, one of the most ototoxic anti-neoplastic agents, causes permanent hearing loss in up to 90% of patients. We assessed ototoxicity rates and prospectively collected audiologic outcomes of ...patients receiving low-dose or high-dose cisplatin with concurrent cochlear-sparing intensity-modulated radiation therapy (IMRT). Patients with head and neck squamous cell carcinoma (HNSCC) receiving definitive or adjuvant cisplatin-based chemoradiotherapy (CRT) were analyzed. Cisplatin was administered either in low doses weekly (40 mg/m2) for up to seven doses or in high doses triweekly (100 mg/m2) for up to three doses. Cochlear-sparing IMRT was delivered in all cases. Audiologic data were prospectively collected before, during, and after treatment completion. The primary endpoint was a hearing change grade of ≥3 after CRT completion. Of the 96 HNSCC patients evaluated, 69 received weekly cisplatin and 58 received definitive CRT. Of patients receiving weekly cisplatin, 13% developed ≥G3 ototoxicity vs. 56% of patients who received triweekly cisplatin (p < 0.001). In multivariable modeling, the cisplatin dose schedule remained significant (OR: 8.4, 95%CI: 2.8–27.8, p < 0.001) for risk of severe irreversible ototoxicity. Triweekly cisplatin CRT significantly increased the ≥G3 severe irreversible ototoxicity risk compared to low-dose weekly cisplatin, irrespective of the cumulative cisplatin dose, even with the use of cochlear-sparing IMRT. No significant difference in oncologic outcomes was observed between the two schedules.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell ...carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78, of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package “tmesig” was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the “stats” package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a ...predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. Methods A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. Results 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. Conclusions Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective. Keywords: Head and neck cancer, Head and neck squamous cell carcinoma, Immunotherpay, Immune checkpoint inhibitors, Survival in head and neck cancer
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Extranodal extension (ENE) is a pattern of cancer growth from within the lymph node (LN) outward into perinodal tissues, critically defined by disruption and penetration of the tumor through the ...entire thickness of the LN capsule. The presence of ENE is often associated with an aggressive cancer phenotype in various malignancies including head and neck squamous cell carcinoma (HNSCC). In HNSCC, ENE is associated with increased risk of distant metastasis and lower rates of locoregional control. ENE detected on histopathology (pathologic ENE; pENE) is now incorporated as a risk-stratification factor in human papillomavirus (HPV)-negative HNSCC in the eighth edition of the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC) TNM classification. Although ENE was first described almost a century ago, several issues remain unresolved, including lack of consensus on definitions, terminology, and widely accepted assessment criteria and grading systems for both pENE and ENE detected on radiological imaging (imaging-detected ENE; iENE). Moreover, there is conflicting data on the prognostic significance of iENE and pENE, particularly in the context of HPV-associated HNSCC. Herein, we review the existing literature on ENE in HNSCC, highlighting areas of controversy and identifying critical gaps requiring concerted research efforts.
Background
Central nervous system tumors are now the most common primary neoplasms seen in children, and radiation therapy is a key component in management. Secondary malignant neoplasms (SMNs) are ...rare, but dreaded complications. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT), and multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors.
Methods
A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting the incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, and the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs. protons.
Results
Twenty-four studies were included for analysis. A total of 418 SMNs were seen in 38,163 patients. The most common SMN were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), and thyroid cancers (4.2%). The median follow-up was 8.8 years 3.3–23.2.The median latency to SMN for photons and protons were 11.9 years 5-23 and 5.9 years 5-6.7, respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1%–2.6%, I
2
= 94%) with photons and 1.5% (95% CI: 0%–4.5%, I
2
= 81%) with protons. The pooled incidence of all SNs was not different photons: 3.6% (95% CI: 2.5%–4.8%, I
2
= 96%) vs. protons: 1.5% (95% CI: 0–4.5%, I
2
= 80%); p = 0.21.
Conclusion
We observed similar rates of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors. We observed a shorter latency to SMN with PBT compared to RT. With increasing use of pencil beam scanning PBT and VMAT, further studies are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.
