Adjuvant Approach Research Articles

Abstract P5-12-06: Non-adherence to endocrine therapy is associated with a significant increased risk of local recurrence in women ≥65 years with stage T1N0 breast cancer treated with adjuvant endocrine therapy alone after breast-conserving surgery

Abstract Purpose: Clinical guidelines recommend that for women ≥65 years with stage T1N0 breast cancer (BC) treated with breast-conserving surgery (BCS) that breast RT may be omitted and treatment with ET alone is acceptable. However, population-based studies report that up to two-thirds of women with T1N0 BC do not complete 5 years of ET. The effect of non-adherence to ET on recurrence risks in women treated with ET alone is unclear. We established a contemporary population-based cohort of women aged ≥65 years with stage T1N0, hormone receptor positive, breast cancer treated with single modality adjuvant ET or RT alone. We examined the effect of non-adherence in those treated with ET alone and compared the outcomes (ipsilateral LR, any breast event and any invasive in-breast event) of women who were non-adherent to those who were adherent to ET or those treated with RT alone. Methods: A population-based cohort of women diagnosed with T1N0 BC from 2010-2016, aged ≥65 years at diagnosis, treated with BCS and single modality adjuvant therapy with RT alone or ET alone was identified from the Ontario Cancer Registry. ER-/PR-, ER unknown/PR unknown, HER2+ cases and those without sentinel node biopsy or axillary dissection were excluded. Treatment and outcomes were ascertained using deterministic linkages of administrative databases. Receipt of adjuvant ET was identified using dispensing records from the Ontario Drug Benefit Claims database. Adherence percentage at any specific time was calculated by dividing the number of days dispensed (up to that time) by the number of days since diagnosis. This was updated every 3 months for each woman receiving ET. Adherence to ET was captured as a 3-level time-varying covariate (RT only, <80% ET adherence, ≥80% ET adherence). Patients were censored at the time of recurrence. Differences in recurrence risks were compared by Chi-square test. Multivariable Cox regression adjusted for age was used to evaluate risks of ipsilateral LR, any in-breast event (ipsilateral or contralateral, DCIS or invasive) and any first invasive in-breast recurrence. Results: The cohort includes 1551 women; 1054 women treated with BCS + adjuvant RT alone and 497 treated with BCS + adjuvant ET alone. The median follow-up time was 5 years. Almost half (45.7%) of cases prescribed ET alone were <80% adherent. For those who were followed for 5 years, 35% of follow-up time was spent non-adherent to ET. The 5-year risk of LR was 5.8% in patients treated with ET alone who spent <80% of time adherent to ET, 0.4% in patients treated with ET alone who were >80% adherent and 0.9% in those treated with RT alone (p<.001). The 5-year risk of any in-breast event was 6.6% in women <80% adherent, 0.7% in those adherent to ET and 3.2% in those treated with RT alone (p=.001). Women treated with ET alone who were <80% adherent during their follow-up time had a 5-fold increased risk of LR (HR=4.93, 95%CI: 2.13, 11.42, p=0.0002), a 1.6 fold increased risk of any breast event (HR=1.65, 95% CI: 0.89, 3.07, p=0.11) and a 1.6 fold increased risk (HR=1.68, 95% CI: 0.87, 3.25, p=0.13) of any invasive in-breast event compared to those treated with either RT alone or compared to those who were >80% adherent to ET. There was no significant difference in outcomes between those treated with ET who were >80% adherent during their follow-up time and those treated with RT alone. Conclusions: Almost half of women older than 65 years with stage T1N0 breast cancer treated with breast-conserving surgery and adjuvant ET alone are <80% adherent to ET. Non-adherence to ET is associated with higher risks of local recurrence compared to those treated with adjuvant RT alone. Adjuvant approaches incorporating RT may be preferable to ET alone. Citation Format: Mira Goldberg, Rinku Sutradhar, Lawrence Paszat, Timothy Whelan, Sumei Gu, Cindy Fong, Eileen Rakovitch. Non-adherence to endocrine therapy is associated with a significant increased risk of local recurrence in women ≥65 years with stage T1N0 breast cancer treated with adjuvant endocrine therapy alone after breast-conserving surgery [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-06.

In Vivo Epigenetic CRISPR Screen Identifies Asf1a as an Immunotherapeutic Target in Kras-Mutant Lung Adenocarcinoma.

Despite substantial progress in lung cancer immunotherapy, the overall response rate in patients with KRAS-mutant lung adenocarcinoma (LUAD) remains low. Combining standard immunotherapy with adjuvant approaches that enhance adaptive immune responses-such as epigenetic modulation of antitumor immunity-is therefore an attractive strategy. To identify epigenetic regulators of tumor immunity, we constructed an epigenetic-focused single guide RNA library and performed an in vivo CRISPR screen in a Kras G12D/Trp53 -/- LUAD model. Our data showed that loss of the histone chaperone Asf1a in tumor cells sensitizes tumors to anti-PD-1 treatment. Mechanistic studies revealed that tumor cell-intrinsic Asf1a deficiency induced immunogenic macrophage differentiation in the tumor microenvironment by upregulating GM-CSF expression and potentiated T-cell activation in combination with anti-PD-1. Our results provide a rationale for a novel combination therapy consisting of ASF1A inhibition and anti-PD-1 immunotherapy. SIGNIFICANCE: Using an in vivo epigenetic CRISPR screen, we identified Asf1a as a critical regulator of LUAD sensitivity to anti-PD-1 therapy. Asf1a deficiency synergized with anti-PD-1 immunotherapy by promoting M1-like macrophage polarization and T-cell activation. Thus, we provide a new immunotherapeutic strategy for this subtype of patients with LUAD.See related commentary by Menzel and Black, p. 179.This article is highlighted in the In This Issue feature, p. 161.

Repurposing the Kir6.2/SUR2 Channel Activator Minoxidil to Treat Gynecological Cancers

Gynecologic cancers, are among the most lethal cancers (more than 70% of patients dying in the 5-years period after diagnosis) because the treatments can be toxic, cost-prohibitive, and eventually, all ovarian cancer patients relapse with a tumor that has developed resistance to chemotherapy (e.g., cisplatin, carboplatin). Ion channels are known to contribute to cellular homeostasis in all cells and mounting evidence indicates that ion channels could be considered potential therapeutic targets against the cancer. Nevertheless, the pharmacologic effect of targeting ion channels in this cancer is still understudied. Our meta-analysis revealed that patients affected by ovarian or endometrial cancers (gynecological cancers) that express high level of the Kir6.2/SUR2 potassium channel complex present better survival rate when compared to patients with low expression. Therefore, we conclude that expression of Kir6.2/SUR2 potassium channel is a potential favorable prognostic factor in gynecologic cancers. We tested the effect of pharmacological stimulation of the Kir6.2/SUR2 channel activity by using the selective activator, FDA approved molecule, minoxidil (Rogaine ®; Loniten ®) on ovarian cancer growth. We found that minoxidil arrested tumor growth in a xenograft model of cisplatin-resistant ovarian cancer. Analysis of the mechanism underlying the anticancer effect of minoxidil revealed that Kir6.2/SUR2 activator inhibit proliferation of cancer cells by arresting the cell cycle. Also, minoxidil alters the cellular metabolic and oxidative state resulting in mitochondrial disruption, production of reactive oxygen species (ROS) and extensive DNA damage. Consequently, these events activate a caspase-3 independent cell death pathway. Our data indicate that repurposing of FDA approved K+ channel activators may represent a novel, safe adjuvant therapeutic approach to traditional chemotherapy for the treatment of gynecologic cancers.

Current evidence-based approaches and international guidelines in primary and secondary prevention strategies of medication-related osteonecrosis of the jaws

Introduction: The presumably multifactorial pathomechanisms of medication-related osteonecrosis of the jaws have not been fully elucidated so far. Management of this rare but serious side effect is a real challenge and requires a multidisciplinary approach. Aim: The aim of the authors was to take stock of our present knowledge about the pathogenesis, risk factors, clinical manifestations and the possibilities of prevention and treatment in the medication-related osteonecrosis of the jaws. In addition, the available international guidelines are compared and the evidence-based, stage-specific conservative and adjuvant therapeutic approaches are also reviewed, having regard to special aspects of medical and dental care. Method: In the last 5 years - due to the increasing number of disorder-oriented database - the number of available systematic reviews, recommendations and meta-analyses has escalated significantly which we reviewed and compared. Results: Since the last Position Paper published by the taskforce of the American Association of Oral and Maxillofacial Surgeons, novel pharmacological groups with the potential to induce osteonecrosis have come in the clinical scope, further elaborating the nomenclature of the disease and further specifying patient groups. The sphere of patients at risk has broadened and novel patient groups (rheumatologic-osteological, immunosuppressed, transplanted or oncological patients treated with monoclonal antibody, known as 'target therapy') are expected to develop this serious side effect. Conclusion: Although a number of issues are still open regarding the treatment of the disorder, evidence-based, individualized, stage-adapted therapeutic approaches have replaced the previous empirical treatment. Orv Hetil. 2020; 161(6): 214-223.

Adjuvant therapy for true ampullary cancer: a systematic review.

Given the lack of evidence on the best adjuvant approach, this review closely examines optimal adjuvant management for resected true ampullary cancer and its histological subtypes. A comprehensive literature search of PubMed was performed to identify studies on resected true ampullary cancers, published between January 2010 and December 2018. Data including the use of radiation, chemotherapy or chemoradiation and the outcomes were extracted. A total of 116 records were identified, of which 65 screened were selected. Finally, nine studies were included. Only two of the studies reported separately the outcomes of pancreatobiliary and intestinal subtypes. Patients in the selected studies were treated with a pancreaticoduodenectomy with negative margins. Patients treated with adjuvant therapy were more likely to be pT3-4 and have positive nodes; median survival ranged from 30 to 47months. A significant benefit for adjuvant treatment was observed in four of the studies, restricted to patients at stage IIB or higher. Likewise, patients with positive nodes may have a longer median survival with adjuvant chemoradiation compared to observation. The present review suggests a benefit for adjuvant treatment for patients with locally advanced tumors. Randomized trials are needed to ascertain the topic, as well as studies reporting toxicity and quality of life of resected true ampullary cancer patients.

Antimicrobial photodynamic and photobiomodulation adjuvant therapies for prevention and treatment of medication-related osteonecrosis of the jaws: Case series and long-term follow-up.

Medication-Related Osteonecrosis of the Jaws (MRONJ) incidence are increasing among elderly. Treatment can be challenging. Prevent or treatment protocols that control evolution of the lesion are warranted. To observe long-term outcomes of two protocols based on photonics [antimicrobial photodynamic therapy (aPDT) and photobiomodulation (PBM)] for prevention and treatment of MRONJ lesions. In a prospective study, patients who needed oral surgery and had been exposed to antiresorptive drugs were long-term followed-up. For MRONJ prevention, immediately after tooth extraction aPDT was applied. For aPDT a 0.01 % methylene blue solution was applied inside socket for 5 min followed by irradiation with a diode laser [660 nm, 0.028cm2, 0.1 W, 3.57 W/cm2, 90 s and 9 J per point, 321 J/cm2, at least at in 3 points (laser probe was placed at central, and two equidistant points) and total energy of 27J]. Irradiation was repeated weekly until total tissue repair. MRONJ treatment included preoperative aPDT sessions until signs and symptoms of infection had reduced. Then, after necrotic bone removal, aPDT was applied inside surgical wounds and re-applied weekly until healing. Antibiotics were administered pre or postoperatively for no longer than 7 days. PBM therapy was applied with 808 nm diode laser, 0.028cm2, 0.1 W, 3.57 W/cm2, 30 s, 107 J/cm², 3 J and total energy of 12 J until evidence of remission. Eighteen patients underwent preventive protocol, and none presented signs of MRONJ after a follow-up of at least 6 months. Seventeen patients presented with MRONJ underwent aPDT protocol and sixteen of them showed total regression of lesions. aPDT and PBM therapy protocols appear to be effective as adjuvant approach not only for preventing MRONJ development due to tooth extraction but for treating MRONJ lesions at early stages with no adverse effects.

Optimal Adjuvant Treatment Approach After Upfront Resection of Pancreatic Cancer: Revisiting the Role of Radiation Based on Pathologic Features.

To identify the survival benefit of different adjuvant approaches and factors influencing their efficacy after upfront resection of pancreatic ductal adenocarcinoma (PDAC). The optimal adjuvant approach for PDAC remains controversial. Patients from the National Cancer Database who underwent upfront PDAC resection from 2010 to 2014 were analyzed to determine clinical outcomes of different adjuvant treatment approaches, stratified according to pathologic characteristics. Factors associated with overall survival were identified with multivariable logistic regression and Cox proportional hazards were used to compare overall survival of different treatment approaches in the whole cohort, and propensity score matched groups. We included 16,709 patients who underwent upfront resection of PDAC. On multivariable analysis, tumor size, grade, positive margin, nodal involvement, lymphovascular invasion (LVI), stage, lymph node ratio, not receiving chemotherapy, and/or radiation were predictors for worse survival. In the presence of at least 1 high-risk pathologic feature (nodal or margin involvement or LVI) chemotherapy with subsequent radiation provided the most significant survival benefit (median survivals: 24.8 vs 21.0 mo for adjuvant chemotherapy; HR = 0.81; 95% CI: 0.77-0.86; P < 0.001 in propensity score matching). The addition of radiation to adjuvant chemotherapy did not significantly improve overall survival in those with no high-risk pathologic features (median survivals: 54.6 vs 42.7 mo for adjuvant chemotherapy; HR=0.90; 95% CI: 0.75-1.08; P = 0.25 in propensity score matching). In the presence of any high-risk pathologic features (nodal or margin involvement or LVI), adjuvant chemotherapy followed by radiation provides a better survival advantage over chemotherapy alone after upfront resection of PDAC.

Adjuvant drug-assisted bone healing: Part I – Modulation of inflammation

Critical-size bone defects after compound fractures, infection, or tumor resection are challenging to treat. The same is true for fractures in patients with impaired bone healing due to metabolic diseases and cancer. Despite considerable progress over the last decade in surgical techniques, material design, and dedicated imaging approaches, these scenarios represent unsolved clinical problems. The high socioeconomic burden of such conditions justifies increasing interest in novel osteoinductive drugs for adjuvant therapeutic approaches. There is an increasing body of experimental and clinical literature on potentially promising effects of growth factors, anti-resorptive, and anabolic agents. The true clinical efficacy of these, however, is discussed controversially. Therefore, we aimed to critically examine the hypothesis that targeted adjuvant therapies have the potential to enhance bone regeneration in critical-size bone defects and under systemic conditions that impair bone healing. This first approach to the topic deals with small molecule drugs and compounds that influence the immune response and inflammatory processes. In particular, literature reporting on selective cyclooxygenase-2 inhibitors has been reviewed with respect to their local and systemic mode of action and to stimulate further research on bone healing under critical conditions.

Novel strategies using modern radiotherapy to improve pancreatic cancer outcomes: toward a new standard?

Pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive solid tumours with an estimated 5-year overall survival rate of 7% for all stages combined. In this highly resistant disease that is located in the vicinity of many radiosensitive organs, the role of radiotherapy (RT) and indications for its use in this setting have been debated for a long time and are still under investigation. Although a survival benefit has yet to be clearly demonstrated for RT, it is the only technique, other than surgery, that has been demonstrated to lead to local control improvement. The adjuvant approach is now strongly challenged by neoadjuvant treatments that could spare patients with rapidly progressive systemic disease from unnecessary surgery and may increase free margin (R0) resection rates for those eligible for surgery. Recently developed dose-escalated RT treatments, designed either to maintain full-dose chemotherapy or to deliver a high biologically effective dose, particularly to areas of contact between the tumour and blood vessels, such as hypofractionated ablative RT (HFA-RT) or stereotactic body RT (SBRT), are progressively changing the treatment landscape. These modern strategies are currently being tested in prospective clinical trials with encouraging preliminary results, paving the way for more effective treatment combinations using novel targeted therapies. This review summarizes the current literature regarding the use of RT for the treatment of primary PDAC, describes the limitations of conventional RT, and discusses the emerging role of dose-escalated RT and heavy-particle RT.

The use of Hyaluronic Acid as an adjuvant Therapeutic Approach to Non-Surgical Periodontal Therapy for Periodontitis

Periodontitis is a highly prevalent infectious-inflammatory disease, characterized by alveolar bone resorption. Hyaluronic acid (HA) has stood out for its anti-inflammatory and antioxidant effects. The present study evaluated, through a literature review, the use of HA as an adjunctive therapeutic approach to non-surgical periodontal therapy (NSPT) of periodontitis (PD), carried out through scaling and root planing. For this, the Pubmed and Medline databases were used with the following descriptors: Hyaluronic Acid AND Periodontitis. Among 58 manuscripts found, 11 studies were selected after analyzing their title and respective abstracts. Pre-clinical or clinical research published from 2010 to 2020, including the use of HA exclusively in the NSPT of PD, were included for this literature review. Studies using other pharmacological interventions in conjunction with HA, other literature reviews and research related to the treatment of gingivitis, periodontal or pulp regeneration, surgical periodontal therapy, apical or peri-implantitis periodontitis were excluded. The main data of the selected manuscripts were compiled in a table and, then, their results were compared and discussed among themselves. Despite a wide variety of methodological protocols carried out by prospective researches, it is noted that HA has potential healing, anti-inflammatory and antimicrobial effects, which can be interesting from the point of view of periodontal treatment, considering the infectious and inflammatory character of PD. There are also different commercial formulations of HA on the market. It is suggested, therefore, that HA can be promising as a chemical adjuvant to PD NSPT, and can be used in the form of subgingival irrigation in deep periodontal pockets.

Contemporary management of early stage testicular seminoma.

Therapy for early stage testicular seminoma has changed radically over the past several decades. Given high cure rates and clinical trials supporting less active therapy in most cases, close observation after radical orchiectomy is now considered standard of care for clinical stage (CS) IA/IB seminoma, with either radiation therapy (RT) or chemotherapy salvage options possible. For CS IIA/IIB seminoma characterized by non-bulky retroperitoneal lymph node involvement (≤5 cm in greatest dimension), RT or combination chemotherapy are the standard of care. Given high comparable survival rates, preventing treatment-related toxicity and second malignancy, and limiting quality of life deficits associated with intense treatment has gained much greater importance. Clinical trials are currently testing the feasibility of retroperitoneal lymph node dissection (RPLND) for low volume CS IIA/IIB metastatic testicular seminoma to this end. Likewise, one cycle of chemotherapy is being evaluated as an adjuvant approach to reduce recurrence rates in CS I disease with unfavorable risk factors. Moreover, recent genomic and molecular studies have recently identified novel signatures and a potential biomarker for testicular seminoma. In this review, we first summarize the evolution of early stage seminoma management and discuss the effectiveness and drawbacks of contemporary treatment strategies. We further outline future perspectives and potential challenges in management of early stage testicular seminoma.

The Sociobiology of Brain Tumors.

Brain tumors are complex cellular ecosystems, composed of populations of both neoplastic and non-neoplastic cell types. While the contributions of the cancer cells in low-grade and high-grade gliomas have been extensively studied, there is comparatively less known about the contributions of the non-neoplastic cells in these tumors. As such, a large proportion of the non-neoplastic cells in gliomas are resident brain microglia, infiltrating circulating macrophages, and T lymphocytes. These immune system-like stromal cells are recruited into the evolving tumor through the elaboration of chemokines, and are reprogrammed to adopt new cellular identities critical for glioma formation, maintenance, and progression. In this manner, these populations of tumor-associated microglia and macrophages produce growth factors that support gliomagenesis and continued tumor growth. As we begin to characterize these immune cell contributions, future therapies might emerge as adjuvant approaches to glioma treatment.

Alternative treatment options for periorbital basal cell carcinoma

Latest developments as well as established procedures offer alternative treatment approaches to basal cell carcinoma (BCC) when micrographically controlled surgical removal is not avalid option. Alternative treatment options for periorbital BCC are presented. A literature search was carried out and a structured display and analysis of the results are given. Micrographically controlled surgical removal represents the gold standard in treatment of BCC. When for various reasons surgical removal is not avalid option, other procedures are required. The alternative treatment options can be divided into three main groups: treatment options for locally advanced or metastasized BCC, topical approaches for small and superficial BCC and prophylactic measures. While radiotherapy and systemic therapy are suitable for locally advanced BCC and are discussed in a tumor board, small and superficial BCC can be treated by topical medication. In cases of aprevious BCC history, aprophylactic treatment can be considered. Combinations of systemic treatment and also neoadjuvant or adjuvant approaches before and after surgery are promising options for a successful outcome, which can further improve the standard treatment for locally advanced BCC. Alternative treatment options for periocular BCC are available; however, the use is only indicated when microscopically controlled excision with subsequent oculoplastic reconstruction is not possible. According to the national guidelines a prior presentation to a suitable tumor board is practically compulsory.

High-fat diet exacerbates SIV pathogenesis and accelerates disease progression.

Consuming a high-fat diet (HFD) is a risk factor for obesity and diabetes; both of these diseases are also associated with systemic inflammation, similar to HIV infection. A HFD induces intestinal dysbiosis and impairs liver function and coagulation, with a potential negative impact on HIV/SIV pathogenesis. We administered a HFD rich in saturated fats and cholesterol to nonpathogenic (African green monkeys) and pathogenic (pigtailed macaques) SIV hosts. The HFD had a negative impact on SIV disease progression in both species. Thus, increased cell-associated SIV DNA and RNA occurred in the HFD-receiving nonhuman primates, indicating a potential reservoir expansion. The HFD induced prominent immune cell infiltration in the adipose tissue, an important SIV reservoir, and heightened systemic immune activation and inflammation, altering the intestinal immune environment and triggering gut damage and microbial translocation. Furthermore, HFD altered lipid metabolism and HDL oxidation and also induced liver steatosis and fibrosis. These metabolic disturbances triggered incipient atherosclerosis and heightened cardiovascular risk in the SIV-infected HFD-receiving nonhuman primates. Our study demonstrates that dietary intake has a discernable impact on the natural history of HIV/SIV infections and suggests that dietary changes can be used as adjuvant approaches for HIV-infected subjects, to reduce inflammation and the risk of non-AIDS comorbidities and possibly other infectious diseases.

Prognostic factors associated with survival in a large cohort of gastric cancer patients resected over a decade at a single Italian center: the Cremona experience.

Incidence of gastric cancer (GC) shows different distribution in Italy, with higher incidence in the north and center. We retrospectively analyzed the clinical data of patients resected at the Hospital of Cremona between January 2007 and December 2016. Available clinical variables were linked with survival to identify possible prognostic factors. Variables analyzed were age, sex, type of surgery, site, histology, invasion, nodal status, resection margins, grade, HER2 status, Helicobacter pylori infection (neo)adjuvant chemotherapy, adjuvant chemoradiotherapy, neutrophil-to-lymphocyte ratio, number of nodes removed and type of lymphadenectomy. Overall survival (OS) was estimated by the Kaplan-Meier method and differences between groups by the log-rank test. Data on OS were analyzed by Cox regression and the final model was obtained using the step-wise method. 379 patients were considered, out of which 195 were operated from 2007 to 2011 and 184 from 2012 to 2016. Median follow-up was 25.5months, median OS 31.3months and time to recurrence 23.2months. D2 resection rate increased from 36% (period 2007-2011) to 74% in 2012-2016 (p = 0.01) with a higher mean number of nodes collected (20.98 for 2007-2011 and 23.53 for 2012-2016, p = 0.040). Only 37% of patients received a postoperative treatment. At multivariate analysis, variables associated with OS were age (p = 0.002), stage (p < 0.001), resection margins status (p < 0.001), adjuvant chemotherapy (p < 0.010) and tumor location (cardia vs non-cardia) (p = 0.029). Our analysis shows that completeness of resection and lower stage are strong predictors of long-term survival in GC, providing the rationale for adjuvant and neoadjuvant approaches (chemotherapy, radiotherapy or combined). Cardial GC has worse prognosis compared to distal cancers. Service evaluation number 256, protocol 16821/17, date 05 June 2017.

Prophylactic Limbo: How Low Can We Go on HPV+OPSCC Prophylactic Nodal Coverage?

The last 2 decades has seen an increase in HPV-associated oropharyngeal cancers. As they are notable for their radiosensitivity and younger population, efforts to de-intensify therapy to minimize long-term morbidity from treatment are under investigation. We hypothesize reducing the dose and volume of elective nodal coverage in these patients can maintain disease control with an improvement in QOL. Herein we characterize the recurrence patterns and salvage options for patients treated in a dose- and volume-reduced approach. We retrospectively characterized a cohort of patients with HPV-associated oropharyngeal cancer irradiated at our institution from 2013-2018. After IRB approval, we collected patient demographics, definitive vs. adjuvant approach, radiation doses and volumes, chemotherapy, QOL factors, and recurrence and survival outcomes. Survival and recurrence were measured from the final day of radiotherapy until death or last follow-up. A total of 270 patients were identified at our institution with an ICD9/10 code that suggested a neoplasm of the oropharynx. A preliminary assessment of the first 104 patients identified 44 with HPV+ confirmed OPSCC. By AJCC7 criteria, a majority of tumors were T1 or T2 (34/44) and most patients demonstrated clinical N2 disease (35/44). 9 patients were treated in a post-operative setting, almost all (42/44) received concurrent chemotherapy with 15 receiving induction as well. With the exception of 3 post-operative patients, all received >60 Gy to the primary tumor volume in 200-220 cGy per fraction. 4 patients did not receive any radiation to low-risk nodal levels and 34 received a dose of 44-48.4 Gy to these echelons, the remaining six received doses 50-50.6 Gy. 11 out of 44 patients received unilateral hemineck irradiation due to well-lateralized tumors. Of these 44 patients assessed at this time, 4 demonstrated recurrence or persistent disease by biopsy or PET scan. Three were in the primary site (2) or high-dose involved nodal level (1) whereas the last developed an HPV-associated squamous cell carcinoma of the glottic larynx with extension to the untreated neck. No recurrences were identified in the reduced-dose prophylactic nodal levels or in the volume-reduced non-irradiated neck. This suggests that prophylactic doses of 44-50.6 Gy with concurrent chemotherapy may be sufficient to control low-risk nodal echelons. In well-selected patients, further reduction in the treatment volumes may confer additional morbidity benefit without sacrificing disease control. Subsequent analysis will characterize treatment-related morbidity and QOL.

Utilizing the Radiosensitivity Index (RSI) to Predict Pelvic Failure in Endometrial Cancer Treated with Adjuvant Radiotherapy

Various adjuvant approaches are utilized in the management of endometrial cancer based on surgical pathology and institutional preference. The radiosensitivity index (RSI) is a previously validated multi-gene expression index that estimates tumor radiosensitivity. In this study, we evaluate RSI as a genomic predictor for pelvic failure (PF) in patients treated with adjuvant radiotherapy. A total of 204 consecutively treated patients with endometrial cancer were identified from our IRB-approved institutional tissue biorepository. All patients underwent hysterectomy with bilateral salpingo-oophorectomy with the majority undergoing lymph node dissection (n=181; 88%) between 01/99 and 04/11 and followed until 01/19. Gene expression was from Affymetrix Hu-RSTA-2a520709 (Affymetrix; Santa Clara, CA). The RSI 10-gene signature was calculated for each sample using the previously published algorithm. Radiophenotype was determined by dichotomization of RSI at the previously identified cutpoint of 0.375; ≥0.375 = radioresistant (RR) and <0.375 = radiosensitive (RS). Time to event analysis was performed with Kaplan-Meier estimates and the log-rank test. Associations between radiophenotype and outcomes were explored with univariable (UVA) and multivariable (MVA) Cox regression. The threshold for statistical significance in all tests was set at p<0.05. Median follow-up was 38.5 months (range: 0.2-216). The median RSI was 0.42 (range: 0.11-0.70). There were no significant differences in RS and RR patients in age (p=0.99), serosa and/or adnexa involvement (p=0.37), vaginal and/or parametrial involvement (p=0.48), cervical stromal invasion (p=0.59), receipt of adjuvant chemotherapy (p=0.12), and node involvement (p=0.78). A total of 83 (41%) patients were treated with adjuvant radiotherapy with vaginal brachytherapy (n=19; 23%), pelvic radiotherapy (n=26; 31%), or both (n=38; 46%). In patients treated with radiation, RR patients were more likely to undergo PF (3 year pelvic control 84% vs 100%; p=0.02) with worse PF free survival (PFFS) (3 year PFFS 65% vs. 89%; p=0.04). However, since RSI is a radiation specific signature it did not predict PF (p=0.86) or PFFS (p=0.57) in patients not treated with radiation. Factors found to predict PF on UVA included grade 3/1-2 (HR 3.8; 95% CI 1.2-14.8, p=0.03), serosa and/or adnexa involvement (5.9; 95% CI 1.6-20.2, p=0.008), lymph node involvement (4.9; 95% CI 1.5-18.8, 0.009), and RR/RS (7.7; 95% CI 1.5-140.9, 0.01). On MVA, factors that continued to predict for PF included RR/RS (10.7; 95% CI 1.9-202.4, p=0.004), lymph node involvement (4.1; 95% CI 1.2-16.3, p=0.03), and serosa and/or adnexa involvement (4.3; 95% CI 1.2-16.4, p=0.03). RSI was found to be a significant predictor of PF in patients treated with adjuvant radiotherapy on MVA. We propose RSI may be a method to predict which patients are most likely to fail in the pelvis and candidates for treatment escalation in the adjuvant setting.

Partial-Breast Irradiation: Review of Modern Trials

Following partial mastectomy, whole-breast irradiation (WBI), delivered over 3 to 6 weeks, has been the standard adjuvant radiation approach for early-stage breast cancer. A growing body of literature over the past decade has suggested that irradiation of the partial breast, including the tumor bed plus a margin, may be a suitable alternative for appropriately selected patients. The use of partial breast irradiation (PBI) has been studied in multiple prospective randomized trials, now with up to 10 years of follow-up, establishing similar safety and efficacy compared with WBI. Advantages of PBI include (1) reduced treatment duration, (2) potential reductions in treatment-related toxicity, (3) improved cosmetic outcomes, and (4) reduced costs. The purpose of this article is to review appropriate patient selection criteria, clinical and toxicity outcomes data, clinical consensus practice guidelines, and the various PBI techniques. The National Surgical Adjuvant Breast and Bowel Project (NSABP) B39/Radiation Therapy Oncology Group (RTOG) 0413 study (NRG Oncology) is the most recently published (abstract form only) prospective randomized trial comparing PBI using 3D conformal external beam radiation therapy (3D-CRT, 38.5 Gy/10 fractions, twice daily) or brachytherapy (interstitial catheters or applicator based, 34 Gy/10 fractions, twice daily), vs. WBI (50 Gy ± tumor a bed boost). With a median follow-up of 10.2 years, the 10-year ipsilateral breast tumor recurrence-free interval was 95.2% vs. 95.9% for PBI and WBI, although it did not meet the statistical significance for equivalence. Similarly, the randomized trial of accelerated partial breast irradiation using 3-dimensional conformal radiotherapy (RAPID) trial is a prospective randomized trial comparing primarily 3D-CRT (38.5 Gy/10 fractions, twice daily) with WBI, (42.5 Gy/16 daily fractions or 50 Gy/25 daily fractions ± tumor bed boost). Rates of ipsilateral breast tumor recurrence (IBTR) at 8 years were not statistically significantly different (PBI vs WBI, 3% vs. 2.8%; HR = 1.27; 90% VI, 0.84–1.91). There is a growing body of literature supporting the use of PBI in appropriately selected patients and its use should continue to increase.

Management of high-risk endometrial cancer: are we there yet?

Management of high-risk endometrial cancer: are we there yet?

The exploration and practice of clinical translational medicine research for pancreatic cancer

Pancreatic cancer is a digestive system malignant tumor with extremely poor prognosis. With the rapid development of science and technology, although breakthrough results has been achieved in basic research of pancreatic cancer and some achievement in surgical techniques and adjuvant treatment approach, the survival of patients with pancreatic cancer has not been significantly improved. Among them, the serious disconnection between basic research and clinical practice has led to a slow improvement in the diagnosis and therapy. As a bridge between basic research and clinical work, translational medicine can promote progress of the early detection and precision treatment of pancreatic cancer, thus providing new hope for patients with pancreatic cancer. Key words: Pancreatic neoplasms; Pancreatic cancer; Translational medicine; Diagnosis; Therapy