Predicting patient-specific radiotherapy responses in head and neck cancer to personalize radiation dose fractionation

AbstractHuman papillomavirus (HPV) related oropharyngeal cancer (OPC) is one of the few types of cancers increasing in incidence. HPV+ OPC treatment with radiotherapy (RT) provides 75-95% five-year locoregional control (LRC). Why some but not all patients with similar clinical stage and molecular profile are controlled remains unknown. We propose the proliferation saturation index, PSI, as a mathematical modeling biomarker of tumor growth and RT response. The model predicts that patients with PSI<0.75 are likely to be cured by radiation, and that hyperfractionated radiation could improve response rates for patients with higher PSI that are predicted to fail standard of care RT. Prospective evaluation is currently ongoing.

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Proliferation Saturation Index in an adaptive Bayesian approach to predict patient-specific radiotherapy responses

10.1101/469957 ◽

2018 ◽

Author(s):

Enakshi D. Sunassee ◽

Dean Tan ◽

Tianlin Ji ◽

Renee Brady ◽

Eduardo G. Moros ◽

...

Keyword(s):

Treatment Response ◽

Bayesian Approach ◽

Saturation Index ◽

Treatment Protocol ◽

Tumor Grade ◽

High Accuracy ◽

Radiation Response ◽

Dose Fractionation ◽

Patient Specific ◽

Multiple Variables

AbstractPurposeRadiotherapy prescription dose and dose fractionation protocols vary little between individual patients having the same tumor grade and stage. To personalize radiotherapy a predictive model is needed to simulate radiation response. Previous modeling attempts with multiple variables and parameters have been shown to yield excellent data fits at the cost of nonidentifiability and clinically unrealistic results.Materials and MethodsWe develop a mathematical model based on a proliferation saturation index (PSI) that is a measurement of pre-treatment tumor volume-to-carrying capacity ratio that modulates intrinsic tumor growth and radiation response rates. In an adaptive Bayesian approach, we utilize an increasing number of data points for individual patients for predicting response to subsequent radiation doses.ResultsModel analysis shows that using PSI as the only patient-specific parameter, model simulations can fit longitudinal clinical data with high accuracy (R2=0.84). By analyzing tumor response to radiation using daily CT scans early in the treatment, response to the remaining treatment fractions can be predicted after two weeks with high accuracy (c-index=0.89).ConclusionThe PSI model may be suited to forecast treatment response for individual patients and offer actionable decision points for mid-treatment protocol adaptation. The presented work provides an actionable image-derived biomarker prior to and during therapy to personalize and adapt radiotherapy.

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RADIATION DOSE FRACTIONATION AND HIGH PRESSURE OXYGEN IN RADIOTHERAPY OF THE DBA MOUSE MAMMARY CARCINOMA

American Journal of Roentgenology ◽

10.2214/ajr.99.4.895 ◽

1967 ◽

Vol 99 (4) ◽

pp. 895-899 ◽

Cited By ~ 16

Author(s):

HERMAN SUIT ◽

ROBERT LINDBERG ◽

CHIROTCHANA SUCHATO ◽

ALFRED OZENNE

Keyword(s):

High Pressure ◽

Radiation Dose ◽

Mammary Carcinoma ◽

Dose Fractionation ◽

Mouse Mammary Carcinoma ◽

Pressure Oxygen ◽

High Pressure Oxygen ◽

Radiation Dose Fractionation

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Induction Chemotherapy in Locally Advanced Head and Neck Cancer: A New Standard of Care?

Hematology/Oncology Clinics of North America ◽

10.1016/j.hoc.2008.08.004 ◽

2008 ◽

Vol 22 (6) ◽

pp. 1155-1163 ◽

Cited By ~ 22

Author(s):

Jochen H. Lorch ◽

Marshall R. Posner ◽

Lori J. Wirth ◽

Robert I. Haddad

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Induction Chemotherapy ◽

Neck Cancer ◽

Locally Advanced ◽

Standard Of Care ◽

Advanced Head

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Perioperative mortality of head and neck cancers

BMC Cancer ◽

10.1186/s12885-021-07998-z ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Yannan Wang ◽

Mengxue Wang ◽

Yan Tang ◽

Bincan Sun ◽

Kai Wang ◽

...

Keyword(s):

Head And Neck Cancer ◽

Head And Neck ◽

Neck Cancer ◽

Cardiopulmonary Arrest ◽

Clinical Stage ◽

Maxillofacial Surgery ◽

Head And Neck Cancers ◽

Oral And Maxillofacial Surgery ◽

Perioperative Mortality ◽

Advanced Clinical Stage

Abstract Background Head and neck cancers are aggressive cancers, most clinical studies focused on the prognosis of patients with head and neck cancer. However, perioperative mortality was rarely mentioned. Methods A retrospective analysis was performed using all head and neck cancer patients admitting in the Department of Oral and Maxillofacial Surgery of the Second Xiangya Hospital, Central South University from January 2010 to December 2019. The analysis of overall survival and progression-free survival were performed using the Kaplan–Meier method, and cross tabulation with chi-squared testing was applied to analyze the difference in parameters between groups. Results From January 2010 to December 2019, a total of 6576 patients with head and neck cancers were admitted to our department and 7 died in the hospital, all of whom were middle-aged and elderly patients including 6 males and 1 female. The perioperative mortality rate (POMR) was about 1‰. The causes of death included acute heart failure, rupture of large blood vessels in the neck, hypoxic ischemic encephalopathy due to asphyxia, respiratory failure and cardiopulmonary arrest. Conclusion Preoperative radiotherapy, previous chemotherapy, hypertension, diabetes, advanced clinical stage and postoperative infection are risk factors for perioperative mortality of head and neck cancer.

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Randomized prospective evaluation of genome sequencing versus standard-of-care as a first molecular diagnostic test

Genetics in Medicine ◽

10.1038/s41436-021-01193-y ◽

2021 ◽

Author(s):

Deanna G. Brockman ◽

Christina A. Austin-Tse ◽

Renée C. Pelletier ◽

Caroline Harley ◽

Candace Patterson ◽

...

Keyword(s):

Diagnostic Test ◽

Genome Sequencing ◽

Standard Of Care ◽

Molecular Diagnostic ◽

Prospective Evaluation ◽

Molecular Diagnostic Test

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PROSPER: Phase III RandOmized Study Comparing PERioperative nivolumab versus observation in patients with renal cell carcinoma (RCC) undergoing nephrectomy (ECOG-ACRIN EA8143).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps4596 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS4596-TPS4596

Author(s):

Mohamad E. Allaf ◽

Se Eun Kim ◽

Viraj A. Master ◽

David F. McDermott ◽

Sabina Signoretti ◽

...

Keyword(s):

Immune System ◽

Clinical Outcomes ◽

Clinical Stage ◽

Randomized Study ◽

Standard Of Care ◽

Phase Iii ◽

Perioperative Therapy ◽

Tumor Biopsy ◽

Care Surgery ◽

Metastatic Rcc

TPS4596 Background: There is no standard adjuvant systemic therapy that increases overall survival (OS) over surgery alone for non-metastatic RCC. Anti-PD-1 nivolumab (nivo) improves OS in metastatic RCC and is well tolerated. In mouse models, priming the immune system prior to surgery with anti-PD-1 results in superior OS compared to adjuvant dosing. Remarkable pathologic responses have been seen with neoadjuvant PD-1 in multiple ph 2 studies in bladder, lung and breast cancers. Phase 2 neoadjuvant RCC trials of nivo show preliminary feasibility and safety with no surgical delays. PROSPER RCC seeks to improve clinical outcomes by priming the immune system with neoadjuvant nivo prior to nephrectomy followed by continued immune system engagement with adjuvant blockade in patients (pts) with high risk RCC compared to standard of care surgery alone. Methods: This global, unblinded, phase 3 National Clinical Trials Network study is accruing pts with clinical stage ≥T2 or TanyN+ RCC of any histology planned for radical or partial nephrectomy. Select oligometastatic disease is permitted if the pt can be rendered ‘no evidence of disease’ within 12 weeks of nephrectomy (≤3 metastases; no brain, bone or liver). In the investigational arm, nivo is administered 480mg IV q4 weeks with 1 dose prior to surgery followed by 9 adjuvant doses. The control arm is nephrectomy followed by standard of care surveillance. There is no placebo. Baseline tumor biopsy is required only in the nivo arm but encouraged in both. Randomized pts are stratified by clinical T stage, node positivity, and M stage. 805 pts provide 84.2% power to detect a 14.4% absolute benefit in recurrence-free survival at 5 years assuming the ASSURE historical control of ̃56% to 70% (HR = 0.70). The study is powered to evaluate a significant increase in OS (HR 0.67). Critical perioperative therapy considerations such as safety, feasibility, and quality of life metrics are integrated. PROSPER RCC embeds a wealth of translational studies to examine the contribution of the baseline immune milieu and neoadjuvant priming with anti-PD-1 on clinical outcomes. As of February 10, 2021, 704 patients have been enrolled (N = 805). Clinical trial information: NCT03055013.

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ARC-9: Phase Ib/II study to evaluate etrumadenant (AB928)-based treatment combinations in patients with metastatic colorectal cancer (mCRC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.tps150 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. TPS150-TPS150

Author(s):

Michael Cecchini ◽

Kartik Krishnan ◽

Nick Giafis ◽

Jennifer Scott ◽

Cheng Seok Quah ◽

...

Keyword(s):

Adenosine Receptor ◽

Phase 1 ◽

Clinical Stage ◽

Atp Release ◽

Standard Of Care ◽

Stopping Rules ◽

Clinical Activity ◽

Open Label ◽

Curative Intent ◽

Platinum Based Chemotherapy

TPS150 Background: ATP release from dying cancer cells in response to platinum-based chemotherapy increases extracellular immunosuppressive adenosine, which binds and activates the A2a and A2b receptors on immune cells. Adenosine-mediated signaling impairs activation, proliferation, and cytotoxic activity of effector T cells, resulting in inhibition of antitumor activity. Concomitant adenosine receptor blockade may therefore enhance the therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (AB928), the first clinical-stage, small-molecule, dual adenosine receptor antagonist, is highly potent, pharmacodynamically active, and has been well tolerated in dose escalation studies as monotherapy or combined with chemo/immunotherapy. Recently, results were reported for the ARC-3 phase 1/1b study of etrumadenant + modified 5-fluorouracil + oxaliplatin (mFOLFOX-6) in patients (pts) with mCRC. In this study, etrumadenant + mFOLFOX-6 was well tolerated without significant additive toxicity. Disease control was observed in patients with RAS/BRAF mutated mCRC, as well as 3L+ disease previously treated with FOLFOX and/or FOLFIRI (PR and/or SD >4 mo). Due to deep responses in 1L-3L+ pts, 6 pts had the opportunity to pursue surgery and radiotherapy with curative intent. The encouraging results from ARC-3 warrant further evaluation of etrumadenant-based combination therapy for mCRC. Methods: ARC-9 is a phase 1b/2, multicohort, open-label, randomized platform study designed to evaluate safety and clinical activity of etrumadenant (150 mg orally once daily [QD]) in combination with standard-of-care (SOC) regimens or novel therapeutics in pts with mCRC (Table). Cohort eligibility is based on prior anticancer treatment history. Pts enrolled in Cohorts A and B will be randomized (2:1) into the experimental vs SOC arms. Cohort C consists of a single arm to allow inclusion of novel agents as they become available with built in early stopping rules for futility. Pts who progress on the SOC arm of Cohort A can enroll in Cohort B; pts who progress on the SOC arm of Cohort B can crossover to the experimental arm. Primary endpoints across cohorts are shown in Table. Safety monitoring will occur throughout the trial, disease assessments will occur every 8 weeks, and correlative study pre- and on-treatment biopsies will be performed. [Table: see text]

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Minimal residual disease by circulating tumor DNA analysis for colorectal cancer patients receiving radical surgery: An initial report from CIRCULATE-Japan.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3608 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3608-3608

Author(s):

Hiroki Yukami ◽

Yoshiaki Nakamura ◽

Jun Watanabe ◽

Masahito Kotaka ◽

Kentaro Yamazaki ◽

...

Keyword(s):

Colorectal Cancer ◽

Dna Analysis ◽

Residual Disease ◽

Clinical Stage ◽

Circulating Tumor Dna ◽

Patient Specific ◽

Detection Rates ◽

Initial Report ◽

Post Surgery ◽

Tumor Dna

3608 Background: Circulating tumor DNA (ctDNA) analysis can be used to predict the risk of recurrence by detecting molecular residual disease (MRD) in patients with colorectal cancer (CRC). We are conducting a prospective observational study to monitor MRD status in patients with clinical stage II–IV or relapsed CRC amenable to radical surgical resection (GALAXY study), as part of the CIRCULATE-Japan, a nationwide ctDNA-guided precision adjuvant therapy project. Methods: Analysis of ctDNA is being performed at pre- and post-surgery timepoints and will continue periodically for up to 2 years using Signatera, a personalized, tumor-informed ctDNA assay that is designed to track 16 patient-specific somatic variants based on whole-exome sequencing of tumor tissue. The association of peri-operative ctDNA status with clinicopathological characteristics was investigated. Results: As of January 13, 2021, 941 patients have been enrolled in the GALAXY study, of which 400 patients had their pre-operative ctDNA status evaluated. Of the 400 patients, baseline ctDNA was detected in 92% (367/400) of the patients: consisting of 35 patients with pathological stage (pStage) I, 135 with pStage II, 152 with pStage III, and 78 with pStage IV or relapsed disease (pStage IV/R). Patient-specific Signatera assays targeting 16 variants were designed for 100% of the patients. Out of the 6400 designed variants 99.3% passed quality control in the plasma analysis and produced the final results. Among 4425 genes selected for 400 patients, 3330 genes were selected for only one patient, while TP53 was the most commonly selected in 113 patients (28%). Median ctDNA levels, measured in mean tumor molecules per mL of plasma and ctDNA detection rate, stratified by stage are presented in table. Positive ctDNA status post-surgery was significantly associated with advanced pStage, pT and pN, and lymphovascular invasion. Of the 13 patients with recurrence, 10 were detected with a positive ctDNA at 4-weeks post-surgery, before confirmation of recurrence by the radiological imaging. Conclusions: Preoperative ctDNA detection rates were observed to be in >90% in patients with pStage II–III by personalized ctDNA assay based on unique somatic variants, specific to each patient. ctDNA- based MRD detected post-surgery (4W) was significantly associated with certain known clinicopathological factors for recurrence with ctDNA positivity associated with a very short-term of recurrence. Clinical trial information: 000039205. [Table: see text]

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