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Head and Neck Squamous Cell Carcinoma — Reference List

Literature underpinning hnscc_qsp_model.dot, hnscc_mrgsolve_model.R and hnscc_shiny_app.R. Every parameter value or structural choice in the model that is not a free fitted quantity traces to one of the entries below.

References marked [ANCHOR] are the six clinical results used to fit the five free tumour-control parameters. References marked [HELD-OUT] were deliberately not used in fitting and are the tests the model had to pass afterwards. That split is the whole basis for claiming the model has any predictive content, so it is recorded here as well as in README.md.

1 · Epidemiology, aetiology and field cancerisation

  1. Sung H, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality. CA Cancer J Clin 2021. https://pubmed.ncbi.nlm.nih.gov/33538338/
  2. Chaturvedi AK, et al. Human papillomavirus and rising oropharyngeal cancer incidence in the United States. J Clin Oncol 2011. https://pubmed.ncbi.nlm.nih.gov/21969503/
  3. Gillison ML, et al. Distinct risk factor profiles for human papillomavirus type 16-positive and -negative head and neck cancers. J Natl Cancer Inst 2008. https://pubmed.ncbi.nlm.nih.gov/18334711/
  4. Hashibe M, et al. Interaction between tobacco and alcohol use and the risk of head and neck cancer (INHANCE consortium). Cancer Epidemiol Biomarkers Prev 2009. https://pubmed.ncbi.nlm.nih.gov/19190158/
  5. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007. https://pubmed.ncbi.nlm.nih.gov/17646865/
  6. Warnakulasuriya S, et al. Areca nut and oral cancer. Addict Biol 2002 / IARC Monograph 85. https://pubmed.ncbi.nlm.nih.gov/12006218/
  7. Slaughter DP, Southwick HW, Smejkal W. Field cancerization in oral stratified squamous epithelium. Cancer 1953. https://pubmed.ncbi.nlm.nih.gov/13094644/
  8. Braakhuis BJM, et al. A genetic explanation of Slaughter's concept of field cancerization. Cancer Res 2003. https://pubmed.ncbi.nlm.nih.gov/12727832/
  9. Kutler DI, et al. High incidence of head and neck squamous cell carcinoma in patients with Fanconi anemia. Arch Otolaryngol Head Neck Surg 2003. https://pubmed.ncbi.nlm.nih.gov/12874067/
  10. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nat Rev Cancer 2018. https://pubmed.ncbi.nlm.nih.gov/29497144/

2 · HPV16 oncogenic program

  1. Scheffner M, et al. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 1993. https://pubmed.ncbi.nlm.nih.gov/8402913/
  2. Dyson N, et al. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science 1989. https://pubmed.ncbi.nlm.nih.gov/2537532/
  3. Klaes R, et al. Overexpression of p16INK4A as a specific marker for dysplastic and neoplastic epithelial lesions of the cervix uteri. Int J Cancer 2001. https://pubmed.ncbi.nlm.nih.gov/11340556/
  4. Lewis JS Jr, et al. p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 2010. https://pubmed.ncbi.nlm.nih.gov/20386991/
  5. Park JW, et al. Deregulation of DNA damage response signalling by human papillomavirus E7. J Virol 2014 / Wallace NA, Galloway DA. Annu Rev Virol 2015. https://pubmed.ncbi.nlm.nih.gov/26958917/
  6. Rieckmann T, et al. HNSCC cell lines positive for HPV and p16 possess higher cellular radiosensitivity due to an impaired DSB repair capacity. Radiother Oncol 2013. https://pubmed.ncbi.nlm.nih.gov/23830196/
  7. Kimple RJ, et al. Enhanced radiation sensitivity in HPV-positive head and neck cancer. Cancer Res 2013. https://pubmed.ncbi.nlm.nih.gov/23744740/
  8. Weaver AN, et al. DNA double strand break repair defect and sensitivity to poly ADP-ribose polymerase inhibition in HPV-positive HNSCC. Oncotarget 2015. https://pubmed.ncbi.nlm.nih.gov/26356814/
  9. Klingenberg B, et al. E6/E7 and the tumour immune microenvironment in HPV-driven oropharyngeal cancer. Br J Cancer 2010 / Wansom D, et al. Arch Otolaryngol 2012. https://pubmed.ncbi.nlm.nih.gov/22986739/
  10. Henderson S, et al. APOBEC-mediated cytosine deamination links PIK3CA helical domain mutations to human papillomavirus-driven tumour development. Cell Rep 2014. https://pubmed.ncbi.nlm.nih.gov/25131207/

3 · Genomics of HPV-negative disease

  1. The Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature 2015. https://pubmed.ncbi.nlm.nih.gov/25631445/
  2. Stransky N, et al. The mutational landscape of head and neck squamous cell carcinoma. Science 2011. https://pubmed.ncbi.nlm.nih.gov/21798893/
  3. Agrawal N, et al. Exome sequencing of head and neck squamous cell carcinoma reveals inactivating mutations in NOTCH1. Science 2011. https://pubmed.ncbi.nlm.nih.gov/21798897/
  4. Poeta ML, et al. TP53 mutations and survival in squamous-cell carcinoma of the head and neck. N Engl J Med 2007. https://pubmed.ncbi.nlm.nih.gov/18160686/
  5. Grandis JR, Tweardy DJ. Elevated levels of transforming growth factor alpha and epidermal growth factor receptor messenger RNA are early markers of carcinogenesis in head and neck cancer. Cancer Res 1993. https://pubmed.ncbi.nlm.nih.gov/8339283/
  6. Chung CH, et al. Increased epidermal growth factor receptor gene copy number is associated with poor prognosis in head and neck squamous cell carcinomas. J Clin Oncol 2006. https://pubmed.ncbi.nlm.nih.gov/16769987/
  7. Lui VWY, et al. Frequent mutation of the PI3K pathway in head and neck cancer defines predictive biomarkers. Cancer Discov 2013. https://pubmed.ncbi.nlm.nih.gov/23619167/
  8. Martin D, et al. The head and neck cancer cell oncogenome: a platform for the development of precision molecular therapies. Oncotarget 2014. https://pubmed.ncbi.nlm.nih.gov/25277197/
  9. Namani A, et al. NRF2-regulated metabolic gene signature in HNSCC / Kim YR, et al. Oncogenic NRF2 mutations in squamous cell carcinomas. J Pathol 2010. https://pubmed.ncbi.nlm.nih.gov/20521232/
  10. Morris LGT, et al. Recurrent somatic mutation of FAT1 in multiple human cancers leads to aberrant Wnt activation. Nat Genet 2013. https://pubmed.ncbi.nlm.nih.gov/23354438/

4 · EGFR signalling and its nuclear/repair role

  1. Grandis JR, et al. Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. J Natl Cancer Inst 1998. https://pubmed.ncbi.nlm.nih.gov/9625170/
  2. Dittmann K, Mayer C, Rodemann HP. Radiation-induced epidermal growth factor receptor nuclear import is linked to activation of DNA-dependent protein kinase. J Biol Chem 2005. https://pubmed.ncbi.nlm.nih.gov/15879598/
  3. Dittmann K, et al. Radiation-induced caveolin-1 associated EGFR internalization is linked with nuclear EGFR transport and activation of DNA-PK. Mol Cancer 2008. https://pubmed.ncbi.nlm.nih.gov/18644176/
  4. Huang SM, Harari PM. Modulation of radiation response after epidermal growth factor receptor blockade in squamous cell carcinomas. Clin Cancer Res 2000. https://pubmed.ncbi.nlm.nih.gov/10741744/
  5. Milas L, et al. In vivo enhancement of tumor radioresponse by C225 antiepidermal growth factor receptor antibody. Clin Cancer Res 2000. https://pubmed.ncbi.nlm.nih.gov/10741709/
  6. Bonner JA, et al. Enhanced apoptosis with combination C225/radiation treatment serves as the impetus for clinical investigation. Semin Radiat Oncol 2002. https://pubmed.ncbi.nlm.nih.gov/12174342/
  7. Sen M, et al. Targeting STAT3 abrogates EGFR inhibitor resistance in cancer. Clin Cancer Res 2012. https://pubmed.ncbi.nlm.nih.gov/22553343/
  8. Madoz-Gúrpide J, et al. Proteomics-based validation of genomic data / Knowles LM, et al. HGF and c-Met participate in paracrine tumorigenic pathways in head and neck squamous cell cancer. Clin Cancer Res 2009. https://pubmed.ncbi.nlm.nih.gov/19351759/

5 · Radiobiology — the linear-quadratic model and the five R's

  1. Withers HR. The four R's of radiotherapy. Adv Radiat Biol 1975 (see also Steel GG, et al. Int J Radiat Oncol Biol Phys 1989 for the fifth). https://pubmed.ncbi.nlm.nih.gov/2646263/
  2. Fowler JF. The linear-quadratic formula and progress in fractionated radiotherapy. Br J Radiol 1989. https://pubmed.ncbi.nlm.nih.gov/2670032/
  3. Brenner DJ. The linear-quadratic model is an appropriate methodology for determining isoeffective doses at large doses per fraction. Semin Radiat Oncol 2008. https://pubmed.ncbi.nlm.nih.gov/18725110/
  4. Bentzen SM, et al. Clinical radiobiology of squamous cell carcinoma of the oropharynx. Int J Radiat Oncol Biol Phys 1991. https://pubmed.ncbi.nlm.nih.gov/2032890/
  5. Withers HR, Taylor JM, Maciejewski B. The hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncol 1988. https://pubmed.ncbi.nlm.nih.gov/3390344/
  6. Bentzen SM, Thames HD. Clinical evidence for tumor clonogen regeneration: interpretations of the data. Radiother Oncol 1991. https://pubmed.ncbi.nlm.nih.gov/1808721/
  7. Fowler JF, Lindstrom MJ. Loss of local control with prolongation in radiotherapy. Int J Radiat Oncol Biol Phys 1992. https://pubmed.ncbi.nlm.nih.gov/1526880/
  8. [HELD-OUT] Hansen O, et al. Importance of overall treatment time for the outcome of radiotherapy of advanced head and neck carcinoma. Radiother Oncol 1997. https://pubmed.ncbi.nlm.nih.gov/9106920/
  9. [HELD-OUT] Bese NS, Hendry J, Jeremic B. Effects of prolongation of overall treatment time due to unplanned interruptions during radiotherapy. Int J Radiat Oncol Biol Phys 2007. https://pubmed.ncbi.nlm.nih.gov/17721981/
  10. Begg AC, et al. Cell proliferation as predictor of response to radiotherapy: Tpot measurement in head and neck cancer. Radiother Oncol 1992 / Int J Radiat Oncol Biol Phys 1990. https://pubmed.ncbi.nlm.nih.gov/1631160/
  11. Baumann M, Krause M, Hill R. Exploring the role of cancer stem cells in radioresistance. Nat Rev Cancer 2008. https://pubmed.ncbi.nlm.nih.gov/18784658/
  12. Prince ME, et al. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA 2007. https://pubmed.ncbi.nlm.nih.gov/17210912/
  13. [HELD-OUT] Horiot JC, et al. Hyperfractionation versus conventional fractionation in oropharyngeal carcinoma: EORTC 22791. Radiother Oncol 1992. https://pubmed.ncbi.nlm.nih.gov/1281137/
  14. [HELD-OUT] Lacas B, et al. Meta-analysis of radiotherapy in carcinomas of head and neck (MARCH): updated individual-patient-data analysis. Lancet Oncol 2017. https://pubmed.ncbi.nlm.nih.gov/28757375/
  15. Overgaard J, et al. Five compared with six fractions per week of conventional radiotherapy (DAHANCA 6 & 7). Lancet 2003. https://pubmed.ncbi.nlm.nih.gov/14522594/

6 · Hypoxia, reoxygenation and hypoxic radiosensitisers

  1. Gray LH, et al. The concentration of oxygen dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol 1953. https://pubmed.ncbi.nlm.nih.gov/13106296/
  2. Nordsmark M, et al. Prognostic value of tumor oxygenation in 397 head and neck tumors after primary radiation therapy: an international multi-center study. Radiother Oncol 2005. https://pubmed.ncbi.nlm.nih.gov/16098619/
  3. Brizel DM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma / head and neck cancer. Cancer Res 1996. https://pubmed.ncbi.nlm.nih.gov/8674032/
  4. [ANCHOR] Overgaard J, et al. A randomized double-blind phase III study of nimorazole as a hypoxic radiosensitizer of primary radiotherapy in supraglottic larynx and pharynx carcinoma (DAHANCA 5-85). Radiother Oncol 1998. https://pubmed.ncbi.nlm.nih.gov/9635689/
  5. Overgaard J. Hypoxic modification of radiotherapy in squamous cell carcinoma of the head and neck — a systematic review and meta-analysis. Radiother Oncol 2011. https://pubmed.ncbi.nlm.nih.gov/21684026/
  6. Toustrup K, et al. Development of a hypoxia gene expression classifier with predictive impact for hypoxic modification of radiotherapy in head and neck cancer. Cancer Res 2011. https://pubmed.ncbi.nlm.nih.gov/21659506/
  7. Rischin D, et al. Tirapazamine, cisplatin, and radiation versus cisplatin and radiation for advanced squamous cell carcinoma of the head and neck (TROG 02.02, HeadSTART). J Clin Oncol 2010. https://pubmed.ncbi.nlm.nih.gov/20516441/
  8. Lee N, et al. Prospective trial incorporating pre-/mid-treatment [18F]-misonidazole PET for head-and-neck cancer. Int J Radiat Oncol Biol Phys 2009. https://pubmed.ncbi.nlm.nih.gov/18929449/
  9. Semenza GL. Targeting HIF-1 for cancer therapy. Nat Rev Cancer 2003. https://pubmed.ncbi.nlm.nih.gov/13130303/
  10. Hoff CM, et al. Importance of hemoglobin concentration and its modification for the outcome of head and neck cancer patients treated with radiotherapy. Acta Oncol 2012. https://pubmed.ncbi.nlm.nih.gov/22150165/
  11. Browman GP, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993. https://pubmed.ncbi.nlm.nih.gov/8426619/

7 · Chemoradiotherapy — the platinum backbone

  1. [ANCHOR] Pignon JP, et al. Meta-analysis of chemotherapy in head and neck cancer (MACH-NC): an update on 93 randomised trials and 17,346 patients. Radiother Oncol 2009. https://pubmed.ncbi.nlm.nih.gov/19446902/
  2. Lacas B, et al. MACH-NC update: individual patient data network meta-analysis. Lancet Oncol 2021. https://pubmed.ncbi.nlm.nih.gov/34049003/
  3. Adelstein DJ, et al. An intergroup phase III comparison of standard radiation therapy and two schedules of concurrent chemoradiotherapy in unresectable head and neck cancer. J Clin Oncol 2003. https://pubmed.ncbi.nlm.nih.gov/12506176/
  4. Forastiere AA, et al. Concurrent chemotherapy and radiotherapy for organ preservation in advanced laryngeal cancer (RTOG 91-11). N Engl J Med 2003 / long-term J Clin Oncol 2013. https://pubmed.ncbi.nlm.nih.gov/14645636/
  5. Cooper JS, et al. Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck (RTOG 9501). N Engl J Med 2004. https://pubmed.ncbi.nlm.nih.gov/15128893/
  6. Bernier J, et al. Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer (EORTC 22931). N Engl J Med 2004. https://pubmed.ncbi.nlm.nih.gov/15128894/
  7. Bernier J, et al. Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent chemoradiation in the RTOG 9501 and EORTC 22931 trials. Head Neck 2005. https://pubmed.ncbi.nlm.nih.gov/16161069/
  8. Ang KK, et al. Human papillomavirus and survival of patients with oropharyngeal cancer (RTOG 0129). N Engl J Med 2010. https://pubmed.ncbi.nlm.nih.gov/20530316/
  9. Strojan P, et al. Cumulative cisplatin dose in concurrent chemoradiotherapy for head and neck cancer: a systematic review. Head Neck 2016. https://pubmed.ncbi.nlm.nih.gov/26894744/
  10. [HELD-OUT] Noronha V, et al. Once-a-week versus once-every-3-weeks cisplatin chemoradiation for locally advanced head and neck cancer: a phase III randomized noninferiority trial. J Clin Oncol 2018. https://pubmed.ncbi.nlm.nih.gov/29331199/
  11. [HELD-OUT] Kiyota N, et al. Weekly cisplatin plus radiation for postoperative head and neck cancer (JCOG1008): a multicenter, noninferiority, phase II/III trial. J Clin Oncol 2022. https://pubmed.ncbi.nlm.nih.gov/35357907/
  12. Wilkins AC, et al. Cisplatin plus radiotherapy: mechanisms of interaction / Boeckman HJ, et al. Cisplatin sensitizes cancer cells to ionizing radiation via inhibition of nonhomologous end joining. Mol Cancer Res 2005. https://pubmed.ncbi.nlm.nih.gov/15956241/
  13. Sears CR, Turchi JJ. Complex cisplatin-double strand break (DSB) lesions directly impair cellular non-homologous end-joining (NHEJ) independent of downstream damage response signaling. J Biol Chem 2012. https://pubmed.ncbi.nlm.nih.gov/22992740/
  14. Olaussen KA, et al. DNA repair by ERCC1 in non-small-cell lung cancer and cisplatin-based adjuvant chemotherapy. N Engl J Med 2006 (ERCC1 principle applied to HNSCC in Handra-Luca A, et al. Clin Cancer Res 2007). https://pubmed.ncbi.nlm.nih.gov/17671124/

8 · Cetuximab and EGFR-directed de-escalation

  1. [ANCHOR] Bonner JA, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 2006. https://pubmed.ncbi.nlm.nih.gov/16467544/
  2. Bonner JA, et al. Radiotherapy plus cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 randomised trial. Lancet Oncol 2010. https://pubmed.ncbi.nlm.nih.gov/20004617/
  3. [ANCHOR] Gillison ML, et al. Radiotherapy plus cetuximab or cisplatin in human papillomavirus-positive oropharyngeal cancer (NRG Oncology RTOG 1016): a randomised, multicentre, non-inferiority trial. Lancet 2019. https://pubmed.ncbi.nlm.nih.gov/30449625/
  4. [ANCHOR] Mehanna H, et al. Radiotherapy plus cisplatin or cetuximab in low-risk human papillomavirus-positive oropharyngeal cancer (De-ESCALaTE HPV): an open-label randomised controlled phase 3 trial. Lancet 2019. https://pubmed.ncbi.nlm.nih.gov/30449623/
  5. [HELD-OUT] Ang KK, et al. Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without cetuximab for stage III to IV head and neck carcinoma (RTOG 0522). J Clin Oncol 2014. https://pubmed.ncbi.nlm.nih.gov/25154822/
  6. Vermorken JB, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer (EXTREME). N Engl J Med 2008. https://pubmed.ncbi.nlm.nih.gov/18784101/
  7. Bibeau F, et al. Impact of FcγRIIa-FcγRIIIa polymorphisms and KRAS mutations on the clinical outcome of patients treated with cetuximab. J Clin Oncol 2009. https://pubmed.ncbi.nlm.nih.gov/19204207/
  8. Taylor RJ, et al. FcγRIIIa polymorphisms and cetuximab-induced cytotoxicity in squamous cell carcinoma of the head and neck. Cancer Immunol Immunother 2009. https://pubmed.ncbi.nlm.nih.gov/18987856/
  9. Dirix P, Vanstraelen B, Nuyts S. Cetuximab-induced skin rash and survival / Bonner JA, et al. Association of acneiform rash severity with outcome. Ann Oncol 2010. https://pubmed.ncbi.nlm.nih.gov/20130225/
  10. Schrag D, et al. Cetuximab therapy and symptomatic hypomagnesemia. J Natl Cancer Inst 2005 (mechanism: Groenestege WMT, et al. J Clin Invest 2007). https://pubmed.ncbi.nlm.nih.gov/17671655/
  11. Chung CH, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-alpha-1,3-galactose. N Engl J Med 2008. https://pubmed.ncbi.nlm.nih.gov/18334654/
  12. Dirix P, et al. Population pharmacokinetics of cetuximab / Fracasso PM, et al. A phase 1 escalating single-dose and weekly fixed-dose study of cetuximab. Clin Cancer Res 2007. https://pubmed.ncbi.nlm.nih.gov/17332291/

9 · Immune microenvironment and checkpoint blockade

  1. Ferris RL, et al. Nivolumab for recurrent squamous-cell carcinoma of the head and neck (CheckMate 141). N Engl J Med 2016. https://pubmed.ncbi.nlm.nih.gov/27718784/
  2. Burtness B, et al. Pembrolizumab alone or with chemotherapy versus cetuximab with chemotherapy for recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-048). Lancet 2019. https://pubmed.ncbi.nlm.nih.gov/31679945/
  3. Cohen EEW, et al. Pembrolizumab versus methotrexate, docetaxel, or cetuximab for recurrent head and neck squamous cell carcinoma (KEYNOTE-040). Lancet 2019. https://pubmed.ncbi.nlm.nih.gov/30509740/
  4. Kulangara K, et al. Clinical utility of the combined positive score for PD-L1 expression and the approval of pembrolizumab for treatment of gastric cancer / PD-L1 CPS scoring in HNSCC. Arch Pathol Lab Med 2019. https://pubmed.ncbi.nlm.nih.gov/30407860/
  5. Lee NY, et al. Avelumab plus standard-of-care chemoradiotherapy versus chemoradiotherapy alone in patients with locally advanced squamous cell carcinoma of the head and neck (JAVELIN Head and Neck 100). Lancet Oncol 2021. https://pubmed.ncbi.nlm.nih.gov/33002432/
  6. Machiels JP, et al. Pembrolizumab plus concurrent chemoradiotherapy versus placebo plus chemoradiotherapy for locally advanced HNSCC (KEYNOTE-412). Lancet Oncol 2024. https://pubmed.ncbi.nlm.nih.gov/38848741/
  7. Uppaluri R, et al. Neoadjuvant and adjuvant pembrolizumab in resectable locally advanced head and neck squamous cell carcinoma. Clin Cancer Res 2020. https://pubmed.ncbi.nlm.nih.gov/32398345/
  8. Mandal R, et al. The head and neck cancer immune landscape and its immunotherapeutic implications. JCI Insight 2016. https://pubmed.ncbi.nlm.nih.gov/27942583/
  9. Cillo AR, et al. Immune landscape of viral- and carcinogen-driven head and neck cancer. Immunity 2020. https://pubmed.ncbi.nlm.nih.gov/31924475/
  10. Ferris RL, et al. Tumor antigen-targeted, monoclonal antibody-based immunotherapy: clinical response, cellular immunity and immunoescape. J Clin Oncol 2010. https://pubmed.ncbi.nlm.nih.gov/20940192/
  11. Leibowitz MS, et al. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother 2011. https://pubmed.ncbi.nlm.nih.gov/21519829/
  12. Ogino T, et al. HLA class I antigen down-regulation in primary laryngeal squamous cell carcinoma lesions as a poor prognostic marker. Cancer Res 2006. https://pubmed.ncbi.nlm.nih.gov/16982766/
  13. Golden EB, Apetoh L. Radiotherapy and immunogenic cell death. Semin Radiat Oncol 2015. https://pubmed.ncbi.nlm.nih.gov/25732004/
  14. Deng L, et al. STING-dependent cytosolic DNA sensing promotes radiation-induced type I interferon-dependent antitumor immunity. Immunity 2014. https://pubmed.ncbi.nlm.nih.gov/25517616/
  15. Tang C, et al. Ipilimumab with stereotactic ablative radiation therapy / Twyman-Saint Victor C, et al. Radiation and dual checkpoint blockade activate non-redundant immune mechanisms. Nature 2015. https://pubmed.ncbi.nlm.nih.gov/25754329/
  16. Ahn MJ, et al. Nivolumab plus ipilimumab in recurrent/metastatic HNSCC (CheckMate 651). J Clin Oncol 2023. https://pubmed.ncbi.nlm.nih.gov/36867686/
  17. Postow MA, Sidlow R, Hellmann MD. Immune-related adverse events associated with immune checkpoint blockade. N Engl J Med 2018. https://pubmed.ncbi.nlm.nih.gov/29320654/
  18. Wang PF, et al. Immune-related adverse events associated with anti-PD-1/PD-L1 treatment for malignancies: a meta-analysis. Front Pharmacol 2017. https://pubmed.ncbi.nlm.nih.gov/29075197/

10 · Induction chemotherapy, taxanes and 5-fluorouracil

  1. Vermorken JB, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer (TAX 323). N Engl J Med 2007. https://pubmed.ncbi.nlm.nih.gov/17960013/
  2. Posner MR, et al. Cisplatin and fluorouracil alone or with docetaxel in head and neck cancer (TAX 324). N Engl J Med 2007. https://pubmed.ncbi.nlm.nih.gov/17960012/
  3. Haddad R, et al. Induction chemotherapy followed by concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone (PARADIGM). Lancet Oncol 2013. https://pubmed.ncbi.nlm.nih.gov/23578174/
  4. Cohen EEW, et al. Phase III randomized trial of induction chemotherapy in patients with N2 or N3 locally advanced head and neck cancer (DeCIDE). J Clin Oncol 2014. https://pubmed.ncbi.nlm.nih.gov/24958820/
  5. Longley DB, Harkin DP, Johnston PG. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 2003. https://pubmed.ncbi.nlm.nih.gov/12724731/
  6. Amstutz U, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for dihydropyrimidine dehydrogenase genotype and fluoropyrimidine dosing. Clin Pharmacol Ther 2018. https://pubmed.ncbi.nlm.nih.gov/29152729/
  7. Bruno R, et al. Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer. J Clin Oncol 1998. https://pubmed.ncbi.nlm.nih.gov/9508171/

11 · Platinum pharmacokinetics and organ toxicity

  1. Urien S, Lokiec F. Population pharmacokinetics of total and unbound plasma cisplatin in adult patients. Br J Clin Pharmacol 2004. https://pubmed.ncbi.nlm.nih.gov/15606443/
  2. Vermorken JB, et al. Pharmacokinetics of free and total platinum species after short-term infusion of cisplatin. Cancer Treat Rep 1984 / Erdlenbruch B, et al. Br J Clin Pharmacol 2001. https://pubmed.ncbi.nlm.nih.gov/11736867/
  3. Calvert AH, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol 1989. https://pubmed.ncbi.nlm.nih.gov/2681557/
  4. Ciarimboli G, et al. Organic cation transporter 2 mediates cisplatin-induced oto- and nephrotoxicity. Am J Pathol 2010. https://pubmed.ncbi.nlm.nih.gov/20431035/
  5. Miller RP, et al. Mechanisms of cisplatin nephrotoxicity. Toxins 2010. https://pubmed.ncbi.nlm.nih.gov/22069601/
  6. Rybak LP, et al. Mechanisms of cisplatin-induced ototoxicity and prevention. Hear Res 2007. https://pubmed.ncbi.nlm.nih.gov/17706109/
  7. Breglio AM, et al. Cisplatin is retained in the cochlea indefinitely following chemotherapy. Nat Commun 2017. https://pubmed.ncbi.nlm.nih.gov/29162831/
  8. Ross CJD, et al. Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy. Nat Genet 2009 / Xu H, et al. ACYP2. Nat Genet 2015. https://pubmed.ncbi.nlm.nih.gov/26301491/
  9. Friberg LE, et al. Model of chemotherapy-induced myelosuppression with parameter consistency across drugs. J Clin Oncol 2002. https://pubmed.ncbi.nlm.nih.gov/12488408/
  10. Frame D. Best practice management of CINV in oncology patients / Hesketh PJ. Chemotherapy-induced nausea and vomiting. N Engl J Med 2008. https://pubmed.ncbi.nlm.nih.gov/18525043/

12 · Normal-tissue injury: mucositis, xerostomia, dysphagia, late effects

  1. Sonis ST. The pathobiology of mucositis. Nat Rev Cancer 2004. https://pubmed.ncbi.nlm.nih.gov/15057287/
  2. Sonis ST. Pathobiology of oral mucositis: novel insights and opportunities. J Support Oncol 2007. https://pubmed.ncbi.nlm.nih.gov/17958279/
  3. Trotti A, et al. Mucositis incidence, severity and associated outcomes in patients with head and neck cancer receiving radiotherapy with or without chemotherapy: a systematic literature review. Radiother Oncol 2003. https://pubmed.ncbi.nlm.nih.gov/12873674/
  4. Elting LS, et al. Risk, outcomes, and costs of radiation-induced oral mucositis among patients with head-and-neck malignancies. Int J Radiat Oncol Biol Phys 2007. https://pubmed.ncbi.nlm.nih.gov/17544601/
  5. Dörr W, Hendry JH. Consequential late effects in normal tissues. Radiother Oncol 2001. https://pubmed.ncbi.nlm.nih.gov/11395258/
  6. Eisbruch A, et al. Dose, volume, and function relationships in parotid salivary glands following conformal and intensity-modulated irradiation of head and neck cancer. Int J Radiat Oncol Biol Phys 1999. https://pubmed.ncbi.nlm.nih.gov/10487552/
  7. Deasy JO, et al. Radiotherapy dose-volume effects on salivary gland function (QUANTEC). Int J Radiat Oncol Biol Phys 2010. https://pubmed.ncbi.nlm.nih.gov/20171519/
  8. [HELD-OUT] Nutting CM, et al. Parotid-sparing intensity modulated versus conventional radiotherapy in head and neck cancer (PARSPORT): a phase 3 multicentre randomised controlled trial. Lancet Oncol 2011. https://pubmed.ncbi.nlm.nih.gov/21236730/
  9. Konings AWT, Coppes RP, Vissink A. On the mechanism of salivary gland radiosensitivity. Int J Radiat Oncol Biol Phys 2005. https://pubmed.ncbi.nlm.nih.gov/16226396/
  10. Eisbruch A, et al. Dysphagia and aspiration after chemoradiotherapy for head-and-neck cancer: which anatomic structures are affected and can they be spared by IMRT? Int J Radiat Oncol Biol Phys 2004. https://pubmed.ncbi.nlm.nih.gov/15519788/
  11. Hutcheson KA, et al. Dynamic Imaging Grade of Swallowing Toxicity (DIGEST): scale development and validation. Cancer 2017. https://pubmed.ncbi.nlm.nih.gov/27808424/
  12. Straub JM, et al. Radiation-induced fibrosis: mechanisms and implications for therapy. J Cancer Res Clin Oncol 2015. https://pubmed.ncbi.nlm.nih.gov/25573644/
  13. Nabil S, Samman N. Incidence and prevention of osteoradionecrosis after dental extraction in irradiated patients: a systematic review. Int J Oral Maxillofac Surg 2011. https://pubmed.ncbi.nlm.nih.gov/21396799/
  14. Boomsma MJ, Bijl HP, Langendijk JA. Radiation-induced hypothyroidism in head and neck cancer patients: a systematic review. Radiother Oncol 2011. https://pubmed.ncbi.nlm.nih.gov/21255848/
  15. Dorresteijn LDA, et al. Increased risk of ischemic stroke after radiotherapy on the neck in patients younger than 60 years. J Clin Oncol 2002. https://pubmed.ncbi.nlm.nih.gov/11844823/
  16. Bjordal K, et al. A 12 country field study of the EORTC QLQ-C30 and the head and neck cancer specific module (EORTC QLQ-H&N35). Eur J Cancer 2000. https://pubmed.ncbi.nlm.nih.gov/10974628/

13 · Host state, nutrition and cachexia

  1. Fearon K, et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol 2011. https://pubmed.ncbi.nlm.nih.gov/21296615/
  2. Baracos VE, et al. Cancer-associated cachexia. Nat Rev Dis Primers 2018. https://pubmed.ncbi.nlm.nih.gov/29345251/
  3. Johnen H, et al. Tumor-induced anorexia and weight loss are mediated by the TGF-beta superfamily cytokine MIC-1 (GDF-15). Nat Med 2007. https://pubmed.ncbi.nlm.nih.gov/17982465/
  4. Langius JAE, et al. Critical weight loss is a major prognostic indicator for disease-specific survival in patients with head and neck cancer receiving radiotherapy. Br J Cancer 2013. https://pubmed.ncbi.nlm.nih.gov/23695023/
  5. Wendrich AW, et al. Low skeletal muscle mass is a predictive factor for chemotherapy dose-limiting toxicity in patients with locally advanced head and neck cancer. Oral Oncol 2017. https://pubmed.ncbi.nlm.nih.gov/28688688/
  6. Piccirillo JF, et al. Development of a new head and neck cancer-specific comorbidity index (ACE-27). Arch Otolaryngol Head Neck Surg 2002. https://pubmed.ncbi.nlm.nih.gov/12365042/

14 · Staging, biomarkers and response assessment

  1. Lydiatt WM, et al. Head and Neck cancers — major changes in the American Joint Committee on Cancer eighth edition cancer staging manual. CA Cancer J Clin 2017. https://pubmed.ncbi.nlm.nih.gov/28128848/
  2. O'Sullivan B, et al. Development and validation of a staging system for HPV-related oropharyngeal cancer by the ICON-S group. Lancet Oncol 2016. https://pubmed.ncbi.nlm.nih.gov/26670617/
  3. Eisenhauer EA, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 2009. https://pubmed.ncbi.nlm.nih.gov/19097774/
  4. Chera BS, et al. Plasma circulating tumor HPV DNA for the surveillance of cancer recurrence in HPV-associated oropharyngeal cancer. J Clin Oncol 2020. https://pubmed.ncbi.nlm.nih.gov/32348703/
  5. Chera BS, et al. Rapid clearance profile of plasma circulating tumor HPV type 16 DNA during chemoradiotherapy correlates with disease control. Clin Cancer Res 2019. https://pubmed.ncbi.nlm.nih.gov/31088830/
  6. Ferris RL, et al. Extranodal extension and its prognostic significance / Amin MB. AJCC Cancer Staging Manual 8th ed. Head Neck 2019. https://pubmed.ncbi.nlm.nih.gov/31179584/

15 · QSP / modelling methodology

  1. Fowler JF. Rapid repopulation in radiotherapy: a debate on mechanism. Radiother Oncol 1991 / Fowler JF. Biological factors influencing optimum fractionation. Acta Oncol 2001. https://pubmed.ncbi.nlm.nih.gov/11441937/
  2. Webb S, Nahum AE. A model for calculating tumour control probability in radiotherapy including the effects of inhomogeneous distributions of dose and clonogenic cell density. Phys Med Biol 1993. https://pubmed.ncbi.nlm.nih.gov/8346284/
  3. Zaider M, Minerbo GN. Tumour control probability: a formulation applicable to any temporal protocol of dose delivery. Phys Med Biol 2000. https://pubmed.ncbi.nlm.nih.gov/10701509/
  4. Bentzen SM, Tucker SL. Quantifying the position and steepness of radiation dose-response curves. Int J Radiat Biol 1997. https://pubmed.ncbi.nlm.nih.gov/9246191/
  5. Curtis SB. Lethal and potentially lethal lesions induced by radiation — a unified repair model. Radiat Res 1986. https://pubmed.ncbi.nlm.nih.gov/3737748/
  6. Brenner DJ, et al. A convenient extension of the linear-quadratic model to include redistribution and reoxygenation. Int J Radiat Oncol Biol Phys 1995. https://pubmed.ncbi.nlm.nih.gov/7635772/
  7. Baker RE, Peña JM, Jayamohan J, Jérusalem A. Mechanistic models versus machine learning, a fight worth fighting for the biological community? Biol Lett 2018. https://pubmed.ncbi.nlm.nih.gov/29769297/
  8. Elmokadem A, et al. Quantitative systems pharmacology and physiologically-based pharmacokinetic modeling with mrgsolve: a hands-on tutorial. CPT Pharmacometrics Syst Pharmacol 2019. https://pubmed.ncbi.nlm.nih.gov/31654579/
  9. Baron KT, et al. mrgsolve: Simulate from ODE-Based Models. R package. https://mrgsolve.org/
  10. Chelliah V, et al. Quantitative systems pharmacology approaches for immuno-oncology: adding virtual patients to the development paradigm. Clin Pharmacol Ther 2021. https://pubmed.ncbi.nlm.nih.gov/32433790/
  11. Jafarnejad M, et al. A computational model of neoadjuvant PD-1 inhibition in non-small cell lung cancer. AAPS J 2019. https://pubmed.ncbi.nlm.nih.gov/30984968/
  12. Wang H, et al. In silico simulation of a clinical trial with anti-CTLA-4 and anti-PD-L1 immunotherapies in metastatic breast cancer using a systems pharmacology model. R Soc Open Sci 2019. https://pubmed.ncbi.nlm.nih.gov/31417737/

How the anchors and held-out tests are used

Role Trial / source Quantity Used for
[ANCHOR] Bonner 2006 / 2010 (79, 80) 3-yr LRC 34 % (RT) and 47 % (cetuximab-RT), HPV-unselected fits ALPHA0, FCSC0
[ANCHOR] MACH-NC (65, 66), RTOG 0129 (72) LRC ≈ 58 % for cisplatin-RT, HPV-negative fits PHIPT
[ANCHOR] RTOG 1016 (81), De-ESCALaTE (82) 5-yr LRC 90 % (cisplatin) vs 83 % (cetuximab), HPV-positive fits KHRA
[ANCHOR] DAHANCA 5-85 (57) 5-yr LRC 33 % → 49 % with nimorazole fits KOXTR
[HELD-OUT] RTOG 0522 (83) cetuximab added to cisplatin-RT: no PFS/OS benefit model over-predicts — see README.md
[HELD-OUT] Hansen 1997 (46), Bese 2007 (47), Withers 1988 (43) ≈ 1 % LRC lost per day of prolongation; 0.6-0.9 Gy/day reproduced, and predicted to be position-dependent
[HELD-OUT] EORTC 22791 (51), MARCH (52) hyperfractionation improves LRC reproduced
[HELD-OUT] Noronha 2018 (74), JCOG1008 (75) weekly vs 3-weekly cisplatin roughly comparable direction reproduced, magnitude wrong
[HELD-OUT] PARSPORT (133), QUANTEC (132) IMRT parotid sparing preserves salivary flow reproduced
[HELD-OUT] KEYNOTE-048 (92), KEYNOTE-040 (93) benefit increases with PD-L1 CPS reproduced as a monotone gradient
[HELD-OUT] Nordsmark 2005 (55), Begg 1992 (48) hypoxic fraction 10-25 %, T_pot 4-5 days reproduced as emergent values