paranasal sinuses cancers Ester Orlandi Radiotherapy Department Centro Nazionale di Adroterapia Oncologica CNAO Pavia Italy 03072023 Pag 2 Salivary gland cancers ID: 1009796
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1. Salivary glands & paranasal sinuses cancers Ester Orlandi,Radiotherapy Department,Centro Nazionale di Adroterapia Oncologica (CNAO) Pavia, Italy
2. 03/07/2023Pag. 2Salivary gland cancers
3. Salivary gland cancers (SGCs): Major salivary gland cancers (SGCs): 5% of head and neck cancers in Europe. Incidence rates: 0.69 per 100 000 people per year.Data for minor SGCs are limited. Incidence rate: 0.4 cases per 100 000 people in the 2000-2007 diagnosis period.Malignant SGCs include >20 distinct histological subtypes (WHO classification system). Sixth and seventh decades of life and has a male predominance but age at diagnosis and gender predominance vary by histology.Molecular diagnostics in SGC is evolving.Surgery+postop RT in resectable stages, definitive RT in unresectable ones.
4. Adenoid cystic carcinoma (ACC)Rare and morphologically (and biologically) heterogeneous disease. 15–30% of ACC cases originating in minor salivary glands of the nasal cavity, paranasal sinuses and oral cavity.Target volume shape often embracing radiosensitive structures following neural pathways.Well-known radioresistance.Surgery+postop RT in resectable stages, definitive RT in unresectable ones.For unresectable or R2 cases treated with (IMRT) >70 Gy: 5-yr LC: 26-44%. Orlandi E,2016; Loap P, 2021; da Cruz Perez DE 2009, Geiger GL, 2021, van Herper C 2022
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6. Results from RTOG-MRC phase III trial (neutron therapy vs 2DRT) on inoperable or unresectable malignant SGCs: 2-yr LC: 67% vs 25%; 10-yr LC: 56% vs 17% (p<0.05). For unresectable or R2 cases treated with IMRT >70 Gy: 5-yr LC: 40-45%.Clinical experience: definitive RT for unresectable SGCsGriffin TW 1988; Cowie VJ 1984; Spratt DE 2014; Pommier P 2006; Huber PE 2001; Laramore GE 1993; Miglianico L 1987; Mendenhall WM 2004; Mendenhall WM 2005; da Cruz Perez DE 2009
7. ACC: comparing experiencesInstitutionsNo of patientsTreatmentLocal Control (%)Overall Survival (%)Iowa, 20095410Surgery alonePhoton alone72 (5y)27 (5y)85 (5y)25 (5y)Florida, 2004101Photon alone27 (5y)25 (5y)MGH, 200623Surgery+protons93 (5y)77 (5y)GSI, 20053429Photon alonePhoton + carbon boost25 (4y)78 (4y)78 (4y)76 (4y)NIRS, 201115132119Carbon alone (all pats)Carbon alone (T1-T3)Carbon alone (T4 or recurrence)74 (5y)96 (5y)71 (5y)72 (5y)92 (5y)69 (5y)HIT, 20155837Photon + carbon boostPhoton (IMRT) 59.6 (5y)39,9 (5y)76.5 (5y)58,7 (5y)Japan (4 centers), 2018289Carbon alone74 (5y)68 (5y) (unpublished l data)184Carbon alone 75 (3y)53 (5y)85 (3y)65 (5y)
8. Sulaiman et al. Int J Radiat Oncol Biol Phys. 2018 5-y LC：74%5-y LC：74%5-y OS：68%Median FU: 30 mosACC and CIRT in Japan (J-CROS-1402): CIRT full course2003-2014
9. Late toxicity: 2 pts G5 (hemorrhage); 43 pts (15%) G3, mainly osteonecrosis of the jaw bone 14 pts (5%) G4 (visual, hemorrhage, brain)ACC and CIRT in Japan (J-CROS-1402)Sulaiman et al. Int J Radiat Oncol Biol Phys. 2018
10. Parotid gland carcinoma and CIRT (NIRS data)5-y OS:70.1%5-y PFS: 49.2% 604836241201.0.9.8.7.6.5.4.3.2.10.0604836241201.0.9.8.7.6.5.4.3.2.10.05-y LC: 74.5%SurvivalLocal control83% of patients could maintain facial nerve function after C-ion RT!Koto M, et al, Head Neck 2017 46 patients Median FU: 62 mos46 pts16 ACC8 MEC8 adenocarcinoma14 othersT2 3T3 18T4a 8T4b 1725 unresected20 local recurrence after surgery1 R2MRI (Pre C-ion RT) MRI (5-y after C-ion RT)
11. CIRT for ACC @ HIT (Germany):mixed beam approachSchulz-Ertner D et al, Cancer 2005METHODS1995 -200363 patientsConventional or mixed approach with C-ions boost of 18 GyRBE RESULTSMedian FU 16 mos2- and 4y-LC: 77.5%moderate toxicity
12. CIRT for ACC @ HIT (Germany)P=0.015P=0.033Jensen et al, Cancer 2015METHODS 1997 and 2009R2 or unresected 58 ACC with C12 boost (18 GyRBE) and IMRT vs 37 with photons (IMRT or FSRT) Median F/U =74 months in the C12 vs 63 in the photon groupNo difference in terms of clinical features between the two groups (manly T4 and paranasal sinus) RESULTS5 ys LC in C12 vs photon: 59.6% vs 39.9%5 ys PFS in C12 vs photon: 48.4% vs 27%5 ys OS in C12 vs photon: 76.5% vs 58.7%No difference in terms of tox between the two groupsMost of recurrences in fieldneed for dose escalation COSMIC trial with C12 boost dose increased up to 24 GyRBE (Jensen et al, IJROBP, 2015)
13. Lavoro sulla verde CIRT for ACC @ HIT (Germany)1998-2013Median FU:33.9 mosJensen et al, Radiother Oncol 20155-y LC：58.5%5-y OS：74.6%Extensive and potentially mutilating surgical procedures may have to be re-evaluated.Grade II :6% (olfactory, oculomotor, or facial nerve paralysis: 6%, corneal ulcer: 1%, xerostomia: 3%), grade III in one patient (peridontal disease)grade IV in 2 patients (hemorrhage, loss of vision); 5 pts developed ORNLate tox
14. March 2013 -July 2020184 naive or recurrent patients (never treated with RT)Minor/Major salivary glands 112(61%)/72(39%)CIRT full courseNCT05203250 REGAL CNAO Registry Trial (Longitudinal Registry Including Patients Treted with Heavy particles)CIRT for ACC @ CNAO (Italy)
15. Descriptive statistics (1): population112 miSGs-ACC pts, M/F = 55/57; median age:55 ys, range (22-85); N0 stage: 94%; M1 (oligo-lung): 3%; Perineural involvement: 98%.T stagePrimary site%)%CIRT for ACC @ CNAO (Italy)
16. 27/36, 75%, with R2 at MRI pre-CIRTDescriptive statistics (2): treatmentMedian time from surgery to CIRT: 48 days (range 28-92)92%CIRT for ACC @ CNAO (Italy)GTV: Mean 54.2 cc; median 44.6 cc
17. Fractionation scheme:CIRT: 4.3 Gy[RBE] FS/ 16fs/ 68.8Gy[RBE] CIRT: 4.1 Gy[RBE]FS/ 16 frs/ 65.6 Gy [RBE]Sequential strategy LR-CTV: 9-10 frs HR-CTV: 6-7 frs (IR-CTV optional)CIRT for ACC @ CNAO (Italy)
18. Outcome resultsMedian FU: 45 mos (range, 7-90) CIRT for ACC @ CNAO (Italy)5-y LC：45.5%5y-OS: 58.8%
19. Overall Survival Variable 24-mos OS 60-mos OS p-value Hazard RatioUnivariable analysisMultivariable analysisCIRT for ACC @ CNAO (Italy)
20. Univariable analysisVariable 24-mos OS 60-mos OS p-value Hazard RatioLocal Progression Free Survival Multivariable analysisCIRT for ACC @ CNAO (Italy)
21. ToxicityMainly skin and mucosal toxicity Acute LateAt Multivariable analysis the presence of flap was found to be an indipendent prognostic factor for late toxicity≥ G3. (CTCAE v 4.0)CIRT for ACC @ CNAO (Italy)
22. First endpoint: LC
23. 03/07/2023SIBACIRTSecondary endpoints:Local Control (at least 12 months after starting of treatment) development of multivariate predictive models, including clinical and dosimetric parameters, for different toxicity endpoints; 3) Quality of Life (EORTC QLQ C30 and QLQ 43 questionnaires assessed at baseline, at the end of treatment and every 6 months after the end of treatment)Monocentric, single arm prospective phase II clinical trialStudy duration: 36 months42 head and neck ACC patients (unresectable or after surgery)CIRT with SIB approachtotal dose to HR-CTV of 65.6 GyRBE in 16 fractions (4.1 GyRBE/fraction)LR-CTV simultaneously receiving a total dose of 54.4 GyRBE (3.4 GyRBE/fraction) or 48 GyRBE (3 GyRBE/fraction) depending on different prognostic factorsPrimary endpoint: acute and subacute toxicity (within 180 days after the end of treatment) (CTCAE v5.0.)INDAGAproject ID 3438215funded by Fondazione Regionale per la Ricerca Biomedica, Regione Lombardia, call Unmet Medical Needs
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25. Young female pt with a parotid unresectable high grade MEC (CRCTC1-MAML2 pos)PT+CIRT: dosimetric advantagesSIB-VMATMEC: involvement of cancer stem cells (CSCs) in tumor progression and radioresistance phenotypeoverexpression of HIF-1α upregulation of genes involved in cell adhesionParticles: In preclinical studies: increased effectiveness of C-ions against CSCs irradiation with C-ions strongly reduced HIF-1α levels, a gene that can enhance survival by inducing hypoxia after exposure to X-rays the down-regulation by C-ions and PT of genes involved in cell adhesion, cell motility, which are generally upregulated by conventional radiotherapyBiological advantagesCIRT boost+PT
26. 03/07/2023Pag. 26Sinonasal cancers
27. 03/07/2023Pag. 27Sinonasal cancers (SNCs) are very rare diseases account for 3% of all HNC.Malignant SNCs include >20 distinct histological subtypes (WHO classification system). Excluding some histotypes, SNCs are characterised by poor prognosis, with historical 5-year PFS ranging between 14% and 21%.In the majority of cases of LA-SNCs, the therapeutic strategy relies on the combination of surgery, radiotherapy (RT) and chemotherapy. For unresectable disease or inoperable patients, definitive RT is proposed, often with concurrent chemotherapy.Variable “degree” in radioresistance.Traslation genomics is a relavant field of research for SNCs.Data on the efficacy of Protons (PT) and carbon ions (CIRT) is relentlessly growing.Sinonasal cancers (SNCs)
28. Translational genomics of sinonasal cancersHermsen et al, Seminars in cancer Biology, 2020Besides targeted therapies, identifing RSI differential forphoton and particle RT might help in addressing patientsto best treatment according to radiosensitivityRadio-sensitivity Squamous Cell Carcinoma (SCC) (90%)+++Undifferentiated Carcinoma++++Adenocarcinoma++Adenoid-cystic carcinoma Mucosal Melanoma +Concerning radiotherapy…
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30. 03/07/2023Pag. 3041 observational studies with 43 cohorts included: 7 PT, 3 PT+photon, 2 CIRT+photon, 1 CIRT+PT, 30 photonsA subgroup analysis comparing PT with IMRT showed significantly higher DFS at 5 years (p=0·045) and LRC at longest follow-up (p=0·011).Neurological tox higher with PT but:PT studies more detailed on toxicity vs IMRT (92% vs 57%; p=0·03). Challenging cases sent to PT instead of IMRT, but more favourable histologiesHigher biological and phyiscal doses delivered in PT studies compared to IMRT2011Paranasal sinuses cancers (no ACC): 7observation studies (1CIRT, 4 PRT, and 2 IMRT): 5 ys LC statistacally better for pts treated with PT vs IMRT. Lower tox with PT compared to IMRTMucosal melanoma 20 observation studies (2CIRT, 18 IMRT): 5 ys-OS statistically better for pts treated with CIRT vs IMRT)Overall poor quantity and quality of data regarding CIRT ->international registry2014
31. 03/07/2023Pag. 31Main results of Zhang’s meta-analysis: 20202282 pts: 911 in the CIRT group, 599 in the PRT group, and 772 in the IMRT group)from 44 observational studies (7 CIRT, 16 PRT, and 21 IMRT); Study period: 31990-2019The OS was significantly higher after CIRT (75.1%) than PT (66.2%, P < .0001) or IMRT (63.8%, P < .0001). LC was significantly higher after CIRT (80.2%), than PT (72.9%, P = .003) or IMRT (67.8%,P < .0001). However, no significant difference between PRT and IMRT for OS and LC was observed.Limited data on tox.Heterogenous cohorts -> no conclusive data
32. 03/07/2023Pag. 3239 pts, 2011-2019most common histologies: SCC and ONB T4 disease:46%.Various settings: definitive RT, postop RT, reirradiation One acute G3 neurologic PAT (blurred vision) resolved, and no late G3–4 neurologic PATs were observed.No significant changes were noted in PROs from baseline to the chronic periodLCOS
33. 03/07/2023Pag. 33Primary IMRT (n = 90, 40%) or Postoperative IMRT+CIRT (n = 137, 60%; R2, n = 86, 63%) Primary radiotherapy including IMRT and carbon ion boost for dose-escalation results in adequate LC with less long-term grade 3 toxicity compared to postoperative bimodal radiotherapy in sinonasal ACC patients. The high rate of macroscopic tumor disease in the postoperative group makes the interpretation of the beneficial results in LC for primary RT difficult
34. Multidisciplinary approach for poor prognosis sinonasal tumors: Phase II study of chemotherapy, surgery, photon and heavy ion radiotherapy integration for more effective and less toxic treatment inoperable and inoperable patients SINTART1 (OPERABLE PATIENTS)Study design:Ph II, single-arm, open-label, multicenter studiesSINTART2 (INOPERABLE PATIENTS) Study design:RC/RP >80%: heavy ion based RT+ CTno RC or RP <80%: Surgery + Heavy ion based RT+CThistology-driven CThistology-driven CTheavy ion basedRT+ CTAJCC stage: II-III-IVaAJCC stage: Tb4Sample size: 40 patientsSample size: 25 patientsPrimary endpoint: 5-yr PFS from 40 to 65% Primary endpoint: 5-yr PFS from 14% to 40% RARE AND BAD PROGNOSIS HISTOLOGIES - Squamous Cell Carcinoma (SCC); - Sinonasal Undifferentiated Carcinoma (SNUC); - Small Cell Carcinoma Neuroendocrine Type (SmCCNET); - Pure Sinonasal Neuroendocrine Carcinoma (SNEC); - Intestinal Type Adenocarcinoma (ITAC) with a functional p53 gene; - Esthesioneuroblastoma with differentiation grade III-IV by Hyams First phase II trials including histology-driven CT and heavy ion based RT
35. First phase II trials including histology-driven CT and heavy ion based RT 5 ys PFS 38% 5 ys OS 46% PFS to RECIST to ICH OS to RECIST to ICH5 ys PFS 26.8 % 5 ys OS 23.8% PFS to RECIST to ICH OS to RECIST to ICHHow to select patients for particles?
36. 03/07/2023Pag. 36No guidelines are available to help clinicians in the choice between IMRT and particle therapy, particularly as pertains proton therapy.For radiosensitive tumors (SCC, SNUC) in definitive setting (or postoperative); radioresistant tumors in postoperative setting: IMRT/VMAT vs PRT according to a comparative dosimetric strategy (to deliver the technique that mostly minimizes the overall ocular/neurological tox).For unresectable radioresistant tumors or resectable tumors without organ preservation. Full course of CIRT or combined IMRT-CIRT or PRT-CIRT: to increase tumor control and potentially maintain the organ (not always its function). How select patients for particles. .
37. 03/07/2023Pag. 37Which patients for protons?Over 22 patients, 17 would benefit from PT (77,3%)In silico comparative study , 22 LA or unresectable SNUCUnpublished data70 Gy
38. 03/07/2023Pag. 38IMRT/VMAT vs PRTRT with full course of CIRT Mixed beams with CIRT
39. Available genetic signatures in the search for differential radiosensitivity index (RSI) for radiation type differences among SNCs subtypesSNUC cases separated from nonkeratinizing squamous cell carcinomas (NKSCCs) and from sinonasal neuroendocrine cancers (SNECs) for a neuroendocrine genetic signature, detected in all the samples of 82 genesCorrelation with prognosis in another SNCs series (data not published)1. in sinonasal tumor samples:used the NCI-60 cell lines and three additional lines to develop a database of responses of cancer cells to ionizing radiationcompared clonogenic survival, apoptosis, and gene expression response by microarray22 genes were differentially regulated in cells with low survival after 2-Gy X rays; 14 genes identified lines more sensitive to 8 Gy. 2. in a panel of NCI-60 cell lines from different origin:
40. Future projects @ CNAOIn silico study for RADioresistance GEnomic Signatures in Sinonasal cancers (SNCs) experimental models after particle therapy Barbara Vischioni, Laura Deborah Locati, Angelica Facoetti, Giorgia Fulgini, Giovanni B Ivaldi, Loris De Cecco, Mario Hermsen, Ester Orlandiin cell lines and organoids
41. THANK YOU!https://www.hitriplus.eu/