Antineoplastic Agents

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Docetaxel

Leucovorin

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Levoleucovorin

Cisplatin

Ifosfamide

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Isophosphamide mustard

Tubulin Modulators

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Antibiotics, Antitubercular

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Immunologic Factors

Antidotes

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Vitamin B Complex

Trace Elements

Antineoplastic Agents, Alkylating

Alkylating Agents

Folinic Acid

Folate

Vitamin B9

Squamocellular Carcinoma, Sinonasal Undifferentiated Carcinoma:

* Docetaxel at 75 mg/m2 as IV infusion on Day 1 q3w
* Cisplatin at 80 mg/m2 as IV infusion on Day 1 q3w
* 5-fluorouracil at 800 mg/m2/day as IV infusion from Day 1 to Day 4 q3w

Small cell carcinoma neuroendocrine type, Pure neuroendocrine carcinoma and grade III-IV Esthesioneuroblastoma:

First Cycle and every other cycle:

* Cisplatin at 33 mg/m2/day as IV infusion from Day 1 to Day 3 q3w
* Etoposide at 150 mg/m2/day as IV infusion from Day 1 to Day 3 q3w

Second Cycle and every other cycle:

* Adriamycin at 20 mg/m2/day as IV infusion from Day 1 to Day 3 q3w
* Ifosfamide at 3000 mg/m2/day as IV infusion from Day 1 to Day 3 q3w

Intestinal Type Adenocarcinoma with functional p53:

* Leucovorin\* at 250 mg/m2/day as IV infusion from Day 1 to Day 5 q3w
* Cisplatin at 100 mg/m2 as IV infusion on Day 2 q3w
* 5-fluorouracil at 800 mg/m2/day as IV infusion from Day 2 to Day 5 q3w

Followed by Radiotherapy

80 mg/m2 or 33 mg/m2 or 100 mg/m2 - Concentrate for solution for infusion.

75 mg/m2 - Concentrate for solution for infusion

800 mg/m2/day - Concentrate for solution for infusion

5-fluorouracil

150 mg/m2/day - Concentrate for solution for infusion

20 mg/m2/day - Powder for solution for infusion

Adriamycin

3000 mg/m2/day - Powder for solution for infusion

250 mg/m2/day - Powder for solution for infusion

1. Particle boost with ENI:

   HR-PTV: carbon ions 18 - 21 Gy (RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy IR-PTV: this volume is optional, if used it will receive the first 3 fractions i.e. 9 Gy (RBE) of the boost.
2. Photons boost with ENI:

HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical and postoperative setting will be prescribed. IR-PTV: 59.4-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed

Radiotherapy - Patients needing Elective Nodal Volume (ENI)

1. Treatment with particles IR-PTV: this volume can be larger or equal to HR-PTV according to individual situations. 50.4-54 Gy with 1.8-2 Gy per fraction will be prescribed to IR-PTV with protontherapy with concomitant chemotherapy. HR-PTV: carbon ions 18 - 21 Gy (RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy. The first 3 fractions may be given to the bigger IR-PTV.
2. Treatment with photons. HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical and postoperative setting will be prescribed. IR-PTV: 54-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed

Radiotherapy - Patients not needing ENI

LR-PTV: 50.4-54 Gy with 1.8-2 Gy per fraction will be prescribed. This volume will always be treated with photons IMRT.

1. Particle boost:

   HR-PTV: carbon ions 18 - 21 Gy (RBE) in fractions of 3 Gy (RBE) without concomitant chemotherapy IR-PTV: this volume is optional, if used it will receive the first 3 fractions i.e. 9 Gy (RBE) of the boost.
2. Photons boost. HR-PTV: at least 70 Gy with 2-2.12 Gy per fraction and 66 Gy at 2Gy per fraction in radical and postoperative setting will be prescribed. IR-PTV: 59.4-60 Gy with 1.8 Gy-2 Gy per fraction will be prescribed.

Concomitant chemotherapy will be administered only in case of radiotherapy with photon beams exclusively.

Radiotherapy - Patients needing curative neck irradiation

Lisa Licitra, MD

Piero Nicolai, MD

Paolo Calstelnuovo, MD

Marco Benazzo, MD

Andrea Sponghini, MD

Sinonasal tumors are rare diseases, so no standard treatment for such aggressive tumors has been reported, given rarity, absence of prospective study and heterogeneity of histologies and stages of diseases. This study proposes innovative integration of multiple modality of treatment depending by histology, molecular profile and response to induction CT. Moreover, such strategies allows the use of latest technology with greater biological effectiveness and reduction of toxicities.

So far, surgery followed by radiotherapy (RT) has been the usual approach for advanced disease. Technical improvements in surgical approaches have been reported, providing less invasive surgery with lower morbidity. In this scenario, multimodality treatment seems the best approach, even if there is lack of prospective data.

Some studies explored the role and feasibility of induction chemotherapy (CT) and the prognostic value of response to CT. Histology and molecular pattern can guide the type of administered CT. The first drives the choice of drug to be associated with Cisplatin, while mutational status of p53 (wild type, WT vs mutated, MUT) is a predictive value for response to CT with Cisplatin plus 5-Fluorouracil and Leucovorin in ITAC.

In addition, heavy ion therapy may produce less toxic side effects in a particularly critical area exposed to late RT toxicities and potentially can help in organ preservation strategies when exenteratio orbitae is requested.

Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors in Operable Patients

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 in Operable Patients

Progression Free Survival (PFS) at 5 years, defined as the time from enrollment to progression of disease or death for any cause; last date of follow up will be registered for patients alive not in progression

Overall survival defined as the time from enrollment (ITT population) or treatment start (PP population) to the date of death from any causes; last date of follow up will be registered for patients alive.

Ocular function preservation by visual field tests.

Hearing preservation performed by audiogram test

Overall safety profile of the whole treatment characterized by type, severity graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4.03), timing and relationship to study therapy of adverse events and laboratory abnormalities collected.

Objective Response Rate (CR and PR by RECIST criteria version 1.1)

Adverse events (characterized by type, severity, timing) (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4.03), induced by radiotherapy (both photon RT and heavy ion RT).

Laboratories abnormalities (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events \[NCI CTCAE\] Version 4.03), induced by radiotherapy (both photon RT and heavy ion RT).

Radiological response as per RECIST criteria (version 1.1) after last cycle of induction CT; pathological response defined as obtaining or not a pathologic complete response (i.e., absence of any residual viable tumor cell).

Quality of Life (QoL) according to EORTC QLQ-30.

Quality of Life (QoL) according to EORTC QLQ-HN35

Regione Lombardia

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Infections

Respiratory Tract (Lung and Bronchial) Diseases

Ear, Nose, and Throat Diseases

All Conditions

Symptoms and General Pathology

Neoplasms

Musculoskeletal Diseases

Rare Diseases

Sinusitis

Epistaxis

Skull Base Neoplasms

Paranasal Sinus Neoplasms

Communicable Diseases

Respiratory Tract Infections

Paranasal Sinus Diseases

Nose Diseases

Respiratory Tract Diseases

Otorhinolaryngologic Diseases

Hemorrhage

Signs and Symptoms, Respiratory

Skull Neoplasms

Bone Neoplasms

Bone Diseases

Nose Neoplasms

Otorhinolaryngologic Neoplasms

Head and Neck Neoplasms

Respiratory Tract Neoplasms

Chronic Graft Versus Host Disease

Those who are undergoing endoscopic sinonasal surgery for benign and malignant tumor removal.

Those who are receiving Endoscopic Skull Base Surgery (ESBS) for minimally-invasive access for removal of skull base tumors, most commonly for ones of pituitary origin.

Individuals with chronic rhinosinusitis (CRS) with or without polyposis that are to have endoscopic sinus surgery, a minimally invasive procedure to open the sinuses.

Those who have severe nose bleeds and requires going into the operating room for management.

During sinus tumor resection, margins will initially be estimated with the naked eye. Then the dye, Indocyanine Green (ICG), will be injected through the intravenous line to identify tumor margins and be compared to estimated margins.

Sinonasal Benign or Malignant Tumor Resection

In this surgery, a piece of individuals septum will be used for the reconstruction. The amount of time for the flap to fluoresce Indocyanine Green (ICG) will be measured. It will be ensured that the it is still lighting up at the end of the surgery, indicating it is still receiving a good supply and ensures longevity of the flap.

Skull Base Surgery (Assessment of Nasoseptal Flap)

During the surgery, the timing of Indocyanine Green (ICG) administration to fluorescence of anterior and posterior ethmoidal artery and of the internal carotid artery will be measured.

Endoscopic Sinus Surgery

During surgery timing of Indocyanin Green (ICG) administration to fluorescence of the sphenopalatine artery will be measured.

Posterior Epistaxis Management (SPA Ligation)

The endoscope is a device placed into the nasal cavity to remove chronic sinus disease or tumor or create access into the skullbase for extensive tumor removal. Indocyanine Green (ICG) is a dye that is injected through an intravenous site and is used to light up vasculature and margins of a tumor during surgery. This helps avoid damage to important vasculature and obtain clear margins during surgery. This study aims to further assess the utility of ICG when operating within the nasal cavity or skullbase.

The investigators aim to evaluate the effectiveness and feasibility of using a fluorescent dye, Indocyanine Green (ICG), in endoscopic sinus, skullbase, sinus tumor resection, or posterior epistaxis surgery.

Adults 19 years or older, seen in the Principal Investigator and Sub investigator's offices presenting with either CRS, benign or malignant sinonasal, skull base tumors, or posterior epistaxis will be identified by the Principal Investigators and invited to participate in this prospective study. Patients will be recruited into the study in a consecutive manner. After providing consent, baseline characteristics will be collected. The investigators aim to recruit 10 patients in each study group respectively given the patients diagnosis.

Sinus tumor resection - Initially margins will be estimated with the naked eye. Then they will be compared to the margins that are fluorescing with the dye.

Skull base tumor resection - The investigators will use a part of the participant's septum for the reconstruction. The investigators will measure the time it takes for the flap to fluoresce and ensure that it is still lighting up at the end of the surgery. This means that it is still receiving a good supply and ensures longevity of the flap.

Sinus Surgery - During the participant's surgery, the investigator will come across important vessels that will be preserved. The investigator will see if the ICG is able to light up those vessels and if it does, then measure the time it takes to light up will be measured.

Posterior epistaxis - If a participant experiences a nose bleed that requires going into the operating room, the investigator will use ICG to locate the vessel that needs to be cauterized. The investigators will measure the time it takes for that vessel to light up.

The investigator will see the participants back on their day of surgery. During surgery, Indocyanine Green (ICG) will be injected through their intravenous line. The investigator will start with the smallest dose and increase to a dose that allows us to see the structures of interest such as vessels or tumor margins. The time it takes for a vessel or margins of a tumor to light up will be measured. Intra-operative data specific to each type of surgery being performed will be collected.

Dose-Escalation Protocol Intravenous injection

* 1.25mg (0.5mL)
* 2.5mg (1mL)
* 3.75mg (1.5mL)
* 5mg (2mL)
* 6.25mg (2.5mL) \[at discretion of surgeon\]
* 7.5mg (3mL) \[at discretion of surgeon\]

Intralesional injection

* 1.25mg (0.5mL)
* 2.5mg (1mL)
* 3.75mg (1.5mL)
* 5mg (2mL)
* 6.25mg (2.5mL) \[at discretion of surgeon\]
* 7.5mg (3mL) \[at discretion of surgeon\]

Descriptive statistics (count, absolute frequency, and 95% confidence interval) will be used to analyze the baseline characteristic data.

Prospective Case-Series and Feasibility Study

Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery

The Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery - A Prospective Case-Series and Feasibility Study

During surgery, the amount of time it takes for the area of interest to fluoresce will be recorded.

The total amount of ICG administrated to reach fluorescence of distinct structure will be recorded.

The maximum does/interval of ICG administrated to reach fluorescence of distinct structure will be recorded.

Images of the structure of interests origins and margins will be captured. Images estimated by the surgeon and ICG will be collected.

Any adverse events to ICG that are experienced will be collected.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors in Operable Patients	NCT02099175	Sinonasal Tumor...	Cisplatin Docetaxel 5-fluorouracil Etoposide Adriamycin Ifosfamide Leucovorin Radiotherapy - ... Radiotherapy - ... Radiotherapy - ...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors in Operable Patients	NCT02099175	Sinonasal Tumor...	Cisplatin Docetaxel 5-fluorouracil Etoposide Adriamycin Ifosfamide Leucovorin Radiotherapy - ... Radiotherapy - ... Radiotherapy - ...	18 Years -	Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
Utility of Indocyanine Green Fluorescence in Endoscopic Sinonasal and Skull Base Surgery	NCT04374448	Chronic Sinusit... Tumor of Nasal ... Posterior Epist... Skull Base Neop...	Sinonasal Benig... Skull Base Surg... Endoscopic Sinu... Posterior Epist...	19 Years -	St. Paul's Sinus Centre

Spots Global Cancer Trial Database for sinonasal tumors