Multidisciplinary Approach for Poor Prognosis Sinonasal Tumors in Operable Patients

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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

Conditions
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Sinonasal Tumors

Intervention / Treatment
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* Drug: Cisplatin
* Drug: Docetaxel
* Drug: 5-fluorouracil
* Drug: Etoposide
* Drug: Adriamycin
* Drug: Ifosfamide
* Drug: Leucovorin
* Radiation: Radiotherapy - Patients needing Elective Nodal Volume (ENI)
* Radiation: Radiotherapy - Patients not needing ENI
* Radiation: Radiotherapy - Patients needing curative neck irradiation


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated IEC-approved Informed Consent Diagnosis of sinonasal tumor with the following histotypes: 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 The inclusion of the maxillary sinus carcinomas is reserved only in cases requiring exenteratio orbitae for a radical surgery. AJCC stage II-III-IVa with the exception of Esthesioneuroblastoma and Intestinal Type Ethmoid Adenocarcinoma where stage III-IV only will be included. Resectable disease. ECOG performance status 0-2. Adequate bone marrow, renal and hepatic functionality, defined as haemoglobin >10 g/dL, neutrophils >1500/mmc, platelets > 100.000/mmc, creatinine value ≤ 1.5 x ULN or calculated creatinine clearance (by Cockcroft and Gault's formula) > 60 mL/min, transaminases values < 1.5 times over the upper normal limit (ULN). Polychemotherapy treatment clinical feasibility as per Investigator's Judgment. Male or female patients ≥ 18 years of age. Negative pregnancy test (if female in reproductive years). Agreement upon the use of effective contraceptive methods (hormonal or barrier method of birth control, or abstinence) prior to study entry and for the duration of study participation, if men and women of child producing potential. Exclusion Criteria: Previous radiotherapy or chemotherapy for head and neck district tumors (surgical treatment relapses are admitted). Metastatic disease. Cardiac, pulmonary, infective, neurological disease or any other medical condition that could interfere with treatment. Unable and unwilling to comply with scheduled visits, therapy plans, and laboratory tests required in this protocol. Previous diagnosis of other malignant neoplasm in the last 3 years (in situ cervical cancer or completely excised basocellular/squamocellular skin cancer are always admitted). Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this study or could compromise protocol objectives in the opinion of the Investigator and/or the Sponsor. Current or concomitant enrollment in another therapeutic clinical trial.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Multimodality treatment<br>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 | Drug: Cisplatin<br>* 80 mg/m2 or 33 mg/m2 or 100 mg/m2 - Concentrate for solution for infusion.<br>* Other names: CDDP;Drug: Docetaxel<br>* 75 mg/m2 - Concentrate for solution for infusion<br>* Other names: Taxotere;Drug: 5-fluorouracil<br>* 800 mg/m2/day - Concentrate for solution for infusion<br>* Other names: Adrucil;Drug: Etoposide<br>* 150 mg/m2/day - Concentrate for solution for infusion<br>* Other names: Vepesid;Drug: Adriamycin<br>* 20 mg/m2/day - Powder for solution for infusion<br>* Other names: Doxorubicin;Drug: Ifosfamide<br>* 3000 mg/m2/day - Powder for solution for infusion<br>* Other names: Ifex;Drug: Leucovorin<br>* 250 mg/m2/day - Powder for solution for infusion<br>* Other names: Folinic acid;Radiation: Radiotherapy - Patients needing Elective Nodal Volume (ENI)<br>* 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. 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<br>Radiation: Radiotherapy - Patients not needing ENI<br>* 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. 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<br>Radiation: Radiotherapy - Patients needing curative neck irradiation<br>* 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. 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. 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.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression Free Survival (PFS) | 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 | PFS will be assessed at 5 years. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival (OS) | 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. | Overall survival will be assessed at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. | 
| Ocular function preservation by visual field tests. | Ocular function preservation by visual field tests. | At the enrollment. During follow-up after: 3 months, 12 months, 24 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. | 
| Hearing preservation performed by audiogram test. | Hearing preservation performed by audiogram test | At the enrollment. During follow-up after: 3 months, 12 months, 24 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. | 
| Overall safety profile of the whole treatment. | 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. | from the day of the Informed Consent Form signature up to 90 days after the last dose of the last therapy administered (i.e., radiotherapy and/or chemotherapy). | 
| Objective Response Rate | Objective Response Rate (CR and PR by RECIST criteria version 1.1) | At the enrollment, at the end of 1st, 3rd and 5th cycle of induction therapy and before the radiotherapy. During f-up at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months. | 
| Adverse events | 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). | During the treatments and at follow-up at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. | 
| Laboratories abnormalities | 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). | During the treatments and at follow-up at the following time frames: 3 months, 6 months, 9 months, 12 months, 18 months, 24 months, 30 months, 36 months, 48 months, 60 months, 72 months, 84 months, 96 months. | 
| Correlation between radiological response after induction chemotherapy and pathological response in patients undergoing surgery | 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). | Radiological response assessed after the cycle 5 of induction chemotherapy (each cycle is 21 days); pathological response assessed after surgery (from +21days to +35 days after end of cycle 5) | 
| Quality of Life Questionnaires: EORTC QLQ-30 | Quality of Life (QoL) according to EORTC QLQ-30. | At pretreatment, after last cycle of induction chemotherapy, after surgery, at the end of treatment and during the follow-up (3,12 and 24 months) | 
| Quality of Life Questionnaires: EORTC QLQ-HN35 | Quality of Life (QoL) according to EORTC QLQ-HN35 | At pretreatment, after last cycle of induction chemotherapy, after surgery, at the end of treatment and during the follow-up (3,12 and 24 months) |