Study of Interest of Personalized Radiotherapy Dose Redistribution in Patients With Stage III NSCLC (RTEP7)

Randomized Phase II-III Study of Personalized Radiotherapy Dose Redistribution in Patients With Inoperable Stage III Non-small Cell Lung Cancer and a Persistent FDG Uptake at 42 Grays During Concomitant Radio-chemotherapy

In patients with locally advanced stage III non-small cell lung cancer, the probability of local control remains low (about 17% at 1 year). Concomitant radio-chemotherapy is the standard treatment. An increase in total radiotherapy dose (from 66 to 74 Gray) has been proposed to improve local control, with contradictory results.

Relevant FDG-PET scan images can be acquired during radio-chemotherapy, with a demonstrated prognostic impact and recently in a multicentre prospective study. A significant reduction in FDG uptake / volume (metabolic response) suggests that the radiotherapy target volume could be reduced during radiotherapy possibly improving organs at risk tolerance. Conversely, a lack of metabolic response may justify treatment intensification before the end of radiotherapy. The investigators hypothesis is to investigate the individual tumour heterogeneity on FDG-PET during radio-chemotherapy to reduce the volume to a biological target that could receive a higher total dose (personalized dose redistribution).

Study Overview

• Status: Unknown
• Conditions: Non-small Cell Lung Cancer
• Intervention / Treatment: Radiation: Personalized dose redistribution; Radiation: No personalized dose redistribution

Detailed Description

The investigators objective is to determine whether tumour radiotherapy dose escalated up to 74 Gy in 6.6 weeks can improve the disease Local Regional Control rate at 15 months (1 year after completion of RCT) by adapting radiotherapy target volume to the metabolic response as assessed on FDG-PET/CT performed at 42 Gy of concomitant radio-chemotherapy in stage III non-small cells lung cancer and warrant more extensive phase III study.

Eligible patients will be allocated to one of 2 treatment groups:

• Arm A: Patients in the experimental arm will receive an individualized radiotherapy prescription up to a total dose of 74 Gy given in 6.6 weeks if they have a positive FDG-PET at 42Gy.
• Arm B: Patients in the standard arm will receive a single prescription of 66 Gy in 33 fractions in 6.6 weeks, with 2 Gy fractions given once daily, 5 days a week, without target volume reduction or adaptation (whatever the FDG-PET result).

In both arms, all patients will undergo 2 cycles of induction chemotherapy (based platinum salts) and a curative radio-chemotherapy. In both arms all fields must be treated daily.

• Study Type: Interventional
• Enrollment (Anticipated): 150
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Pierre Vera, MD, PhD; Phone Number: 0232082258; Email: pierre.vera@chb.unicancer.fr
• Study Contact Backup: Name: Doriane Richard, PhD; Phone Number: 0232082985; Email: doriane.richard@chb.unicancer.fr

Study Locations

• France
  • Rouen, France, 76038
    • Recruiting
    • Centre Henri Becquerel
    • Contact: Pierre Vera, MD, PhD; Phone Number: 0232082258; Email: pierre.vera@chb.unicancer.fr
    • Contact: Doriane Richard, PhD; Phone Number: 0232082985; Email: doriane.richard@chb.unicancer.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 75 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Male or female patients,
• Age over 18 years and below 75-year-old,
• Good general condition: WHO performance status ≤ 1,
• Histological evidence of non-small cell lung cancer,
• Measureable tumour according to RECIST 1.1 evaluation criteria,
• Mediastinoscopy or endobronchial ultrasound to prove the histological stage N2/N3,
• Patient eligible to curative-intent radio-chemotherapy,
• Absence of pleural involvement, of pulmonary or extra-thoracic metastatic localisation,
• Absence of co-morbidity contra-indicating radio-chemotherapy,
• Lung function: FEV1 ≥ 40% of theoretical value and DLCO/VA ≥ 60% of theoretical value and PaO2 ≥ 60 mm Hg,
• Tumour FDG uptake higher than mediastinal background noise on baseline PET/CT,
• Haematological parameters:
• Neutrophil count ≥ 1.5x109/L and platelet count ≥ 100x109/L,
• Haemoglobin ≥ 9 g/dL,
• Provisional RT plan confirming that the dose objectives (minimal dose of 62.7 Gy (95% of the prescribed dose) in 98% of target volumes and 70.3 Gy for the "boosted" volume at 74 Gy) and constraints (lungs, spinal cord) are met (ICRU83),
• Estimated creatinine clearance ≥ 60 mL/min,
• Signed informed consent
• Affiliated or beneficiary of a social benefit system

Exclusion Criteria:

• Histology other than non-small cell lung cancer,
• Absence of FDG uptake on FDG-PET/CT scan before induction chemotherapy,
• Patients for whom curative radiotherapy is not indicated (tumour extension, metastases, general condition, co-morbidities),
• Significant interstitial disease on CT scan,
• Previous neoplastic disease of less than 5 years duration or progressive (without basal cell carcinoma of the skin, in situ carcinoma of the cervix),
• Previous thoracic radiotherapy,
• Patient enrolled in another therapeutic trial,
• Pregnant women or women of child-bearing potential or breast feeding mothers,
• Adult subjects who are under protective custody or guardianship,
• Patient unable to comply with the specific obligations of the study (geographic, social or physical reasons),
• Uncontrolled diabetes with blood glucose ≥10 mmol/L,
• Hypersensitivity to the active substance (FDG) or to any of the excipients,
• Patients unable to understand the purpose of the study (language, etc.).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
EXPERIMENTAL: Personalized dose redistribution; Patients in the will receive an individualized radiotherapy prescription up to a total dose of 74 Gy given in 6.6 weeks if they have a positive FDG-PET at 42Gy (about two thirds of patients are expected as positive). An initial dose of 50 Gy will be delivered in 5 weeks (single daily fractions of 2 Gy), then an additional dose up to 24 Gy will be delivered over 1.6 week using a twice-a-day fractionated radiotherapy.	Radiation: Personalized dose redistribution; Patients will receive an individualized radiotherapy prescription up to a total dose of 74 Gy given in 6.6 weeks if they have a positive FDG-PET at 42Gy. An initial dose of 50 Gy will be delivered in 5 weeks (single daily fractions of 2 Gy), then an additional dose up to 24 Gy will be delivered over 1.6 week.; Other Names: boost
SHAM_COMPARATOR: No dose redistribution; Patients will receive a single prescription of 66 Gy in 33 fractions in 6.6 weeks, with 2 Gy fractions given once daily, 5 days a week, without target volume reduction or adaptation (whatever the FDG-PET result).	Radiation: No personalized dose redistribution; Patients will receive a single prescription of 66 Gy in 33 fractions in 6.6 weeks, with 2 Gy fractions given once daily, 5 days a week, without target volume reduction or adaptation (whatever the FDG-PET2 result).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Local regional control rate	LCR rate (responders or stable disease) at 1 year after completion of RCT (M15 visit). Disease progression will be assessed by RECIST 1.1 criteria	one year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of local regional control with RECIST 1.1 criteria	Disease progression will be assessed by RECIST 1.1 criteria	assessed at 9 months, 15 months, 27 months and 39 months
interval from the date of registration to date of local or regional progression	the interval from the date of registration to date of local or regional progression	3 years
Percentage of severe (grade 3+ CTCAE, v4) radiation-induced toxicity affecting lung and oesophagus at M9 visit (early toxicity) and M15, M27, M39 visits (late toxicity),	Percentage of severe (grade 3+ CTCAE, v4) radiation-induced toxicity affecting lung and oesophagus at M9 visit (early toxicity) and M15, M27, M39 visits (late toxicity),	assessed at 9 months, 15 months, 27 months and 39 months
Percentage of patients in arm A for whom the radiotherapy dose could be increased	Percentage of patients in arm A for whom the RT dose could be increased	6.6 weeks
correlation of progression free survival with PET measure	standardized uptake value max and metabolic tumor volume of FDG -PET2 will be correlated with progression free survival at M15 visit	one year
correlation of overall survival with PET measure	standardized uptake value max and metabolic tumor volume of FDG -PET2 will be correlated with overall survival at M15 visit	one year
Change in standardized uptake value max	Measurements of the relative change in SUVmax from the 18F-FDG -PET1 (baseline) to the FDG -PET2 at 42 Gy defined as [(PET2- PET1) / PET1] x 100%	weeks 12
Change in metabolic volume	Measurements of the relative change metabolic tumour volume from the 18F-FDG -PET1 (baseline) to the FDG -PET2 at 42 Gy defined as [(PET2- PET1) / PET1] x 100%	weeks 12
Overall Survival	overall survival after M9, M15, M27, M39 follow-up visits	assessed at 9 months, 15 months, 27 months and 39 months
progression-free survival	progression-free survival after M9, M15, M27, M39 follow-up visits	assessed at 9 months, 15 months, 27 months and 39 months

Collaborators and Investigators

• Sponsor: Centre Henri Becquerel
• Collaborators: Intergroupe Francophone de Cancerologie Thoracique
• Investigators: Principal Investigator: Peirre Vera, MD,PHD, Centre Henri Becquerel

Study record dates

Study Major Dates

• Study Start: July 1, 2015
• Primary Completion (ANTICIPATED): December 1, 2018
• Study Completion (ANTICIPATED): December 1, 2020

Study Registration Dates

• First Submitted: June 8, 2015
• First Submitted That Met QC Criteria: June 12, 2015
• First Posted (ESTIMATE): June 16, 2015

Study Record Updates

• Last Update Posted (ESTIMATE): July 28, 2016
• Last Update Submitted That Met QC Criteria: July 27, 2016
• Last Verified: July 1, 2016

More Information

Terms related to this study

• Keywords: radiotherapy; boost; dose redistribution
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Carcinoma, Non-Small-Cell Lung
• Other Study ID Numbers: CHB14.04/IFCT14-02