Individualized Dose Prescription in Advanced Stage Lung Cancer Patients Using Modern (Chemo)Radiotherapy

Stage III Non-small Cell Lung Cancer Clinical Trial

— IDEAL-VMAT  

Official title:

Individualized Dose Escalation for Non-small Cell Lung Cancer (NSCLC) Using Volumetric Modulated Arc Therapy (VMAT)

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT01577212
• Other study ID #: CMO 2011/345
• Secondary ID: NL nr 35536.091.
• Status: Terminated
• Phase: Phase 2
• First received: March 16, 2012
• Last updated: November 6, 2015
• Start date: March 2012
• Est. completion date: September 2014

Study information

• Verified date: November 2015
• Source: Radboud University
• Contact: n/a
• Is FDA regulated: No
• Health authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)
• Study type: Interventional

Clinical Trial Summary

The aim of this present study is to test the feasibility and toxicity of individualized hypofractionated radiotherapy, and to report outcome data. In case this phase II trial has favorable results, a phase II/III trial on maximally tolerable, individualized, hypofractionated radiotherapy within a shorter overall-treatment time is aimed for.

Description:

In the Netherlands, approximately 10.000 new patients are diagnosed with lung cancer every year. Of these, 80% present with non-small-cell lung cancer. Between 1995 and 2008, the national incidence has risen with 16% caused by an impressive increase of 53% in women suffering from this disease. The aggressive nature of this disease leads to a one-year survival rate of 45% and a 5-year survival rate of only 14%.

It is widely accepted that surgery provides the best chance of cure in patients with operable NSCLC (www.oncoline.nl). In practice, only 20% of patients are amenable for tumor resection with curative intent. Alternatively, stereotactic body radiation therapy (SBRT) results in excellent local control in localized early stage disease.

In locally advanced, inoperable disease, combined chemotherapy and external-beam radiotherapy (EBRT) are increasingly being used. Evidence suggests that concurrent schedules are more effective than sequential treatments despite increased toxicity, although the true magnitude of the additional benefit remains uncertain. However, a large number of patients with locally advanced NSCLC is not suitable for concurrent chemoradiotherapy due to their general condition, age, comorbidity or tumor-related factors. Therefore, there is a need to increase effectiveness of treatment for all patients with advanced stage NSCLC undergoing either radiotherapy alone, neoadjuvant chemotherapy followed by radiotherapy, or concurrent treatment.

Apart from the addition of chemotherapy, treatment modification by intensification of the radiotherapy schedule or by dose escalation has been proven beneficial. Several phase I/II trials explored altered EBRT fractionation schedules that increased the biological effective dose to the primary tumor and reduced local relapse rate. Thereby, two main principles were pursued: reduction of the dose per fraction (≤ 1.8 Gy), giving two or three fractions per day (so-called hyperfractionation), aimed at sparing normal tissues while increasing the dose to the primary tumor; increase of the fraction dose (≥ 2 Gy), combined with a reduction in the total number of fractions (so-called hypofractionation) aimed at increasing the effective tumor dose in less radiation-sensitive primary tumors. On the one hand, hyperfractionation limits the treatment-related side-effects, on the other hypofractionation is attractive for the patient and radiation department as the number of treatment fractions can be reduced.

Intensification of the irradiation schedule by continuous, hyperfractionated radiotherapy (CHART) delivered in 12 consecutive days showed an absolute improvement in two-year survival. With the advent of highly conformal dose planning and delivery techniques during the last decade (i.e., 3-dimensional conformal radiation therapy, 3D-CRT; intensity-modulated radiation therapy, IMRT; volumetric-modulated arc therapy, VMAT/RapidArc; Tomotherapy), organ-sparing technology became widely available. Recently, van Baardwijk and collaborators published an individualized dose prescription study in 166 stage-III NSCLC patients. Already in 2006, Belderbos et al. reported favorable toxicity data and an encouraging failure-free interval in 88 inoperable NSCLC patients treated with intensified, hypofractionated 3D-CRT based on the MTD to the lung.

Apart from these reported studies, there are three hypofractionation trials being conducted elsewhere. In the UK, two 3D-CRT based phase I/II trials have been approved investigating individualized dose escalation based on normal tissue dose constraints in patients with stage II or stage III NSCLC (ISRCTN12155469 and I-START; CRUK/10/005). In the US, the University of Wisconsin is conducting a helical tomotherapy-based hypofractionation study (NCT00214123) with pulmonary toxicity (pneumonitis grade 3 lasting for more than 2 weeks) as primary endpoint.

The reported hypo- and hyperfractionation studies have a 'trial-and-error' approach for dose-level estimation in common. In a recent in silico trial in 26 stage III NSCLC patients, we have investigated the use of a dedicated software tool for individual dose escalation by hypofractionation. Based on an existing, clinical IMRT/VMAT treatment plan (66 Gy in 33 fractions), radiation dose was escalated by scaling the radiation dose until the maximum tolerated dose constraints for the healthy lung, the esophagus, spinal cord, brachial plexus or heart was met. The aim of this present study is to test the feasibility and toxicity of individualized hypofractionated radiotherapy, and to report outcome data. In case this phase II trial has favorable results, a phase II/III trial on maximally tolerable, individualized, hypofractionated radiotherapy within a shorter overall-treatment time is aimed for.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 6
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 85 Years

Eligibility

Inclusion Criteria:

1. Histologically or cytologically confirmed stage IIIA/B NSCLC (excluding pleural effusion and mixed pathology)

2. Irresectable disease (as assessed by multidisciplinary team) or patient refusing surgery

3. Disease which can be encompassed within a radical radiotherapy treatment plan in keeping with standard practice at the participating center

4. Proposed treatment consists of radiotherapy alone or concurrent chemoradiation

5. WHO performance status 0 or 1

6. Adequate respiratory function: FEV1 = 1.5 L and DLCO > 40%, predicted on baseline pulmonary function tests

7. Age = 18 years, no upper age limit

8. Estimated life expectancy of more than 6 months

9. Patient is available for follow-up

10. Written informed consent obtained

Exclusion Criteria:

1. Clinically diagnosed NSCLC

2. Previous or current malignant disease likely to interfere with the protocol treatment or comparisons

3. Prior thoracic radiotherapy

4. Proposed treatment consist of sequential chemoradiation

5. Prior lobectomy / pneumonectomy

6. Prior chemotherapy using gemcitabine or bleomycine

7. Superior sulcus tumors if the brachial plexus is within the high-dose volume

8. Medically unstable (e.g., ischaemic heart disease, esophageal disorders)

9. Pregnancy

10. Connective tissue disorders

11. Abnormal kidney function interfering with administration of iv contrast agent (GFR<60)

12. Uncontrolled diabetes mellitus hampering 18FDG-PET

13. Inability to comply with protocol or trial procedures

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Individualized Radiation Dose Escalation
• Lung Neoplasms
• Stage III Non-small Cell Lung Cancer

Intervention

Radiation:
• Individualized dose escalation
Individualized dose escalation on the basis of the maximally tolerable dose to organs at risk - lung, esophagus, spinal cord, heart, brachial plexus

Locations

Country	Name	City	State
Netherlands	Radboud University Nijmegen Medical Centre	Nijmegen

Sponsors (1)

Lead Sponsor	Collaborator
Radboud University

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Pulmonary toxicity grade 2-4		2 years	Yes
Primary	Esophageal toxicity grade 2-4		2 years	Yes
Secondary	Increase in tumor control probability (TCP)		2 years	No
Secondary	Local-regional failure		2 years	No
Secondary	Progression-free survival		2 years	No
Secondary	Quality of life		2 years	No
Secondary	Overall survival		2 years	No