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

Phase 2
18 Years
85 Years
Open (Enrolling)
Stage III Non-small Cell Lung Cancer, Individualized Radiation Dose Escalation

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Trial Information

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

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 ( 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

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.

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

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

12. Uncontrolled diabetes mellitus hampering 18FDG-PET

13. Inability to comply with protocol or trial procedures

Type of Study:


Study Design:

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

Outcome Measure:

Pulmonary toxicity grade 2-4

Outcome Time Frame:

2 years

Safety Issue:


Principal Investigator

Jan Bussink, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Radboud University


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:

CMO 2011/345



Start Date:

March 2012

Completion Date:

March 2016

Related Keywords:

  • Stage III Non-Small Cell Lung Cancer
  • Individualized Radiation Dose Escalation
  • stage III NSCLC
  • (chemo)radiotherapy
  • individualized dose-escalation
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms