Increasing ("boosting") the radiation dose for patients with non-small cell lung carcinoma to the individual maximal dose which can safely be given. The question is if patients should receive this boost on the whole tumor on part of the tumor. Therefore patients are randomized for one of these two treatment options. All patients will receive 24 radiations. Dose increasement will be enabled by a so called integrated boost.

Furthermore:

- PET imaging of hypoxia using [18F]HX4, single injection and then PET CT scanning two and four hours post injection.

A randomized phase II study will be conducted in patients with inoperable stage IB, II or III non-small cell lung cancer (NSCLC). The patients will be randomized to receive the standard 66 Gy given in 24 fractions of 2.75 Gy with an integrated boost to the primary tumor as a whole (Arm A) or with an integrated boost to the 50% SUVmax area of the primary tumor (of the pre-treatment FDG-PET scan) (Arm B). Both treatment arms may be combined with chemotherapy (concurrent or sequential). Patients fulfilling the eligibility criteria will be registered in the study, and an initial radiotherapy treatment planning will be performed. When an integrated boost to the primary tumor as a whole up to 72 Gy is not possible because of dose constraints, the patient will receive 66 Gy or lower according to the normal tissue tolerance (see below). They will not be randomized, but will be followed in the trial. As such, it will be clear which proportion of patients can receive an integrated boost and what the outcome is when dose-escalation is not possible.

Stage IB-II patients receive radiotherapy alone, and stage III patients combined chemotherapy and radiation. The patients may have received induction chemotherapy up to two cycles before registration in this trial. The statistical calculations have been performed to deal with this patient heterogeneity.

The primary objective of this study is to determine the local progression-free survival (LPFS)at 1 year.

Secondary objectives will be

• Toxicity as a function of radiotherapy dose and volume of the tissue irradiated.
• Overall survival.
• Quality of life

Furthermore:

• PET imaging of hypoxia using [18F]HX4, single injection and then PET CT scanning two and four hours post injection.
• Dynamic Contrast-Enhanced CT imaging

Inclusion Criteria:

1. Patients > 18 years with any subtype of pathologically proven (biopsy or cytology), non-small cell lung cancer. The diagnosis may be established from biopsy or cytology obtained from the primary tumor and/ or from metastatic lymph nodes.

2. Minimal diameter of the primary tumor 4 cm, this to allow for boosting of sub-volumes.

3. UICC TNM Stage T2-4, N0-3, M0 disease (TNM definition see appendix 2).

4. Only stage IB-II patients who are nog candidates for surgery are study candidates.

5. Measurable disease at registration.

6. ECOG-performance status ≤ 2 (see appendix 6)

7. Lung function: FEV1 and DLCO at least 40 % of the age-adjusted normal value

8. Willing and able to give a written informed consent.

9. Patients with locoregional recurrent lung tumor following surgery or a second primary cancer (at least 3 years after treatment) are eligible, unless a pneumonectomy was performed.

10. SUVmax in the pre-treatment FDG-PET scan ≥ 5 for the primary tumor.

11. Adequate organ function, including the following:

    • Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L, and hemoglobin ≥ 9 g/dL.
    • Hepatic: bilirubin ≤ 1.5 times the upper limit of normal (x ULN); alkaline phosphatase (AP), aspartate aminotransferase (ASAT), and alanine aminotransferase (ALAT) ≤ 3.0 x ULN (AP, AST, and ALT ≤ 5 x ULN is acceptable if liver has tumor involvement).
    • Renal: calculated creatinine clearance (CrCl) ≥ 45 ml/min based on the original weight based Cockcroft and Gault formula

12. For women: Must be surgically sterile, postmenopausal, or compliant with a highly reliable contraceptive method (failure rate <1%) during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days before study enrollment and must not be breast-feeding.

13. For men: Must during chemotherapy take adequate contraceptive measures.

Exclusion Criteria:

1. Prior radiotherapy to the thorax.
2. Clinical superior vena cava syndrome, malignant pleural effusion or malignant pericardial effusion.
3. T4, specified as:Tumor growth in large blood vessels on spiral CT scan or encasement >50%
4. multiple nodules in the same or ipsilateral lobe(s).
5. Post-obstructive atelectasis or infiltration that cannot be distinguished from tumor on a CT-PET scan.
6. Patients with a diagnosis of other cancer within the last 3-years (except in situ carcinoma's and / or non-melanoma skin cancer).
7. Pregnant women, lactating women