A recent meta-analysis of 83 randomized clinical trials demonstrated a significant overall improvement in local control and survival with hypoxia modification . Experimental and clinical evidence suggests that tumour hypoxia itself represents a prognostic factor which influences tumour growth, increasing malignant progression due to gene amplification and enhancing metastatic potential. In addition, the hypoxic fraction in solid tumours also reduces their sensitivity to conventional treatment modalities, thereby modulating the response to ionizing radiation and many chemotherapeutic agents [8–10, 22, 23], representing the most important treatment modalities in therapy of NSCLC.
It is recognized that nitroimidazoles bind selectively to hypoxic cells , leading to an intracellular accumulation of nitroimidazole. The FMISO uptake represents a global value for macroscopic tumour parts. As a non-invasive measure, this method is highly feasible for evaluating the state of oxygenation in subjacent tumours. In a prospective study we were able to validate FMISO PET for determination of radiotherapeutically relevant hypoxia by gold standard for measuring tissue oxygenation in human tumors, the computerized polarographic needle electrode system in patients with metastatic neck lymph node from a primary squamous carcinoma of the head and neck. High correlation was found between tumour-to-muscle ratio of FMISO and parameters of hypoxic fraction ≤ 2.5 mmHg and ≤ 5.0 mmHg . Using dynamic and static FMISO PET scans, Eschmann et al could show that high ratios to reference tissues (mediastinum and muscle) correlated with the risk of relapse in NSCLC .
Our study was conducted in order to evaluate the feasibility of FMISO PET for the depiction of tumour oxygenation in NSCLC. Furthermore, we wanted to examine whether there is a reoxygenation after two-cycle chemotherapy, and whether there is an association between tumour metabolism or tumour hypoxia and tumour response or tumour recurrence. After chemotherapy, we were able to show a decrease in the FMISO uptake, reflecting reoxygenation in most patients, which resulted in a good tumour response. On the other hand, an increased (patient 6) or a nearly unchanged, high tumour to muscle ratio (patient 7a) corresponded to worse local tumour outcomes. But no association between initial high FMISO uptake and treatment outcome or tumour response could be detected.
Although there was a significant decrease in Hb concentrations due to chemotherapy (paired T-test; p = 0.033) influencing tumour oxygenation, we did not find a direct association between the reduction of the Hb concentration and FMISO or FDG uptake. Even the patient with an increased FMISO uptake showed stable Hb concentrations with an Hb of 13.4 g/dl at the time of second PET examinations (data not shown). Another patient showed a focal enhancement of FMISO at the chest wall after chemotherapy, representing the localisation of early local recurrence.
Mac Manus et al. prospectively studied the capacity of FDG PET and computed tomography (CT) to determine the response soon after radio- or radio-/chemotherapy in patients with NSCLC. Both CT and PET responses were individually significantly associated with survival duration; but in the multifactor analysis, this included the known prognostic factors of CT response, performance status, weight loss, and stage; only the PET response was significantly associated with the duration of survival (p < 0.0001) .
In another study, FDG PET imaging before and after induction therapy was prospectively evaluated in patients with oesophageal cancer to determine whether changes in PET images could measure the response to therapy. A comparison of the percentage decrease in SUV with the percentage of treatment effects through pathological examinations of oesophagectomy specimens indicated a correlation between large decreases in SUV and pathologic measurements of treatment effect .
In our study, all five patients with a clear decrease in the FDG uptake had a PR after chemotherapy; two had a PR and even three a CR after radio-chemotherapy. On the other hand, patients with nearly unchanged or increased FDG values showed worse tumour control or disease-free survival; therefore, changes in tumour metabolism detected by FDG PET may predict the tumour response and outcome in NSCLC.