9 years tumor free survival after resection, intraoperative radiotherapy (IORT) and whole brain radiotherapy of a solitary brain metastasis of non-small cell lung cancer

Overall five-year survival for patients in NSCLC clinical stage IV is lower than 5% [1], in surgical stage IV (histologically proven distant metastases) nearly 0%. For patients with brain metastases in general, one-year survival amounts to about 10–20% after whole-brain radiotherapy (WBRT) [2]. Several attempts to improve local control of brain metastases have been made, including dose escalation (RTOG 85 – 28). No significant difference in survival was found, median survival amounted to 3–6 months [3]. In recent years, stereotactic radiosurgery has gained importance. One to three metastases of a suitable size (≤4 cm) may be an indication for stereotactic radiosurgery [4], [5]. Electron beam intraoperative radiotherapy (IORT) for patients with malignant brain tumors has been performed at our institution since May 1992 [6]. Only few patients with brain metastases have been treated so far. We report a case of long-term control by surgery, IORT and WBRT.

In October 1995, a 36-year old female patient (smoker) presented with the accidental diagnosis of a mass in the left upper lobe. CT and bronchoscopy confirmed the suspicion. Histology showed adenocarcinoma grade 1–2. The tumor was clinically staged as T2N2M0 (stage IIIA). The patient was then recruited for the Muenster lung cancer trial [7]. She received three cycles of neoadjuvant CE chemotherapy followed by combined hyperfractionated radiochemotherapy with 45 Gy, carboplatin and vindesine. Under this regimen, a good partial remission was achieved. Besides a slight dysphagia, no further acute side effects were observed. She then underwent a radical resection (R0) of the left upper lobe with mediastinal lymphadenectomy (pathological tumor stage: ypT1N0G1–2, Salzer-Kuntschik grade III).

Ten months after the initial diagnosis she experienced severe headaches and scintillations. CT and MRI showed a solitary brain metastasis in the right occipital lobe with a diameter of about 2.5 cm. No further metastases or local recurrence were detected. It was then decided to perform a resection of this metastasis with IORT. No macroscopic residual tumor was left. IORT was carried out at a non-dedicated facility with 14 MeV electrons from a linear accelerator using a 5 cm round cone [6]. The applied IORT dose was 20 Gy relative to the 90% isodose. After surgery and IORT, WBRT was done with a dose of 30 Gy in 10 fractions.

Three years later, MRI showed a newly developed contrast enhancing structure in the right occipital lobe. Brain SPECT with Tl-201 and I-123-AMT showed a focal tracer uptake with an elevated tumor/non-tumor ratio. F-18-FDG-PET showed a moderate glucose hypermetabolism. These findings were suspect for tumor recurrence. Because of the possible differential diagnosis of brain necrosis and since she did not suffer from major symptoms, it was initially decided to watch and wait with regular imaging.

A few months later, she presented with progressive visual field losses and headaches. MRI showed a slight growth of the enhancing structure. It was then decided to perform a re-craniotomy with resection of the suspect tissue. Histological workup of the resected tissue surprisingly showed no vital tumor cells, but only extensive radiation-induced brain necrosis.

After the second operation, the patient still suffers from visual field losses (left-sided homonymous hemianopsy) and intermittent headaches, but also now and then from attacks of vertigo and from intermittent paresthesia of the extremities. Repeated MRI scans of the brain and CT scans of the thorax have not shown any signs of tumor recurrence ever since. Aside from the mentioned symptoms, she is alive and well up to the current day (last follow-up: April 2005).

Surgery is gaining more and more significance for the treatment of solitary brain metastasis. Its value for the improvement of local control as well as overall survival has recently been shown in several randomized trials [8–10]. Patients also seem to benefit from an additional boost to the former metastatic site after surgery and WBRT [11]. The treatment effect of stereotactic radiosurgery for solitary brain metastasis seems to be comparable to the effect of surgery followed by WBRT without an additional radiotherapy boost [4], [12].

Both dose escalation with a single dose of 20 Gy (stereotactic radiosurgery) and surgical removal of the metastasis seem to improve results. IORT combines both concepts; this is why we initially introduced IORT in the 1990s. IORT can only be performed at very few institutions and for selected patients (solitary, resectable metastasis, good general condition). The dose prescription (20 Gy/ 90%) is similar to stereotactic radiosurgery, but this time not as a definitive, but as a postoperative treatment, combined with WBRT.

This case report shows that the combination of surgical resection and dose-escalated radiotherapy (IORT and WBRT) is able to achieve long-term tumor control in patients with solitary brain metastasis. With IORT as part of an intensive treatment (initial multimodality treatment for the advanced primary, later surgery and high-dose radiotherapy for the solitary brain metastasis), there seems to be still a chance for selected patients with a solitary metastasis to reach a long disease-free interval — or maybe even a small chance of cure.

From the histological workup of the re-operation, it could be shown that a single dose of 20 Gy and WBRT of 10×3 Gy led to an extensive brain necrosis in this patient. The neurological deficits that persisted after the second operation (vertigo, hemianopsy, paresthesia) make it clear that IORT – with dose escalation in a relatively large area – must be limited to selected patients and that these patients have to be closely monitored for the development of radiation necrosis.