Scylla or Charybdis: Case Report on Radiation Tolerance of the Spinalcord

A case of rapid cancer progression causing impending spinal cord compression at the margin of a previously irradiated treatment volume close to the thoracic spinal cord in a patient with non-small cell lung cancer is presented. The patient and treating physicians were faced with a difficult decision. Either reirradiate and accept a considerable risk of delayed radiation myelopathy or risk paraplegia as a result of tumour progression. To prevent rapid development of neurological deficits, the patient was reirradiated only 34 days after he had finished his initial course of simultaneous radioand chemotherapy. The high cumulative spinal cord dose (corresponding to 84 Gy in 2-Gy fractions) and short interval to reirradiation resulted in a high risk of radiation myelopathy according to a previously published risk score. However, no treatment-related toxicity developed and neurological function was preserved for almost 5 months. Eventually, tumour progression resulted in paraplegia. This case illustrates important issues around palliative reirradiation of target volumes close to the spinal cord. Figure 1: Preoperative computed tomography imaging showing T3 squamous cell carcinoma of the right lung. Figure 2: Computed tomography scan of the chest showing paravertebral tumour relapse after lobectomy (white arrow). Status before simultaneous radioand chemotherapy. J o u r n a l o f N uc lea r M edicine & Riatio n T h e r a p y ISSN: 2155-9619 Journal of Nuclear Medicine & Radiation Therapy Citation: Dalhaug A, Pawinski A, Tollåli T, Nieder C (2011) Scylla or Charybdis: Case Report on Radiation Tolerance of the Spinalcord. J Nucl Med Radiat Ther 2:114. doi:10.4172/2155-9619.1000114


Background
Metastatic spinal cord compression continues to represent a challenging situation in oncology [1,2]. Primary or locally recurrent tumours might also threaten the neurological function if they are located close to the spinal cord. If tumours arising in previously irradiated regions invade the spinal canal, the radiation tolerance of the spinal cord might seriously limit further radiation treatment [3]. The present case illustrates important aspects around reirradiation options.

Case presentation
A 67-year-old male presented to his pulmologist with constant pain in the right posterior hemithorax 4 months after he had undergone lobectomy of the right lower lobe. This procedure had been performed because of poorly differentiated squamous cell carcinoma, maximum diameter 7cm, stage IIB (T3 N0 M0), as shown in ( Figure  1). The only abnormal haematology or blood chemistry value before surgery was thrombocytosis (593 x 10 9 /l, reference value 130-400).
The patient had declined adjuvant chemotherapy. His medical history was unremarkable (no comorbidity or medication). He had stopped smoking before thoracic surgery. Diagnostic imaging with chest computed tomography (CT) scan revealed local relapse with infiltration of the thoracic wall ( Figure 2). No lymph node or distant metastases were detected. The patient received simultaneous radioand chemotherapy (3-D conformal radiotherapy, 4 coplanar fields, dose per fraction 1.8 Gy, total dose 59.4 Gy, no inclusion of regional lymph nodes). Carboplatinum was given on day 1, 22 and 43 (AUC 3,   Four weeks after the last radiation treatment the patient complained about increasing pain. New CT scans revealed stable disease in the treated area, 2 small ipsilateral lung metastases and a large paravertebral mass invading the 8. and 9. Thoracic vertebra and causing impending spinal cord compression ( Figure 3). The patient had no neurological deficit, unchanged performance status and slight elevation of serum alkaline phosphatase (111 U/l, reference value <105). After discussion of neurosurgical treatment options, the decision was made to proceed with palliative radiotherapy in spite of the fact that parts of the 7. and 8. thoracic vertebra were included in the previous planning target volume. The dose-limiting normal tissue in this area was the spinal cord, which had received a maximum of 87% of the prescription dose, i.e. 33 fractions of 1.57 Gy, though not to the complete cross-section ( Figure 4). According to the linear-quadratic model, this dose is equivalent to 46 Gy in 2-Gy fractions (α/β-value 2 Gy, biologically equivalent dose 92 Gy 2 ) [4]. The following formula might be used to calculate the equivalent dose. BED = n • d • (1+d ÷ α/β), where n = number of fractions and d = dose per fraction. One of the commonly used regimens of palliative radiotherapy for metastatic    Figure 5), resulting in a biologically equivalent dose of 75 Gy 2 (α/β-value 2 Gy). Thus the cumulative maximum spinal cord dose to this small volume equalled 92 + 75 = 167 Gy 2 (equivalent to 84 Gy in 2-Gy fractions). The cumulative dose to 1 cm 3 of the spinal cord was equivalent to 64 Gy in 2-Gy fractions. The length of the overlap was 2.1 cm. We used our previously published risk score to estimate the risk of radiation myelopathy as a consequence of reirradiation to the spinal cord [5,6]. The score is based on cumulative biologically equivalent dose, interval between the series, and high biologically equivalent dose of either initial or subsequent radiotherapy (≥102 Gy 2 ). Regarding cumulative biologically equivalent dose (167 Gy 2 ) the patient scored 5 points. The interval between the last radiation fraction of the initial course and the first fraction of the second course was 34 days, i.e. shorter than the cut-off value of 6 months. Therefore, 4.5 points had to be added to the score. This resulted in a final score of 9.5 points. With a score of 9.5 points, the patient belonged to the high risk group (>6 points). In our previous publication, nine out of ten patients with high risk developed radiation myelopathy.
In order to explore systemic treatment options (epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors) in this case of squamous cell non-small cell lung cancer (NSCLC), the primary tumour was examined for the presence of mutations in exon 18-21 of the EGFR gene, but no such mutation was detected. Therefore, chemotherapy with paclitaxel was chosen (dose 90 mg/m 2 ). The first cycle started 12 days after completion of reirradiation. The patient also started with zoledronic acid 4 mg every 4 weeks. At the start of chemotherapy, CT showed slight regression in both irradiated areas (less than partial remission), no new metastases were detected ( Figure  6 A and B). After 3 cycles, the patient refused further treatment because of grade III neuropathy. No haematological toxicity was observed. Two months later, all lesions were unchanged in size. Another six weeks later, i.e. almost 5 months after reirradiation, the patient collapsed and was hospitalised. CT showed no signs of brain metastases, but local progression in both irradiated areas with considerable spinal cord compression (Figure 7). Neurological examination revealed complete paralysis of both lower extremities. No further oncological treatment was administered. The patient developed increasing cachexia and died approximately 2 months later. Survival was 14.4 months from lobectomy and 6.7 months from reirradiation.

Conclusions
This case illustrates therapeutic challenges which might arise when tumours recur at the margin of a previously irradiated target volume. If inoperable, the tolerance of critical normal tissues might seriously limit further treatment [7]. Initially, i.e. for post-surgical relapse, combined radio-and chemotherapy was administered. One of several platinumbased doublet regimens was chosen. Others would have been possible, but it appears doubtful whether a better response could have been obtained. During initial radio-and chemotherapy a generally accepted, conservative dose limit to the spinal cord was respected (46 Gy in 2-Gy fractions) [8]. Marginal recurrence developed shortly after completion of the initial treatment course. Even retrospectively, the new tumour invading the spinal canal was not visible on the initial diagnostic and treatment planning CT scans. This rapid growth and the fact that the tumour already threatened the spinal cord made the treating physicians believe that neurological deficits would develop in less than 2-3 weeks. It was clear that reirradiation would expose parts of the spinal cord at the level of the 7. and 8. thoracic vertebra to considerable cumulative radiation doses (overlap 2.1 cm), because no healthy tissue separated the cord from the tumour. However, neurosurgery was not considered an option. It has to be emphasized that such cases must be presented to a neurosurgeon before proceeding with other treatments. After deciding that radiotherapy would be the preferred approach, dose and fractionation had to be considered. Recently, hypo fractionated stereotactic body radiotherapy to spinal target volumes has been introduced [9][10][11]. This approach allows for very precise administration of fractionated or single fraction treatment with steep dose gradients. However, the typical dose per fraction is quite high and this might result in an unfavourable therapeutic ratio for the previously irradiated spinal cord [12]. Moreover, small geographical errors (set-up errors) might result in administration of higher doses than anticipated. It was felt that an approach with lower doses per fraction would result in a better therapeutic ratio. In principle, the stereotactic technique (or frameless image-guided approaches) can also be used to administer conventionally fractionated or moderately hypofractionated regimens. However, such treatment was not available in the part of Norway covered by our regional health authority (Helse Nord) and the hospitals belonging to other health authorities were such technology was available had long waiting lists and did not prioritize palliative reirradiation. Therefore, we had to rely on conventional technology. We did not expect the cancer cells to be highly radiosensitive as the response after 59.4 Gy plus concomitant chemotherapy was quite disappointing in spite of the limited volume of the irradiated tumour. Therefore, short course low-dose radiotherapy, e.g. 20 Gy in 5 fractions [1], was not an attractive option. We also felt that the rapid development of lung metastases might indicate a limited survival expectation. This argued against protracted schedules such as 40 Gy in 20 fractions. Therefore, we chose 30 Gy in 10 fractions followed by full-dose systemic therapy with paclitaxel. More aggressive systemic treatment might have been possible, but the patient was reluctant to accept serious side effects and had already opted against adjuvant chemotherapy after lobectomy. He also decided to discontinue paclitaxel chemotherapy after development of neuropathy.
For the reirradiation regimen of 30 Gy in 10 fractions, we evaluated the risk of radiation myelopathy as previously described [5,6]. Based on animal experiments, no recovery from sublethal damage can be expected only 1-2 months after the initial treatment [13]. In the present case both short interval and high cumulative radiation dose contributed to the risk of myelopathy. The third risk factor, high biologically equivalent dose of one of the two treatment series, was absent. The risk score indicated that the present patient belonged to the high risk group. In this group, 9 out of 10 previously published patients developed radiation myelopathy. In some instances, damage developed already after 4-7 months. The next step was to inform the patient about his treatment options and the risk and benefit associated with reirradiation. Here, we might refer to Homer who described the dangerous travel between Scylla and Charybdis. Instead of accepting the rapid development of tumour-related spinal cord damage, the patient chose the slightly more attractive route, which offered hope for prolonged functional independence even if the ultimate outcome might not differ. Reirradiation was effective in stopping the rapid growth of the tumour, but did not result in partial remission. Eventually, the tumour damaged the spinal cord and irreversible deficits developed. Nevertheless, the reirradiation regimen of 30 Gy in 10 fractions appears reasonable with regard to risk-/benefit ratio. In spite of considerable retreatment experience in the authors' institution, the treatment decision was not easy. The cumulative biologically equivalent dose administered here was the third highest in the senior author's experience. The two other cases had received 205 Gy 2 (interval 6 months, survival after reirradiation 5 months, no myelopathy) [6] and 181.5 Gy 2 (interval 12 months, survival after reirradiation 8 months, no myelopathy) [5] in comparable situations where better sparing of the spinal cord was impossible. Based on our previous review [6], which included 11 patients with radiation myelopathy reported by Wong et al. [14], this late side effect might develop after 4-7 months (4 of 11 cases) or later during follow-up. Three out of eleven patients with myelopathy had received reirradiation with short interval (2-4 months), but the case reported here is among those with the shortest interval in the literature. The fact that some patients with high risk for radiation myelopathy might not develop this complication during their remaining life time should not encourage us to uncritically recommend reirradiation. However, under certain circumstances the decision appears justified and might result in clinical benefit. It is also important to notice that the high cumulative radiation dose was not given to the complete cross-section of the spinal cord. So far, there is very limited clinical data regarding the tolerance of the spinal cord to partial high-dose irradiation. Given the intriguing results of a recent randomised trial of bevacizumab versus placebo in patients with radiation necrosis of the brain [15], a condition which resembles pathophysiological characteristics of radiation myelopathy [16], it might be possible to envision a scenario where patients developing early signs of this complication can start with bevacizumab therapy, though it is currently unclear whether or not permanent protection from irreversible neurological deficits can be achieved.