8.3 Spinal Cord
Timothy E. Schultheiss
T. E. Schultheiss, PhD, FACR
Professor, Beckman Research Institute; Director, Radiation Physics, Radiation Oncology, City of Hope Medical Center, 1500 Duarte Rd, Duarte, CA 91010, USA
8.3.1
Introduction
Radiation myelopathy is one of the most dramatic complications of radiation therapy. Consequently, many clinical reports of this injury appeared in the literature during the 1970s and 1980s. This period saw a transition from the use of cobalt-60 to linear accelerators. This was also a period when spilt course treatments with large doses per fraction were used.
It is primarily from these reports that our current understanding of clinical radiation myelopathy is gleaned. However, we are also guided by many experi- mental studies of radiation injury to the spinal cord in mice, rats, guinea pigs, dogs, pigs and monkeys.
Nonetheless, there are many unanswered questions regarding the radiation response of the spinal cord.
8.3.2
Histopathology
Late radiation damage to a tissue or organ can be diffusely distributed over a volume closely corre-
sponding to the irradiated volume, as in late fi brosis.
Conversely, it can be focal and occur at unpredict- able locations within a uniformly irradiated organ.
The latter is the case for radiation myelopathy. The initial lesion occurs exclusively within the white matter of the spinal cord, but its pathogenesis is complex and multifactorial. In its simplest form, the pathogenesis has one of two origins – either (rela- tively) direct damage to white matter parenchyma, ultimately leading to a necrotic lesion via a compli- cated pathway, or a lesion in the white matter that is secondary to microvascular damage. (The white matter parenchyma is understood to include glial cells in this case.) Lesions can appear adjacent to areas that show no evidence of radiation damage but were identically irradiated. Reviews of the pathology and pathogenesis of radiation myelopathy can be found in the works from the laboratories of van der Kogel [van der Kogel and Barendsen (1974), van der Kogel (1986)], Stephens [Schultheiss et al. (1988), Stephens et al. (1989)] and Hopewell (1979).
It seems clear that in most animals, including hu- mans, there is a vascular-based lesion and a paren- chymal-based lesion. Zeman was the fi rst to articulate the dual hypothesis of radiation injury of the spinal cord [Zeman (1961)], but van der Kogel defi nitively verifi ed this hypothesis and explored it in detail in rats [van der Kogel (1979), van der Kogel (1980)].
In his studies, the white matter lesion occurred ear- lier and at higher doses. Clearly, if the later lesion oc- curs at higher doses, it will never be seen. This may explain why only the parenchymal-based lesion is seen in some strains.
These same general observations have been made in humans [Schultheiss et al. (1984), Schultheiss et al. (1988)]. However, the data are much more dif- fi cult to interpret since autopsy reports often refl ect the status of the lesions months or years after the on- set of symptoms.
In humans, latencies as short as 4 months have been observed, but these are very rare. Typically, the onset of symptoms occurs 9 to 48 months after the
CONTENTS
8.3.1 Introduction 367 8.3.2 Histopathology 367
8.3.3 Symptoms and Treatment 368 8.3.4 Dose Response 368
8.3.5 Hyperfractionation 368 8.3.6 Anatomic Level 369 8.3.7 Retreatment 369 8.3.8 Volume 370
8.3.9 Other Observations 370 8.3.10 Conclusions 371 References 371
completion of treatment. There is no difference be- tween latency in the cervical and thoracic levels of the cord. The latency in children is shorter than in the adult, but there does not seem to be much difference in tolerance. Nonetheless, it is customary to respect a lower tolerance in the child.
8.3.3
Symptoms and Treatment
The progression of symptoms for thoracic radiation myelopathy consists of generally altered sensation in the lower extremities, including numbness, tingling and reduced sensitivity to temperature. A sensory level is sometimes seen corresponding to the irra- diated spinal segment. Pain is sometimes reported, more often associated with tingling. This progresses to weakness, which can be manifest as changes in gait or foot drop. Paresis, rectal and bladder in- continence, and complete paralysis may develop.
Symptoms can progress rapidly, with patients some- times presenting with paralysis. Recovery from sen- sory losses may occur over time, but motor defi cits are rarely recovered. Although thoracic myelopathy does not have the morbidity associated with cervi- cal myelopathy, it can still become life threatening as a result of the secondary effects of incontinence and paralysis [Schultheiss et al. (1986)]. No treat- ment has shown long-term effectiveness [Ang et al (1994)].
8.3.4
Dose Response
The most widely used dose limit for the spinal cord is 45-Gy at 1.8 to 2-Gy per fraction. Some clinicians routinely respect an even lower dose for the spinal cord. This policy cannot be challenged as long as the tumor is adequately irradiated. However, it would be imprudent to compromise the tumor dose in order to limit the spinal cord to a dose lower than 45-Gy in patients for whom there is no evidence of increased radiation sensitivity.
It has been reported that the dose producing a 5% rate of radiation myelopathy is between 57 and 61-Gy in conventional dose fractions [Schultheiss (1994)]. According to Wong et al., no case of radia- tion myelopathy has been found at Princess Margaret Hospital after 50-Gy in 25 fractions [Wong et al.
(1994)], although there are literature reports of my- elopathies at this dose. Although it may be an unusual circumstance, 50-Gy (or higher) in 2-Gy fractions should be considered if the tumor would otherwise be underdosed. However, it is imperative that the pa- tient be properly informed of the risk.
Factors other than the dose schedule that affect the spinal cord tolerance, either clinically or experimen- tally, include irradiated volume, chemotherapeutic agents, age, oxygenation, vascular disease, concurrent disease processes and congenital abnormalities.
There have been numerous studies of the effect of chemotherapy on the tolerance of the spinal cord, but the clinical data are mostly anecdotal [Ang et al.
(1986), Bloss et al. (1991), Schultheiss (1994), van der Kogel and Sissingh (1983), van der Kogel and Sissingh (1985)]. With the possible exception of chemotherapeutic agents that are known to be neu- rotoxic, one cannot state unequivocally that chemo- therapy reduces the radiation tolerance of the spinal cord. This is especially true for those agents causing peripheral neuropathy, but not central neuropathy [St Clair et al. (2003)].
8.3.5
Hyperfractionation
The effect of hyperfractionation on the response of the spinal cord is not fully understood. Although the spinal cord has a high capacity for long-term repair of radiation damage, as will be discussed later, its interfraction repair is slower than many other tissues [Ang et al (1992)]. Although there have not been any published reports of unexpected myelopathies occurring after two fractions per day, unanticipated myelopathies have occurred after regimens of three and four fractions per day [Dische and Saunders (1989), Wong et al. (1991)]. In two separate pub- lications, Jeremic has shown that 50.6-Gy in 1.1 or 50.4-Gy in 1.2Gy fractions produced no myelopathies in either the cervical or thoracic cord, respectively [Jeremic et al. (1998), Jeremic et al. (2001)]. In the adult rat, Ang et al. found that the repair was de- scribed better by a bi-exponential function than by a mono-exponential function [Ang et al. (1992)].
However, Ruifrok et al. found no evidence of this
biexponential repair in the newborn rat [Ruifrok et
al. (1992)]. In the rhesus monkey, no difference was
observed in the response at 98.4-Gy at 1.2-Gy per
fraction, compared with 84-Gy – the data were 8/15
versus 6/11, respectively (unpublished data).
8.3.6
Anatomic Level
There is little evidence that any section of the spi- nal cord differs in intrinsic radiosensitivity from any other segment. However, there may be extrin- sic factors affecting spinal cord radiosensitivity that apply more frequently to one section of the cord than another. The thoracic cord’s apparent radiosensitivity may be slightly lower (higher tol- erance) simply because there is a smaller volume of white matter in the cervical cord. However, the spinal cord’s dose response is not very sensitive to changes in volume, and this effect is unlikely to appreciably alter the incidence of radiation my- elopathy.
Dische et al. (1986) have observed a dramatic ef- fect of hemoglobin on the tolerance of the spinal cord. Furthermore, data from van den Brenk et al.
[van den Brenk et al. (1968)] and Coy and Dolman (1971) indicate that the spinal cord is sensitive to ex- trinsic oxygen tension. Publications that report the incidence of thoracic radiation myelopathy come almost exclusively from studies of lung cancer. One may reasonably infer that these patients have seri- ously impaired oxygenation of the spinal cord, owing to a smoking history and to lung cancer. Therefore it is possible that their spinal cord tolerance is in- creased owing to a decrease in the oxygenation of the white matter.
It is diffi cult to compare the clinical response of the cervical cord to that of the thoracic level. The radia- tion regimens from which crude estimates of the inci- dence of radiation myelopathy can be made generally employed high doses per fraction, but the regimens for cervical myelopathy and thoracic myelopathy are too dissimilar to compare directly. Furthermore, the survival of the cohort is generally much shorter in patients with thoracic myelopathy. As a result, the number of patient-years of exposure is very different from what it is in cervical myelopathy.
8.3.7 Retreatment
The spinal cord appears to have a substantial capac- ity for long-term recovery from subclinical radia- tion damage. In animals, this recovery appears to be dependent on the initial dose or level of damage and the time between the initial course of treat- ment and the second course of treatment. In cancer
patients, the level of recovery is probably more vari- able and possibly dependent on intervening thera- pies as well.
Retreatment dose-response studies in rats have been performed by a number of authors. Generally, it appears that following a treatment of approxi- mately 50% of the D
50for an untreated rat, 75% of the dose is recovered in 20 weeks, and close to 100%
is recovered in a year. In guinea pigs, Knowles found the D
50for one-year old animals who received 10-Gy one day after birth was only 5% less than one-year old unirradiated animals [Knowles (1983)]. Both van der Kogel (1991), as well as Wong and Hao [Wong et al. (1997)], have shown the dependence of the retreatment tolerance on the initial dose and the interval between treatments. The relative steepness of the retreatment dose/response function, com- pared with the de novo dose-response function is not certain.
Ang et al. have performed retreatment experi- ments on rhesus monkeys [Ang et al. (1993), Ang et al. (2001)]. Their fi ndings indicate that about 75%
of 44-Gy in 20 fractions is recovered after 1 year and nearly 100% is recovered after 3 years. Forty-four Gy represents 57% of the initial D
50in these animals.
Thus, the primate data is in reasonable agreement with the rodent data.
The largest number of clinical cases of radiation myelopathy following retreatment was reported by Wong et al. In their report on 11 cases, all but two had equivalent doses in 2-Gy fractions of 52-Gy or more (using an _/`=0.87 [Schultheiss and Hanks (1999)]). In those two cases, the break between courses was only 2 months, and little or no repair would be expected. Thus, in all of their reported cases, either the spinal cord tolerance could have been exceeded by one of the treatment courses alone, or there was insuffi cient time for repair between courses. The av- erage latency following the second course of treat- ment was 11 months, with a range of 4 to 25 months.
It is clear that the spinal cord can tolerate a signifi - cant retreatment dose. The clinical decision to retreat part of the spinal cord must be based on the availabil- ity of alternative treatments, the consequences of not treating, the initial cord dose and the interval since the initial treatment. As always, a specifi c and detailed informed consent is mandatory. For palliation or for treatment of cord compression, 30-Gy in 15 fractions should be given consideration if the initial treatment did not exceed 45-Gy to the cord and was given at least 9 months prior to the potential second course.
Care should be taken to minimize the spinal cord vol-
ume, but radiation myelopathy is still a possibility.
8.3.8 Volume
The conventional radiation volume effect on the spi- nal cord is understood as a decrease in the tolerance dose as the length of irradiated cord increases. In rats, there is a striking volume effect at fi eld sizes below 1cm, but very little effect as the length of irradi- ated cord is increased beyond 1cm [van der Kogel (1991)]. This volume behavior may result from the fact that the size of the lesion is not negligible com- pared to 1cm. In rhesus monkeys, the volume effect is consistent with the probability model [Schultheiss et al. (1983)], which has been inappropriately called the “critical element model.” This model is derived using simple probability theory, where the probabil- ity of not producing a lesion in the irradiated volume is simply the product of the probabilities of not pro- ducing lesions in all subvolumes. A consequence of the model is that for steep dose/response functions, there is very little volume effect. This can explain why there is no volume effect in rats at fi eld sizes above 1cm.
No unequivocal volume effect for the spinal cord has been observed in humans. The reason for this, perhaps, is that, for a specifi c dose regimen or clini- cal trial reported to result in radiation myelopathy (for example, in a clinical trial for lung cancer), the variation in fi eld size is not large and the sample size is too small to see any fi eld size effect. In an- ecdotal radiation myelopathy reports, fi eld size effects cannot be demonstrated because controls (patients without myelopathy) are never included.
Nonetheless, it is reasonable to assume that a fi eld size effect is operational in the radiation response of the human spinal cord. However, the increase in risk that accompanies an increase in fi eld length is not likely to be very signifi cant if one is operating within the limits of the conventional standard-of- care for cancer patients. The risk of radiation my- elopathy in patients receiving conventional doses to the spinal cord is so low that no volume effect will be seen clinically at these doses.
Of more immediate concern is the risk of ra- diation myelopathy in patients for whom the dose varies signifi cantly across the spinal cord. With the advent of IMRT, small portions of the cord can be irradiated to doses that would be intolerably high for the whole cord, while the remainder of the cord receives much lower doses. The only study that ad- dresses this issue is a paper by Debus et al., where patients undergoing proton radiation therapy for base-of-skull lesions had part of their brainstems ir-
radiated to high doses [Debus et al. (1997)]. Debus et al. found a relative risk of 11.4 for patients in whom more than 0.9cm
3of the brainstem had received 60- Gy or higher (photon equivalent). Also of signifi cant risk on multivariate analysis were patients having two or more base-of-skull surgical procedures and a diagnosis of diabetes. The maximum dose to the brainstem was not signifi cant (p~0.09) in this study of 348 patients.
Based on the study discussed above, one could reasonably infer that a sharp dose gradient across the spinal cord can be tolerated if the maximum dose is less than 60-Gy. However, it is likely that one cannot achieve as sharp a gradient with photons as with protons. Moreover, these patients were meticu- lously immobilized and imaged prior to treatment.
In routine practice, some dose smearing will oc- cur as a result of setup variations. With IMRT, this smearing should be less problematic because of the care that should be taken in the positioning of pa- tients. Beyond stating that the spinal cord should be able to tolerate a higher maximum dose, provided there is a dose gradient across the cord, it is not cur- rently possible to give quantitative guidance related to the tolerance associated with small hot spots on the spinal cord.
8.3.9
Other Observations
There are species-specific responses of the spinal cord that deserve mention. In the pig, the pathol- ogy and radiation dose response is similar to that which is observed in other animals. The difference in the pig response is that the latent period is far shorter than is seen in other models [Hopewel and van den Aardweg (1992), van den Aardweg et al. (1995)]. In the dog, there are reactions in the meninges and the dorsal root ganglia not seen in other animals [Powers et al (1992)]. Furthermore, the role of the vascular response is relatively greater in the dog [Schultheiss et al. (1992)].
In the rhesus monkey, and in some rat strains, a
primarily vascular lesion is infrequently seen. The
reason for this in the monkey may be that this
type of lesion occurs after the time during which
these animals are typically held (24 months). In
some rat strains, the reason is probably the same,
with the addition that the animals’ life expectancy
may be of similar duration to the latency for a
vascular lesion.
8.3.10 Conclusions
There is no indication that the thoracic and cervical levels of the spinal cord have different intrinsic re- sponses. Extrinsic conditions may result in apparent differences. Differences in the survival of the cohort population may result in fewer thoracic myelopathies being observed. The morbidity of thoracic radiation myelopathy is generally lower than that for cervi- cal myelopathy. Administration of common chemo- therapeutic agents for lung cancer may reduce the radiation tolerance of the spinal cord, but no quan- titative studies have demonstrated this for cisplatin, vinblastine or gemcitabine – the most commonly used chemotherapeutic agents in lung cancer.
In this era of intensity modulated radiation ther- apy, techniques for concurrent boosts of the tumor will be developed, making a cone down no longer necessary. This will result in a lower dose per frac- tion to normal tissues outside the target. The effect of this decrease in the dose per fraction will be more signifi cant in tissues such as the spinal cord, whose late effects are dose-limiting.
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