Cyberknife radiosurgery for breast cancer spine metastases.  A matched-pair analysis
Gregory J. Gagnon Georgetown University Medical Center,  Cancer 2007;110:1796

There are few options for breast cancer patients with spinal metastases recurrent within a previous radiation treatment field. CyberKnife radiosurgery has been used in our institution to treat such patients. To evaluate their outcomes, as there are no comparable radiation treatment options, the outcomes were compared between 18 patients with spinal metastases from breast cancer treated with CyberKnife stereotactic radiosurgery, 17 of which had prior radiotherapy to the involved spinal region and were progressing, and 18 matched patients who received conventional external beam radiotherapy (CRT) up-front for spinal metastases.

METHODS. Radiosurgery was delivered in 3 to 5 fractions to doses ranging from 2100 to 2800 cGy. Women were matched to patients in a CRT group with respect to time from original diagnosis to diagnosis of metastases, estrogen receptor / progesterone receptor (ER/PR) status, presence or absence of visceral metastases, prior radiotherapy, and prior chemotherapy. Survival and complications were compared between treatment groups. Surviving patients were followed out to 24 months.

RESULTS.The CyberKnife and CRT groups were comparable along all matching dimensions and in performance status before treatment. Outcomes of treatment were similar for patients in both groups; ambulation, performance status, and pain worsened similarly across groups posttreatment. Survival and the number of complications appeared to favor the CyberKnife group, but the differences did not reach statistical significance.

CONCLUSIONS.The statistical comparability of the CyberKnife and CRT groups reflects the small sample size and stringent requirements for significance of the matched-pair analysis. Nevertheless, comparability in these difficult cases shows that salvage CyberKnife treatment is as efficacious as initial CRT without added toxicity.

Introduction:  Metastatic breast cancer is marked by a propensity for bony sites. The prevalence of bone metastases from breast cancer is high, with an estimated 217,440 patients suffering this sequelum each year, with a predilection for the axial skeleton. Up to 75% of patients have bone metastases on autopsy, and well over half of these involve the vertebrae. Spinal metastases are associated with significant symptoms, considerable neurologic risk, and further morbidity related to alteration of the structural, weight-bearing, and hematopoietic functions of the spine, and are responsible for a large part of the decrease in quality of life experienced by breast cancer patients with metastatic disease. Unfortunately, treatment options for the spine are limited, largely due to the proximity of neighboring dose-limiting structures, including the spinal cord, nerve roots, peripheral nerves, esophagus, lungs, heart, kidneys, liver, and bowel.

There are few prospective studies of the palliative benefits of radiation therapy for treatment of the spine alone. In 1 study, Tombolini  treated 103 spinal sites from 95 patients with either a single fraction of 8 Gy, hypofractionation regimens of 20 Gy in 4-5 days, or conventional fractionation regimens to 30-40 Gy in 2-4 weeks. No differences between fractionation schemes were seen, with pain responses varying from 80% to 85%. A larger body of literature concerns palliation of bony sites, of which spinal sites typically constitute a large proportion. Several prospective series exploring external-beam palliative regimens of bone metastases have been reported. Most studies included varied primary histologies, although in the study by Steenland  a large proportion of patients (39%) had previous breast or prostate cancer. Their results are in agreement with those of other randomized trials, with rates of partial pain relief ranging from 55% to 89% and complete pain responses of 21% to 58%. The median duration of pain relief was typically less than 1 year and the median retreatment rate was 20% (in the studies that reported this datum), and was as high as 44%. Although standard external beam palliative regimens may be effective in patients with a limited life expectancy, these data raise the concern that they may be inadequate for patients with metastatic breast carcinoma, who are expected to have a median survival of 22.6 months, long enough to develop symptomatic recurrence within the spine.

These spinal recurrences pose a therapeutic challenge. The symptomatology, neurologic risk, and morbidity associated with recurrent spinal disease remain as significant as at the time of initial treatment and options are limited, as before. Surgery is more difficult because of postradiation fibrosis and poorer vascularity within the operative field. Furthermore, these critical structures have considerably lower radiation tolerances than at initial treatment time, which limits radiation options. The burden of morbidity carried by these patients and the lack of other durable palliative treatments necessitates an exploration of alternatives to standard palliative regimens.

The spine is an ideal site for radiosurgical treatment. The spine is relatively immobile, which assists in radiosurgical delivery and facilitates its imaging for confirmation of targeting. The high doses possible when radiosurgical techniques are used, a consequence of reliably excluding the spinal cord and other dose-limiting structures from the high-dose region, may also result in more durable control within the spine in a population of patients failing conventional radiation treatment.

The CyberKnife is a frameless, image-guided robotic radiosurgical system that can deliver radiation precisely to virtually any body site with submillimeter accuracy. Perhaps the leading principle of radiosurgery is that extreme conformity and accuracy can minimize the volume of normal tissue irradiated to such an extent that the need to deliver doses in multiple fractions is minimized, and there can be considerable escalation of dose. A therapeutic benefit is supposed on these grounds, and this has been amply demonstrated in cranial radiosurgery. Although technically possible outside the brain, the benefit of radiosurgical treatment of extracranial sites has not been demonstrated.

We consider retrospectively a series of women with breast cancer metastases to the spine who failed prior external beam radiation and who were subsequently treated with CyberKnife stereotactic radiosurgery. We used a matched-pair analysis to compare outcomes in this group to those in women with breast cancer metastases to the spine who were treated with conventional external-beam techniques (CRT). Women were matched with respect to time from original diagnosis to diagnosis of metastases, age, ambulatory level, and performance status. Most important, the group of women treated with CyberKnife radiosurgery represents a more difficult therapeutic challenge, as 17 of 18 of them had had prior radiotherapy within or immediately adjacent to the radiosurgery field and the remaining patient had prior radiation to within a few vertebral bodies of the active site, whereas no women in the conventionally treated group had such a restriction.

From March 12 2002 to January 1 2005, 18 women 18 years of age with histologically confirmed spinal metastases from breast carcinoma were treated at Georgetown University Hospital with CyberKnife radiosurgery. Patients were treated using fiducial guidance, with fiducial markers implanted into the spine before planning and treatment. Treatment doses varied according to clinical and technical factors such as proximity to spinal cord and previous irradiated dose. With small variations, patients were treated with 3 fractions: 3 800 cGy = 2400 cGy for patients who had not received prior irradiation to the tumor site, and 3 700 cGy = 2100 cGy for patients who had received prior irradiation to the involved spinal level. All patients underwent neurological assessment (by F.C.H.), pain assessment before and after irradiation using the Visual Analogue Scale (VAS), and routine follow-up with the radiation oncology and neurosurgery departments at 1, 3, 6, 12 months and on an as-needed basis at other times.

There are no standard treatment options for women with metastatic breast cancer who suffer a failure within a previously irradiated spinal site. CyberKnife radiosurgery is technically an effective option for these women, but because of the intolerance of the surrounding normal structures, such as the spinal cord, esophagus, and bowel to reirradiation, there are no ideal comparison groups to use for assessment of outcomes. We compared a series of women with recurrent spinal metastases after radiation with a matched cohort treated with standard radiation techniques up-front for spinal metastases. We believe that establishing equivalence with this group would demonstrate the efficacy of this treatment, particularly as the matched group is unmatched in an important prognostic factor - failure of prior radiation treatment - and would be expected to perform better than the group treated by the CyberKnife.

Although not well reported in the literature, there is a general concern that tumors that have failed prior radiation treatment are more resistant to subsequent courses of radiation. To our knowledge this has not been reported for breast cancer, although there are in vitro data from cell lines derived from human cancers that show increased radioresistance in recurrent tumors compared with nonrecurrent tumors. Second, although there are also little supporting published data, there is the possibility that women who have failed prior courses of radiation might be in later stages of their disease process, and more likely to succumb to their disease than those whose disease is controlled. It is clearly possible that the CyberKnife group represented a group with a poorer prognosis, and this would dilute any statistical benefit.

The breast cancer patients treated with CRT were matched with CyberKnife patients on the basis of time interval from initial diagnosis to metastasis, bone versus visceral metastases, prior radiotherapy to the primary region, prior chemotherapy, and ER/PR status. Other prognostic factors, such as performance status, were not matched but were equally distributed between groups. There was equivalence between these regimens with respect to palliative and survival endpoints, although KPS was improved in the short course for CyberKnife patients.

The available reports of spinal radiosurgery have limited follow-up, but they demonstrate the feasibility and safety of the procedure in the treatment of various histologies. Only 1 report of dose-escalation in the spine for breast carcinoma has been published: Gerszten treated 50 patients with breast cancer metastases with single-fraction doses of 15 to 22.5 Gy using radiosurgical techniques. Long-term (mean follow-up of 16 months) pain control was obtained in 96% of patients and long-term tumor control was obtained in each of the 8 patients for whom radiosurgery was the primary treatment modality.

The beneficial results from CyberKnife retreatment might be explained by the biologically equivalent doses delivered, possibly greater than that delivered initially by CRT. Despite the frequency of breast cancer, data concerning the dose-response for breast cancer are fragmentary. In a study by Arriagada in which women with localized breast cancer were treated to the breast with radiotherapy alone (that is, without lumpectomy), a dose-response was found for tumors < 4 cm in size. Doses of 40-50 Gy had a 3-year local control rate of 25%, doses of 50-60 Gy had a local control rate of 59%, doses of 70-80 Gy had a local control rate of 81%, and doses of > 80 Gy had a local control rate of 100%. It is possible to compare different fractionation schemes by using the linear-quadratic formalism, also known as the alpha/beta formalism. Comparisons between standard fraction schemes and hypofractionated schemes such as that used in this series can be made once the / value is known. The fractionation schemes in question can be converted to a suitable reference fractionation scheme, often 2 Gy fractions given 5 days a week. If we assume 300 cGy 10 fractions, a common fraction scheme for palliative irradiation of the spine, and use / values of 4, 6, or 8 Gy, we have biologically equivalent doses in 2 Gy fractions of 3300, 3375, and 3500 cGy. Making a similar calculation for 900 cGy 3 fractions, a dose received by most of the target volume when 800 cGy 3 fractions is prescribed to the periphery using the CyberKnife, then we have biologically equivalent doses in 2 Gy fractions of 4590, 5062, and 5850 cGy for the same / values. If the dose-response data of Arriagada  are generalized to the metastatic setting, then the CyberKnife fractionation scheme should result in significantly better tumor control (expected at about 25%-59% at 3 years) than regimens employing 300 cGy 10 fractions (considerably less than 25%).

As most (17/18) of the CyberKnife patients had prior radiotherapy to the involved spinal site, the general palliative equivalence of these 2 regimens demonstrated in this study is noteworthy. These patients are generally not candidates for further conventional radiation and a palliative retreatment that can be shown to be as effective as initial palliative therapy can be of substantial benefit to these patients. This also suggests further evaluation of CyberKnife radiosurgery of the spine as a primary palliative modality.