A prospective pilot study of curative-intent stereotactic body radiation therapy in patients with 5 or fewer oligometastatic lesions Michael T. Milano, Cancer 2008;112:650 Department of Radiation Oncology, University of Rochester Medical Center, Rochester, New York BACKGROUND. It is hypothesized that oligometastatic disease represents a state of potentially curable, limited metastases. Stereotactic body radiation therapy (SBRT) is an option for patients who are not amenable to or do not want resection. The clinical state of oligometastatic disease was proposed in 1995 by Hellman and Weichselbaum. They hypothesized that, in some patients with a limited number of clinically detectable metastatic tumors, the extent of disease exists in a transitional state between localized and widespread systemic disease. In this model, oligometastatic disease has the potential of progressing to widespread metastatic disease. Thus, local control (LC) of oligometastases may yield improved systemic control. An alternative hypothesis is that oligometastatic disease represents a clinical manifestation of few detectable lesions in the setting of widespread occult disease. Such a model argues that local therapy alone probably would not be curative. Arguably, both models may be correct, and patients may exist in a spectrum between orderly metastatic progression and widespread occult disease, a model that also has been proposed for primary cancer spread. It has been proposed that progressive growth of oligometastatic tumors beyond a threshold size results in an exponential rise in the risk of further metastatic progression. In the absence of micrometastatic disease or in the situation in which micrometastatic disease is controlled by systemic therapy, aggressive treatment of oligometastatic disease can be considered curative-intent therapy, as evidenced by the prolonged disease-free survival observed in patients with resected oligometastatic tumors. Radiotherapy is another means with which to control oligometastatic tumors, particularly in patients who cannot tolerate or do not want surgery or when tumors are situated in areas in which resection would result in unacceptable morbidity. Several institutions use hypofractionated stereotactic body radiotherapy (SBRT) to treat oligometastases. SBRT implies the use of a 3-dimensional frame of reference to localize the tumor accurately. Because setup uncertainty and tumor movement are reduced significantly, the planning target volume (PTV) margins can be reduced compared with the PTV margins of standard conformal radiation. Consequently, SBRT limits the radiation dose to normal tissues and allows delivery of higher doses per fraction. SBRT is well suited for oligometastatic disease, because aggressive fractionation can be used to attempt improved disease control with acceptable toxicity. The American Association of Physicists in Medicine (AAPM) Task Group 101 report will review the available SBRT commercial products and relevant literature on SBRT, outline guidelines for commissioning SBRT, and develop standard protocols for quality assurance and SBRT treatment planning and delivery. A systematic review and guidelines for intracranial stereotactic radiosurgery (SRS) are offered in the AAPM Task Group 42 report. Since 2001, the University of
Rochester has used hypofractionated SBRT to treat patients with
oligometastatic disease. The outcomes in patients who were treated
for liver metastases and lung metastases have been published
recently. In an earlier analysis of patients with metastatic
prostate cancer, our group demonstrated that
patients with
We previously published
results on 69 patients with 174 oligometastatic liver lesions who
were treated with SBRT. In that series, the 20-month LC rate of all
treated lesions was 57%, and the MS was 14.5 months. We also
previously published our results in 49 patients with 125
oligometastatic lung lesions who were treated with SBRT. In those
patients, the 3-year LC rate of the treated tumors was 91%, and the
3-year LC rate of treated patients was 82.5%. In patients who
had
There have been several single-institutional series in which patients were treated for oligometastatic lung lesions or oligometastatic liver lesions with SBRT. These are described in detail elsewhere. In our prior reports and in others' series, toxicity was minimal. The current report examines all
patients who were enrolled in 2 pilot studies who initially
presented with
Rush University retrospectively studied 23 patients with nonsmall cell lung cancer who were treated aggressively for oligometastatic disease, which the authors defined as 1 or 2 metastatic sites.Surgery and/or radiation was used. Metastases were confined to 1 organ, and most patients (n = 14) had brain metastases. All but 3 patients had 1 metastatic site. Their MS was 20 months, and 5 patients remained alive beyond 3 years. The University of Chicago is enrolling patients with from 1 to 5 oligometastases on a Phase I study with escalating doses from 30 Gy to 42 Gy over 3 fractions. In a preliminary analysis, treated lesions were controlled well. Survival results from that study are pending. In our current series, women with oligometastatic disease from primary breast cancer had a significantly better outcome versus other patients. We previously demonstrated that women with lung metastases from breast cancer fared better with respect to survival, and the current results confirmed this finding in a population of patients with oligometastatic disease to different sites. It is not known whether the improved outcome in women with oligometastatic breast cancer reflects a better response to radiation treatment or whether these findings are attributable to a better overall prognosis of metastatic breast cancer and more durable disease control with systemic therapy. We hypothesize that the availability of effective systemic therapy to control subclinical disease, combined with SBRT for clinically detectable disease, is the basis for this success. A recently open Southwest Oncology Group (SWOG) trial will study SBRT in women with oligometastatic breast cancer: Perhaps a larger cohort will help answer this question.
It is noteworthy that
neither the number of organs involved nor the number of detectable
oligometastatic lesions at enrollment significantly correlated with
OS or PFS. Despite the possibility of being underpowered to
detect such differences, the latter finding is consistent with our
previous discovery that men with prostate cancer who have from 1 to
5 bony metastases fare equally well regardless of the number of
metastases with which they present. In a study from the University
of Pittsburgh in which 205 patients with
It is particularly worth noting that, in our study, the net GTV was significant for OS, PFS, DC, and LC, consistent with the hypothesis that a larger tumor burden has a greater risk of local failure as well as increased metastatic potential. The net GTV in patients who experienced local failure was significantly greater than the net GTV in patients who did not experience local failure. Our data suggest that the risk of developing distant failure is not increased significantly by the occurrence of local failure, possibly reflecting the magnitude of patients who fail distantly despite LC. Distant failure is a competing risk with local failure, and, in some patients, the cancer will fail distantly before it has the opportunity to fail locally. Our data also suggest that patients who fail locally are more likely to fail distantly, suggesting the possibility of a greater risk of distant spread from local failure. An alternative explanation is that treatment-resistant tumors can synchronously fail locally and distantly. In the current study, only 3 patients died from local progression without distant progression, and 3 patients had successfully salvaged local failure without further disease progression. An interesting question, which we were unable to address in the current analysis, is whether or not a response to systemic therapy can improve outcome, not only by virtue of inherent sensitivity to treatment but also by virtue of reducing tumor bulk. In summary, the results from our hypothesis-generating pilot study support the premise that aggressive local therapy of limited metastases can result in prolonged life. Conceivably, systemic therapy has the potential to downstage some patients to an oligometastatic stage, allowing for a chance for prolonged life or cure with aggressive local therapy. Arguably, our data suggest that patients with breast cancer have the greatest potential to derive benefit, providing a basis for the SWOG study mentioned above. Larger tumors may require a greater radiation dose to achieve more satisfactory LC rates. Different fractionation schemes, perhaps with a greater dose per fraction, also may help achieve improved LC, although risks of late toxicity must be considered carefully with more hypofractionationed regimens, particularly with bulkier tumors. Certainly, further studies are needed to assess the impact of radiation therapy on patient survival, tumor control, and the natural history of oligometastatic disease. We propose that the TNM metastasis staging system be expanded to incorporate an oligometastatic category, which would then allow and encourage more systematic testing of the oligometastatic hypothesis.
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