Abstract: There are data in the literature to suggest the presence of an oligometastatic state, and local aggressive therapy of the oligometastases may improve outcomes including survival. Stereotactic body radiation therapy has emerged as one of the local therapy options for oligometastases in various body sites, most commonly in the lung and the liver. Retrospective studies and clinical trials have demonstrated promising results with the use of stereotactic body radiation therapy for oligometastases. However, most of the studies have relatively short follow-up intervals. Longer follow-up is necessary to better define the role of stereotactic body radiation therapy in the management of patients with oligometastases. Given the high propensity for distant progression, the combination of novel systemic therapy and stereotactic body radiation therapy is to be explored.
In patients with proven distant metastases from solid tumors, it has been a notion that the condition is incurable and the mainstay of treatment is systemic therapy. However, in some patients, the metastatic disease may be very limited in number and site (oligometastatic) and local aggressive therapy combined with systemic therapy can potentially prolong survival or may even cure some patients (Hellman and Weichselbaum, 1995; Lo et al., 2009). There are clinical data to suggest the existence of an oligometastatic state. For instance, in the surgical literature, it has been demonstrated that surgical resection of limited lung and liver metastases has resulted in prolonged survival and possibly cure in a significant proportion of patients with oligometastases (The International Registry of Lung Metastases, 1997; Fong et al., 1997; Fong et al., 1999; Lo et al., 2009; Miller et al., 2007; Shah et al., 2006).
For patients deemed not to be candidates for surgical resection, non-surgical options such as stereotactic body radiation therapy (SBRT) or other ablative methods such as radiofrequency ablation (RFA) can be offered .There is a fair amount of data in the literature, including data from well-conducted clinical trials, on the use of SBRT in oligometastases, mainly in liver and lung.
Does an Oligometastatic State Truly Exist?
In a retrospective study from University of Chicago, Mehta et al. (2004) tracked the number of individual metastatic sites and the number of organs involved using serial computerized tomography (CT) of the body in 38 patients with stage IIIB or IV non-small cell lung cancer treated with chemotherapy with paclitaxel and oxaliplatin. Seventy four percent of patients (n = 28) had metastatic disease limited to 1-2 organs and 50% (n = 19) had disease limited to the primary tumor and three or less metastatic lesions at presentation. Fifty percent (n = 19) had stable (n = 12) or progressive (n = 7) disease in initially involved sites without development of new metastatic lesion. Among the 17 patients with ≤ 4 metastatic sites with no pleural effusion, 65% (n = 11) had stable or progressive disease in initially involved sites without development of new metastatic lesions. The results of this study suggest that a subset of patients with oligometastases from non-small cell lung cancer may benefit from a combination of systemic therapy and local aggressive therapy.
In another study, records of 387 patients with advanced non-small cell lung cancer were reviewed and 64 patients with measurable advanced stage non-small cell lung cancer who received first-line systemic therapy and follow-up at University of Colorado were identified. Thirty four patients were deemed theoretically SBRT-eligible. Disease in the lung and liver was limited to ≤ 3 sites each. Among the 34 SBRT-eligible patients, the patterns of failure were local only in 68%, distant only in 14%, and mixed in 18% (Rusthoven et al., 2009a). The time to first progression was 3.0 months in those with local only failure. The results of this study suggest that SBRT may improve the time to first progression in a significant proportion of patients with metastatic non-small cell lung cancer.
There are also data in the surgical literature showing survival benefits of surgical resection of lung or liver metastases, with colorectal cancer being the most common primary site examined (The International Registry of Lung Metastases, 1997; Fong et al., 1997; Fong et al., 1999; Miller et al., 2007; Shah et al., 2006). All these clinical findings support the hypothesis that an oligometastatic state does exist.
Proper Selection of Patients
The primary goal of SBRT for the treatment of oligometastases is to achieve excellent rate of local tumor control. However, this goal would only be meaningful when local tumor control would translate into improved survival or clinical outcomes. Survival or clinical outcomes can be affected by multiple factors, such as patient’s age, health and performance status, co-existing medical conditions, extent of disease, and tumor histology. Patients who are more likely to benefit from SBRT or other local ablative therapies for their oligometastases include those who are younger in age and those with high performance status, controlled primary tumor sites, metachronous occurrence of primary and metastatic disease, limited number of metastases, histologies such as colorectal carcinoma, breast cancer, and radioresistant histologies such as renal cell carcinoma, melanoma, and sarcoma (Lo et al., 2009). Positron emission tomography (PET) is frequently used to evaluate the extent of metastastic disease and to determine the candidacy for SBRT. While it can provide very useful staging information, PET cannot accurately predict the subsequent course of the patient’s disease and sound clinical judgment and decision is imperative. In situations where SBRT is used for palliation of symptoms, it is crucial for the clinician to exercise good judgment as to whether treatment of index lesion would achieve the purpose and this has to be balanced against the risk of potential complications from the procedure.
SBRT entails the delivery of individual ablative radiation doses to a planning treatment volume with a steep dose fall-off beyond the lesion treated and it is crucial that the metastatic lesions to be treated must be easily delineated on diagnostic imaging.
The technical details of SBRT have been covered in our previous publications in this and other journals (Hadziahmetovic et al., 2010; Lo et al., 2008a; Lo et al., 2007; Lo et al., 2010a; Lo et al., 2010b; Lo et al., 2008b; Lo et al., 2009; Lo et al., 2010c). The same principles and requirements for immobilization, respiratory motion control, treatment planning, and treatment delivery apply as in primary liver and lung tumors. In patients with lung and/or liver oligometastases, it is not uncommon to treat more than one lesion with SBRT. In treatment planning of SBRT for oligometastases in the liver or lung, it is important to obtain a composite computer plan of all the lesions treated to avoid exceeding the radiation dose constraints for various critical organs or tissues (Lo et al., 2009). In patients with multiple metastases in the lung or liver treated with SBRT, it is important to evaluate the dose-volume histograms of various organs-at-risk based on the composite plan. The lung and the liver are parallel structures with some redundancy in organ function reserve, and in the evaluation of the dose-volume histograms, it is imperative that the amount of lung or liver parenchyma treated to the threshold dose is limited to a safe level to avoid organ failure. In the evaluation of dose-volume histograms for serial structures like the spinal cord, brachial plexus, or esophagus, where the loss of function of one portion of the structure will lead to loss of function of the whole structure, the maximum point dose must be below the tolerance level (Lo et al., 2009). In the current clinical trials for SBRT for various organ sites, dose constraints are set for both parallel and serial structures. Figure 1 shows the coronal view of a computer plan of SBRT for a patient with 2 lung metastases.
When more than one lesion is treated, the treatment time will be significantly prolonged and this may affect the patient’s ability to remain still in the immobilization device. As a result, there may be a shift of the position between the different lesions treated on the same day. An individual set of stereoscopic X-ray or conebeam CT for each lesion treated is recommended. When a megavoltage conebeam CT is used, the additional radiation dose delivered should be accounted for.
There are numerous retrospective studies on the use of SBRT for the treatment of lung oligometastases from North America, Europe and East Asia showing good local control rates with the majority of the study showing local control exceeding 85% (Lo et al., 2010b; Lo et al., 2009). Early results from Sweden and Japan showed excellent crude local control rates although the follow-up times were short (Blomgren et al., 1998; Blomgren et al., 1995; Uematsu et al., 1998). Subsequent reports from various institutions across the world showed promising results (Hof et al., 2007; Norihisa et al., 2008; Okunieff et al., 2006; Wulf et al., 2004). Hof et al. (2007) treated 61 patients with 71 lung metastases with SBRT to a single dose of 12 Gy to 30 Gy. The actuarial local progression-free rates were 88.6%, 73.7%, and 63.1% at 1, 2, and 3 years, respectively. There were no clinically significant toxicities observed. In a report by Wulf et al. (2004), 41 patients with 51 lung metastases were treated with SBRT using fractionation schedules including 10 Gy X 3, 12 Gy X 3, 12.5 Gy X 3, and 26 Gy X 1. At a median follow-up interval of 9 months, the crude local control rate was 90% and all local failures occurred within the first year after SBRT. The actuarial local control rate for the 51 metastases was 80% at ≥12 months. The overall survival rates were 85% and 33% at 1 and 2 years, respectively. The freedom from systemic progression rates were 35% and 23% at 1 and 2 years, respectively. In a study from University of Rochester, a crude local control rate of 94% was observed in 42 patients with 125 lung metastases treated with SBRT to a dose of 50 Gy in 10 fractions. The median follow-up time was 18.7 months. The 1- and 2-year progression-free survival rates were 25% and 16% in patients with 5 or less lung metastases, respectively (Okunieff et al., 2006). In a study from Japan, 34 patients with 1-2 lung metastases with diameter ≤ 4 cm, locally controlled primary tumor, and no other metastatic sites were treated with SBRT to a dose of 48 Gy in 4 fractions or 60 Gy in 5 fractions. The most common primary sites were lung (n = 15) and colorectal (n = 9). Twenty five patients had one lesion and the remaining had two lesions. The overall survival, local relapse-free survival, and progression-free survival rates at 2 years were 84.3%, 90%, and 34.8%, respectively (Norihisa et al., 2008).
Early data on SBRT for liver metastases from Sweden showed promising results (Blomgren et al., 1998; Blomgren et al., 1995). Subsequent studies on SBRT for liver metastases also showed good local control (Katz et al., 2007; Lo et al., 2010b; Lo et al., 2009; van der Pool et al., 2010). In the study from University of Rochester, which represents one of the largest studies in SBRT for liver metastases, 69 patients with 174 liver metastases were treated with SBRT to a median dose of 48 Gy (range, 30-55 Gy) in 2-6 Gy fractions. The mean number of lesions treated was 2.5 (range, 1-6). The most common primary sites were colorectal (n = 20) and breast (n = 16). The median follow-up was 14.5 months. The local control rates were 76% and 57% at 10 and 20 months, respectively and the median overall survival time was 14.5 months (Katz et al., 2007). The 6- and 12-month progression-free survival rates were 46% and 24%, respectively. There were no grade 3 or higher toxicities observed after SBRT. In a study from Netherlands, 20 patients with 1-3 colorectal liver metastases (median, 1) were treated with SBRT to a dose of 37.5 Gy or 45 Gy in 3 fractions. A total of 31 lesions were treated. At a median follow-up time of 26 months, the 2-year actuarial local control and overall survival rates were 74% and 83%, respectively (van der Pool et al., 2010). Grade 2 or lower and grade 3 liver toxicities were reported in 18 and 2 patients, respectively.
There is very limited data on the use of SBRT for the treatment of adrenal metastases. Figure 2 shows a computer plan of SBRT for a right adrenal metastasis. In a study from University of Rochester, 30 patients with adrenal metastases (14 with ≤ 5 metastatic lesions including those in the adrenal gland with the intent of controlling all known sites of metastatic disease, and 16 with the intent for palliation or prophylactic palliation of bulky adrenal metastasis) were treated with SBRT to doses ranging from 16 Gy in 4 fractions to 50 Gy in 10 fractions. Among the 24 patients with > 3 months of follow-up with diagnostic imaging, the 1-year survival, local control, and distant control rate was 44%, 55%, and 13%, respectively. Grade 2 or higher toxicities were not observed (Chawla et al., 2009). Based on this study, adrenal metastases appear to be a high propensity of systemic progression.
Oligometastases — all sites
In a study from Aarhus University Hospital, 64 patients with 141 colorectal cancer metastatic lesions were treated with SBRT to a dose of 45 Gy in 3 fractions. Liver and lung were the two most common sites of metastases. The 2-year actuarial local control rates were 86% for the tumors and the control rates for all tumors in a patient were 63% (Hoyer et al., 2006). No local or distant failures occurred in 19% of the patients after 2 years. The 1-, 2-, 3-, 4-, and 5-year overall survival rates were 67, 38, 22, 13, and 13%, respectively. One patient died of hepatic failure, one required surgery for a colonic perforation, and two developed duodenal ulceration. In a recent retrospective study from South Korea, 59 patients with 78 lesions confined to one organ from colorectal cancer were treated with SBRT to a median dose of 42 Gy in 3 fractions. Patients with 1-4 lesions of largest diameter of < 7 cm who progressed after systemic therapy and were not suitable for surgery were selected for treatment. The most common metastatic sites were lymph nodes, lung, and liver. At a median follow-up of 32 months, the 3- and 5-year local control rates were 66% and 24%, respectively (Kang et al., 2010). Acute grade 1-2 toxicities occurred in 24 of the 59 patients, and late grade 4 toxicities occurred in 2 (3%).
In a dose escalating phase I/II trial of SBRT for lung tumors from Germany, 21 patients (3 treated for primary lung tumor) with 39 tumors were treated with SBRT. The starting radiation dose was 35 Gy in 5 fractions and it was then escalated to 40 Gy in 5 fractions. Complete response, partial response, and stable disease were observed in 51%, 33%, and 3% of tumors, respectively (Ernst-Stecken et al., 2006). In a phase I dose escalation study from Stanford University, 11 patients with a single lung metastasis were treated with single fraction SBRT to a starting radiation dose of 15 Gy, which was escalated to 30 Gy. Radiation-induced complications and treatment related deaths were observed in patients who received doses greater than 25 Gy (Le et al., 2006). Recently, in a multi-institutional phase I/II trial of SBRT for patients with 1-3 lung metastases, the total radiation dose was safely escalated from 48 to 60 Gy in 3 fractions without causing dose limiting toxicity (Rusthoven et al., 2009b). In the phase II portion of the study, the dose was 60 Gy in 3 fractions. There were 38 patients with 63 lesions enrolled in the study. Grade 3 and 4 toxicities were observed in 8% and 0% of patients, respectively. The 1 and 2 year actuarial local control rates were 100% and 96%, respectively, for the 50 evaluable lesions (Rusthoven et al., 2009b). The median survival time was 19 months.
At the University of Heidelberg, a dose escalation study utilizing single dose SBRT regimen was performed. The radiation dose was escalated from 14 to 26 Gy and both primary and metastatic liver tumors were included in the study. Fifty six liver metastases were treated. There were no dose limiting toxicities or radiation induced liver disease after SBRT. The actuarial local control rate was 67% at 18 months. The actuarial local control rate was 81% for tumors treated to ≥ 20 Gy (Herfarth et al., 2001). In a phase I risk-adapted dose escalation study of SBRT for inoperable or medically inoperable liver metastases from University of Toronto, 70 patients with 143 liver tumors were treated. Individualized radiation doses were selected to maintain the same nominal risk of radiation-induced liver disease for three estimated risk levels (5%, 10%, and 20%). The median SBRT dose was 41.8 Gy (range, 27.7 to 60 Gy) in 6 fractions over 2 weeks. No dose-limiting toxicities were observed. The 1-year local control was 71% (Lee et al., 2009). The median overall survival was 17.6 months. In a phase I/II study of SBRT for primary and metastatic liver tumors from the Netherlands, 14 patients with 34 metastatic liver tumors were treated with SBRT to a dose of 37.5 Gy in 3 fractions prescribed at the 65% isodose line. At a median follow-up time of 12.9 months, the local control rate was 94% (Mendez Romero et al., 2006). Three patients developed grade 3 toxicities (elevated gamma glutamyl transferase in 2 and asthenia in one). In a multi-institutional phase I/II trial of SBRT for liver metastases led by University of Colorado, 47 patients with 63 lesions were enrolled. In the phase I portion of the study, the radiation dose was escalated from 36 Gy to 60 Gy in 3 fractions and no dose-limiting toxicities were observed. Grade 3 or higher toxicities were observed only in one patient. The 1 and 2 year actuarial in-field local control rates were 95 and 92%, respectively, for the 49 evaluable lesions. The 2 year actuarial local control was 100% for lesions ≤ 3 cm (Rusthoven et al., 2009c). The median survival time was 20.5 months. In a phase I dose-escalation study of single fraction SBRT for liver tumors from Stanford University, 26 patients with 40 liver tumors (19 had liver metastases) were treated with a starting dose of 18 Gy, escalating to 30 Gy in 4 Gy increments. None of the patients developed dose limiting toxicities (Goodman et al., 2010). For the whole group including patients with primary liver tumors, there were 9 acute grade 1, one acute grade 2, and two late gastrointestinal toxicities. At a median follow-up of 17 months, the local control rate was 77% and the 2-year actuarial overall survival was 50.4%. Eleven of the 19 patients with liver metastases died (Goodman et al., 2010).
Oligometastases — all sites
In a dose escalation trial of SBRT for the treatment of 1-5 metastases at University of Chicago, twenty patients with life expectancy of 3 months or longer and good performance status were enrolled. A total of 56 metastatic lesions (18 lung, 9 liver, 13 nodal, 9 bone, 6 adrenal, and 1 soft tissue) were treated. Twenty four (81%) patients received systemic therapy prior to SBRT. The radiation dose started at 24 Gy in 3 fractions and was escalated in 2 Gy per fraction increment to a maximum dose of 60 Gy in 3 fractions. At a median follow-up of 14.9 months, 59% of the lesions showed radiographic/metabolic response and another 35.7% of the lesions were stable (Salama et al., 2008). The median duration of response was 7.8 months. A radiation dose response has been observed with tumors treated to 36 Gy having an ultimate control rate of 83% compared to 79% and 39%, respectively, in the 30 Gy and 24 Gy groups (Salama et al., 2008). Most patients with progressive disease developed progression in a limited number of organs with five (22%), three (13%), six (26%), and four (17%) of 29 patients progressing in one, 2, 3, and 4 sites, respectively. Progression only in organs known to harbor cancer occurred in 9 (31%) patients. In 14 (48%) patients, progression was deemed to be amenable to further local aggressive therapy (Salama et al., 2008). Grade 3 or higher toxicities were rare.
In a study from University of Rochester, which combined patients enrolled in 2 prospective studies utilizing SBRT with curative intent, 121 patients with ≥ 5 detectable metastases were treated. Colorectal and lung cancer represented the most common primary sites. Patients with oligometastases from breast cancer without brain metastases were included in the first study whereas patients with cancer from any primary site with oligometastases including brain metastases were included in the second study. The most commonly used regimen was 50 Gy in 10 fractions. The overall survival rates were 50% and 28% at 2 and 4 years, respectively. The 2- and 4-year actuarial local control rates for each individual lesion were 77% and 73%, respectively (Milano et al., 2008). The 2- and 4-year distant control rates were 34% and 25%, respectively. Patients with high total tumor volume, non-breast primary, and presence of adrenal metastasis had worse prognosis. Grade 3 toxicities were observed only in one patient. Grade 5 toxicities were not observed. Out of the 121 patients, 45 (37.2%) were alive with 29 (24%) also showing no evidence of disease at a median follow-up time of 36 months (Milano et al., 2008).
In most studies of SBRT for oligometastases in the lung, liver, and all body sites, the reported toxicity rates are generally low (Herfarth et al., 2001; Lee et al., 2009; Mendez Romero et al., 2006; Rusthoven et al., 2009b; Rusthoven et al., 2009c; Salama et al., 2008). In the phase I/II trials of SBRT for lung and liver metastases led by University of Colorado, grade 3 or higher toxicities were rare despite the use of a 3-fraction regimen (Rusthoven et al., 2009b; Rusthoven et al., 2009c). In the dose escalation trial of SBRT for 1-5 metastases from University of Chicago, grade 3 or higher toxicities were also limited (Salama et al., 2008).
Conclusions and Future Directions
SBRT represents one of the options for local aggressive therapy for patients with oligometastases in various body sites, most commonly in the lung and liver. A good amount of data from various studies, both retrospective and prospective, showed promising results. Most studies showed good local tumor control. In a limited subset of patients, relatively long survival could be achieved. One note of caution is that the follow-up times of most studies were relatively short and therefore, long-term outcomes are not yet available. Longer follow-up is necessary to better define the role of SBRT in the management of oligometastases. Currently, they are multiple ongoing clinical trials on the use of SBRT for oligometastases in various body sites and the results of those trials are eagerly awaited. Given the high propensity for distant progression, the combination of novel systemic therapy and SBRT is to be explored. Interested readers can visit the website (www.clinicaltrials.gov) to view a full list of clinical trials of SBRT for various metastatic sites.
In memory of Jian Z. Wang, Ph.D.
Robert Timmerman, M.D., has research grants from Varian Medical Systems and Accuray, Inc. His grant from Elekta Oncology has expired. Other authors have none to disclose.
(Corresponding author: Simon S. Lo, M.D., Associate Professor of Radiation Oncology and Neurosurgery, Director of Stereotactic Body Radiation Therapy, Department of Radiation Oncology, Arthur G. James Cancer Hospital, Ohio State University Medical Center, Columbus, Ohio 43210, USA.)
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[Discovery Medicine; ISSN: 1539-6509; Discov Med 10(52):247-254, September 2010.]