Volume 118, Issue 11 p. 2962-2970
Original Article
Free Access

Stereotactic body radiotherapy for multisite extracranial oligometastases

Final report of a dose escalation trial in patients with 1 to 5 sites of metastatic disease

Joseph K. Salama MD

Corresponding Author

Joseph K. Salama MD

Department of Radiation Oncology, Duke University, Durham, North Carolina

Department of Radiation Oncology, Duke University, Box 3085, Duke University Medical Center, Durham, NC 27710; Fax: (919) 668-7345===Search for more papers by this author
Michael D. Hasselle MD

Michael D. Hasselle MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

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Steven J. Chmura MD, PhD

Steven J. Chmura MD, PhD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Cancer Research Center, University of Chicago, Chicago, Illinois

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Renuka Malik MD

Renuka Malik MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

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Neil Mehta MD

Neil Mehta MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

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Kamil M. Yenice MD

Kamil M. Yenice MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

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Victoria M. Villaflor MD

Victoria M. Villaflor MD

Cancer Research Center, University of Chicago, Chicago, Illinois

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois

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Walter M. Stadler MD

Walter M. Stadler MD

Cancer Research Center, University of Chicago, Chicago, Illinois

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois

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Philip C. Hoffman MD

Philip C. Hoffman MD

Cancer Research Center, University of Chicago, Chicago, Illinois

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois

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Ezra E. W. Cohen MD

Ezra E. W. Cohen MD

Cancer Research Center, University of Chicago, Chicago, Illinois

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois

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Philip P. Connell MD

Philip P. Connell MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Cancer Research Center, University of Chicago, Chicago, Illinois

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Daniel J. Haraf MD

Daniel J. Haraf MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Cancer Research Center, University of Chicago, Chicago, Illinois

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Everett E. Vokes MD

Everett E. Vokes MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Cancer Research Center, University of Chicago, Chicago, Illinois

Section of Hematology/Oncology, University of Chicago, Chicago, Illinois

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Samuel Hellman MD

Samuel Hellman MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

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Ralph R. Weichselbaum MD

Ralph R. Weichselbaum MD

Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois

Cancer Research Center, University of Chicago, Chicago, Illinois

Ludwig Center for Metastasis Research, University of Chicago, Chicago, Illinois

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First published: 21 October 2011
Citations: 263

Presented in part at the 48th Annual American Society for Therapeutic Radiology and Oncology (ASTRO) Conference; November 5-9, 2006; Philadelphia, PA and the National Cancer Institute/ASTRO Workshop, Eradicating Metastases: Emerging Opportunities for Radiation to Help Cure M1 Disease; December 5-6, 2007; Bethesda, MD.

Abstract

BACKGROUND:

A subset of patients with metastatic cancer in limited organs may benefit from metastasis-directed therapy. The authors investigated whether patients with limited metastases could be safely treated with metastasis-directed radiotherapy.

METHODS:

Patients with 1 to 5 metastatic cancer sites with a life expectancy of >3 months received escalating stereotactic body radiotherapy (SBRT) doses to all known cancer sites. Patients were followed radiographically with CT scans of the chest, abdomen, and pelvis and metabolically with fluorodeoxyglucose-positron emission tomography, 1 month after treatment, and then every 3 months. Acute toxicities were scored using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 3.0, and late toxicities were scored using the Radiation Therapy Oncology Group late toxicity scoring system.

RESULTS:

Sixty-one patients with 113 metastases were enrolled from November 2004 to November 2009 on a prospective radiation dose escalation study. Median follow-up was 20.9 months. Patients tolerated treatment well; the maximal tolerated dose was not reached in any cohort. Eleven patients (18.3%) have not progressed. One and 2-year progression-free survival are 33.3% (95% confidence interval [CI], 22.8-46.1) and 22.0% (95% CI, 12.8-34.4); 1-year and 2-year overall survival are 81.5% (95% CI, 71.1-91.1) and 56.7% (95% CI, 43.9-68.9). Seventy-two percent of patients whose tumors progressed did so in limited (1-3) metastatic sites.

CONCLUSIONS:

Patients with 1 to 5 metastases can be safely treated to multiple body sites and may benefit from SBRT. Further investigation should focus on patient selection. Cancer 2011;. © 2011 American Cancer Society.

INTRODUCTION

We previously proposed that a clinical state of oligometastases may exist in which patients, with metastases limited in number and/or destination organ, may benefit from metastasis-directed therapy.1, 2 Analyses demonstrate many metastatic cancer patients present with limited number and location of tumors.3, 4 Prior studies have reported long-term disease control after resection of limited metastases.5-7 Long-term survival has been demonstrated after brain metastases resection,8 with improved survival seen after aggressive treatment of single brain metastasis patients.9, 10

These data confirm the curative potential of ablative treatments for metastases in certain circumstances. With earlier diagnosis and better staging, the number of patients with limited metastatic disease should increase. Furthermore, more effective systemic treatments may control most microscopic metastatic deposits, resulting in a limited number of residual metastases, which could be successfully treated by metastasis-directed methods.

Advanced radiotherapy techniques, described as stereotactic body radiotherapy (SBRT), have achieved high tumor control rates. Studies have demonstrated improved control over conventional techniques in primary tumors11 and metastases in one12-14 organ. The application of SBRT (hypofractionated radiotherapy [RT] >8 gray [Gy] per dose) to multiple organs treated concurrently has not been prospectively tested. Therefore, we conducted a dose escalation trial in patients with 1 to 5 metastatic sites to determine the maximally tolerated SBRT dose. We previously reported on the initial 26 patients enrolled.15 Here we report the final outcomes.

MATERIALS AND METHODS

Patients with pathologically confirmed American Joint Committee on Cancer sixth edition stage IV cancer (any histology) with 1 to 5 metastases were eligible for this prospective radiation dose escalation study. Patients were required to be ≥18 years old, and to have a life expectancy >3 months, Eastern Cooperative Oncology Group performance status ≤2, normal organ and marrow function, and no prior radiotherapy to involved sites. Each metastasis had to be ≤10 cm or ≤500 mL in volume on standard imaging. Brain metastases were required to be treated and considered inactive/controlled before enrollment. Patients could not receive systemic chemotherapy during SBRT; hormonal therapy was allowed. Patients were staged with chest, abdomen, and pelvis computed tomography (CT) and bone scan or positron emission tomography (PET) scan. Informed consent was obtained before protocol treatment. The University of Chicago Institutional Review Board approved the study (approval #136198B).

All patients underwent CT-based treatment planning in custom-made immobilization (Alpha Cradle Smithers Medical Products, North Canton, Ohio). CT images for radiation planning typically included a free breathing CT scan, an end expiratory respiratory gated scan, as well as 4-dimensional CT aided by contrast as needed. Tumors were contoured with no additional margin to account for potential microscopic extension using all available clinical, metabolic and respiratory motion information available. To account for setup error and organ motion, tumor volumes were expanded 5 to 10 mm. Nonoverlapping axial and noncoplanar fields were combined to optimize radiation distribution around metastases, while minimizing uninvolved organ dose. Each metastatic lesion was assigned to a cohort (lung, liver, abdominal, head and neck, and extremity) based on potential normal tissue complication. Each cohort was escalated independently. The starting dose for all sites was 24 Gy (three 8-Gy fractions). A 3 × 3 dose escalation schema was used with cohorts escalated in 6-Gy increments (2 Gy per fraction). The dose ceiling for all cohorts was 60 Gy (three 20-Gy fractions for all cohorts). In general, radiation dose was prescribed to the planning target volume (PTV) edge, typically to the 80% to 90% isodose line, with 95% of the PTV required to receive 95% of the planned dose. Tissue heterogeneity corrections were always used.

Patients received 3 radiation doses separated by >48 and <192 hours. When needed, respiratory motion management (RPM System; Varian Median Systems, Palo Alto, Calif) was used. SBRT was delivered via image guidance most commonly with kilovolt cone beam CT. Patients with abdominopelvic metastases were prescribed antiemetics before treatment. Antianxiety and pain medications were used to ensure patient comfort. After each treatment, a complete examination was performed.

Patients returned every 2 weeks for 1 month, monthly for 3 months, then quarterly. Acute toxicities were scored via the Common Terminology Criteria for Adverse Events version 3.0.16 Late toxicities were scored via the Radiation Therapy Oncology Group late toxicity scoring system.17 Whole body CT ± fluorodeoxyglucose-PET were performed 1 month after the completion of treatment, then quarterly.

Dose-limiting toxicities were defined as grade 3 to 5 (G3-5) nonhematologic toxicity (excluding nausea/vomiting and esophagitis/mucositis lasting ≤7 days) or grade 4 to 5 hematologic toxicity. Toxicities related to a specific target lesion were assigned only to that lesion. Systemic toxicities or those potentially caused by >1 target lesion were assigned to multiple dose cohorts within the same patient. Three patients within a cohort had to be observed at least 30 days before further escalation, except the abdominal cohort, which required 90 days of observation.

Each metastasis was a target lesion independently assessed for response per Response Evaluation Criteria in Solid Tumors.18 Initial response was determined at first follow-up imaging. In addition, metastases (particularly osseous) with a metabolic complete response (CR) on bone or PET scan were scored as CR in the absence of progression on CT scan. Patterns of progression were determined by assessing all treated metastases and nontarget lesions (primary tumors and metastases) on all follow-up studies. Progression was classified as occurring within a treated metastasis, confined to preprotocol controlled cancer sites, or in a new metastatic site. Follow-up images were routinely fused to radiation treatment-planning imaging to determine progression in treated metastases. Time to progression was calculated using the Kaplan-Meier method19 estimated from protocol treatment completion date.

RESULTS

Patients

Patients were enrolled from November 2004 to November 2009. Sixty-two patients were enrolled; 1 with recurrent (not metastatic) disease was ineligible. Therefore, 61 eligible patients, with 113 metastatic sites, comprised our eligible population for survival endpoints. Patient and disease characteristics are detailed in Table 1. Median follow-up was 20.9 months (range, 3.0-60.5 months) for all, and 31.3 months for living patients. The median time to first metastasis from initial diagnosis was 11.6 months (range, 0-302 months). The median time from first metastasis to enrollment was 9.9 months (range, 0.8-85.7 months). Twenty-three patients had previous metastasis-directed therapy, and 49 (80.3%) received systemic therapy before enrollment. One patient was enrolled after an imaging CR to whole brain RT for a single brain metastasis. The mean number of protocol treated metastases was 2; 27 patients (45%) had treatment to multiple sites.

Table 1. Patient and Tumor Characteristics
Characteristic No. % (Range)
Patients evaluable 61 100
Primary sites (histology)a
 Lung
  Nonsmall cell lung cancer 11 18.0
  Small cell lung cancer 5 8.2
 Head and neck
  Squamous cell carcinoma 5 8.2
 Breast 7 11.3
 Colon/rectum 6 9.8
 Renal 8 13
 Sarcoma extremity 3 4.8
 Ovary
  Adenocarcinoma 1 1.6
  Papillary serous 1 1.6
  Poorly differentiated carcinoma 1 1.6
 Parotid
  Adenoid cystic 1 1.6
  Adenocarcinoma 1 1.6
 Skin
  Melanoma 1 1.6
  Basal cell 1 1.6
 Small bowel
  Adenocarcinoma 2 3.2
 Ewing sarcoma 1 1.6
 Gallbladder
  Adenocarcinoma 1 1.6
 Pituitary
  Neuroendocrine carcinoma 1 1.6
 Thymus
  Large cell 1 1.6
 Thyroid
  Follicular 1 1.6
  Hurthle cell 1 1.6
 Uterine
  Leiomyosarcoma 1 1.6
Metastatic lesions treated per protocol 113
 Lung 41 36.3
 Lymph nodes 22 19.4
 Liver 22 19.4
 Osseous 15 13.3
 Adrenal 9 8.0
 Soft tissue 3 2.7
 Pancreas 1 0.9
Mean metastatic sites per patients 2 (1-5)
 1 lesion on protocol 33 55
 2 lesions on protocol 11 18
 ≥3 lesions on protocol 16 27
Median lesion size, cm 2.5 (0.5-9.8)
Exposed to systemic therapy prior to protocol RT 49 80.3
Median courses of systemic therapy 1 (0-9)
Median systemic agents 2 (0-1)
  • Abbreviation: RT, radiotherapy.
  • a Numbers do not add to 100% due to rounding.

Toxicity

Grade 3+ acute and late toxicity are shown in Table 2. Two patients experienced grade 3+ acute toxicity. In the 30-Gy liver cohort, 1 patient experienced grade 3 vomiting after the first radiation dose, but tolerated remaining fractions without toxicity. Per protocol, this was not dose limiting. In the 42-Gy lung cohort, 1 patient had dyspnea starting within 1 month of SBRT. These symptoms were attributed to tumor progression. To be conservative, this cohort was expanded to ensure no additional cardiopulmonary toxicities occurred. An additional patient in this cohort experienced brief grade 3 fatigue. No acute grade 3+ toxicities occurred in the extremity or head and neck cohorts.

Table 2. Description of Grade 3+ Toxicities
Cohort Metastasis Description Dose, Gy Toxicity Clinical Details
Acute toxicity
 Liver 2 liver lesions 30 G3 GI N/V after 1st SBRT fraction required hospitalization and IV fluids. For 2nd and 3rd fractions received prophylactic odansetron and dexamethasone pre-SBRT and post-treatment received Compazine + 1 L of normal saline resulting in no further N/V.
 Lung 2 right lung metastases 42 G3 fatigue Developed fatigue causing decreased performance of ADLs 1 week after SBRT completion and lasting for 4 days. At 2 weeks post-SBRT, fatigue resolved.
Late toxicity
 Abdomen 3 para-aortic lymph nodes 24 G3 GI GI bleed requiring hospitalization, blood transfusion, and eventual laser photocoagulation 3 months after completing SBRT.
 Abdomen L4 vertebrae 36 G3 neurologic and bone G3 late neuritis requiring gabapentin and steroid injections 11 months after completing SBRT and a late L4 compression fracture 30 months after completing SBRT. Note tumor was invading neural foramina at time of SBRT.
 Abdomen Right adrenal 36 G3 endocrine Partial adrenal insufficiency 31 months after SBRT. The left adrenal gland was previously excised during radical nephrectomy. Endocrinology attributed the insufficiency either to radiation or to a recent cortisone injection for arthritis causing transient adrenal suppression. Conservatively scored toxicity.
 Lung 1 right lung metastasis 42 G3 pulmonary Radiation pneumonitis requiring supplemental oxygen and steroids.
 Lung 1 right lung metastasis 24 G3 neurologic Late neuritis requiring nerve block after treatment of lesion adjacent to the thoracic spine. Note, patient had post thoracoscopy pain prior to SBRT. Conservatively scored as toxicity.
 Liver 3 liver metastases 30 Possible G3 hepatic dysfunction Known history of mild alcoholic cirrhosis, but adequate function to meet inclusion criteria. One liver lesion progressed and was treated with RFA. He additionally developed bulky retroperitoneal lymphadenopathy requiring further radiation therapy. Subsequently developed elevation of LFTs, thrombocytopenia, hypoalbuminemia, ascites, and a pericardial effusion. Cytology from the effusion was positive for malignancy; however, peritoneal cytology was inconclusive. This was not scored as toxicity, as it was thought to be related to progressive intra-abdominal disease.
  • Abbreviations: ADL, activity of daily living; G, grade; GI, gastrointestinal; Gy, gray; IV, intravenous; LFT, liver function test; N/V, nausea and vomiting; RFA, radiofrequency ablation; SBRT, stereotactic body radiotherapy.

Chronic toxicity was also limited (Table 2). In the abdominal cohort, 1 patient developed a grade 3 gastrointestinal bleed 3 months after completing SBRT. The protocol was amended to require 3 months of observation in the abdominal cohort before dose escalation. In addition, grade 3 neuritis (11 months after SBRT), an L4 compression fracture (30 months after SBRT), and grade 3 partial adrenal insufficiency (31 months after SBRT to the right adrenal gland) were seen. Because of the emergence of vertebral body SBRT data from other institutions and this toxicity,20 no further vertebral metastases were enrolled.

In the lung cohort, up to 3 grade 3+ toxicities occurred. One patient in the 36-Gy cohort developed hemoptysis requiring hospitalization 10 months after SBRT to a centrally located right upper lobe metastasis. CT and bronchoscopy were suspicious for recurrence; however, biopsy was inconclusive. The patient was discharged and died 1 day later. The cause of death is unknown. This event was scored as recurrence, not toxicity. However, as high toxicity rates with 3-fraction SBRT regimens for central lung lesions have been reported,21 this could represent up to a grade 5 late toxicity. In addition, a patient in the 42-Gy cohort developed grade 3 late radiation pneumonitis. Multiple patients experienced late rib fractures, causing transient pain and not scored as high-grade toxicity. The probability of rib fracture increased with dose. No patients in the 24-Gy or 30-Gy cohorts had rib fracture versus 1 of 6 patients in the 36-Gy cohort, 2 of 10 patients in the 42-Gy cohort, and 1 of 2 patients in the 48-Gy cohort. No late G3+ toxicities occurred in the liver, extremity, or head and neck cohorts. Acute and chronic toxicities were not statistically different between patients treated to 1 or >1 metastatic site.

Dose Escalation

The maximally tolerated dose was not reached in any cohort. The final dose cohorts (Table 3) with sufficient enrollment and follow-up to exclude toxicity were: abdomen 42 Gy, lung 42 Gy, and liver 42 Gy. However, no dose-limiting toxicity was seen in the abdominal patient treated to 48 Gy or the lung patient treated to 48 Gy. Dose escalation was not possible in the head and neck and extremity cohorts because of limited enrollment.

Table 3. Number of Patients Treated in Each Cohort With Number of Target Lesions in Parentheses
Dose Cohort Lung Patients (Lesions) Abdomen Liver Head and Neck Extremity
24 Gy 5 (9) 4 (7) 4 (6) 3 (3) 2 (3)
30 Gy 8 (9) 7 (9) 3 (6)
36 Gy 6 (10) 7 (9) 3 (4)
42 Gy 10 (13) 4 (4) 3 (5)
48 Gy 2 (3) 1 (1)
  • Abbreviation: Gy, gray.

Patterns of Progression

The initial response of treated-metastasis was 46.0% (33 CR and 19 partial response), 49.6% (56 lesions) were stable disease, and 2.6% (3 lesions) were progressive disease. Two metastases were not evaluable. Although not the primary endpoint of this study, and limited by initial low doses of radiation, at last follow-up, 63.7% of metastases have not progressed, with a median imaging follow-up of 15.0 months (range, 1.15-52.7 months; Table 4). The 1-year and 2-year treated metastasis control was 67.2% (95% confidence interval [CI], 57.2%-76.1%) and 52.7% (95% CI, 41.1%-64.4%; Fig. 1, Top).

Details are in the caption following the image

(Top) Overall survival is shown for all patients. (Middle) Freedom from progression is shown for all patients. (Bottom) Freedom from progression is shown for patients with 1 to 3 metastases (red line) versus 4 to 5 metastases (blue line) at protocol enrollment, P = .07 by log-rank test. Dashed lines represent 95% confidence intervals.

Table 4. Control of Targeted Tumors
Dose Cohort Imaging Follow-up for Controlled Lesions, Median mo (range) SBRT Lesion Control
24 Gy 14.8 (2.0-30.9) 16/35 (45.7%)
30 Gy 11.0 (1.3-52.7) 17/26 (65.4%)
36 Gy 24.3 (2.0-49.3) 20/24 (83.3%)
42 Gy 15.2 (1.2-31.9) 15/24 (62.5%)
48 Gy 17.9 (16.2-24.1) 4 /4 (100%)
  • Abbreviations: Gy, gray; SBRT, stereotactic body radiotherapy.

Given limited prospective data available on nonhepatic abdominal SBRT, a detailed analysis is provided for this cohort. Within this cohort, the 2-year treated metastasis control was 66.7% (95% CI, 47.2%-81.7%). Nine of 31 treated lesions progressed; however, 7 of these were in the 24-Gy cohort. Metastases treated in the 30-Gy, 36-Gy, and 42-Gy cohorts had 2-year control of 88.2% (95% CI, 63.3%-97.2%).

Patterns of first progression were recorded. In 7 patients (11.7%), first progression was within protocol-treated metastases, although 1 patient scored as tumor progression in a treated adrenal metastasis had later permanent regression of this lesion without further therapy. Thirty-three patients (55.0%) had progression only in new metastatic sites. Four patients (6.7%) progressed only in known previously treated sites controlled at protocol enrollment. Five patients (8.3%) had simultaneous progression in treated metastases and new metastatic sites.

Initial metastatic progression was usually limited. At time of first progression, the numbers of sites of first progression were 1 (n = 18), 2 (n = 4), 3 (n = 12), 4 (n = 4), 5 (n = 2), and >5 (n = 9). Ultimate patterns of progression were also recorded. At last follow-up, 11 patients had no evidence of active cancer, 10 patients had control of treated metastases with limited new metastatic progression, 3 patients had progression in treated metastases without new metastatic progression, 18 patients were controlled at treated metastatic sites with widespread metastatic progression, 12 patients had progression of treated metastasis and widespread new metastatic progression, and 6 patients had progression of a treated metastasis and new limited metastases amenable to further metastasis-directed treatment. Therefore, 50% (n = 30) had either no (n = 11) or limited metastatic progression (n = 19).

After protocol treatment, 11 patients (18.3%) had no evidence of active cancer. The median, 1-year, and 2-year progression-free survival (PFS) were 5.1 months, 33.3% (95% CI, 22.8-46.1), and 22.0% (95% CI, 12.8-34.4), respectively (see Fig. 1, Middle). Patients with 1 to 3 metastases had longer PFS than patients with 4 to 5 metastases, as shown in the bottom panel of Figure 1 (P = .07 by log-rank test for 1-3 vs 4-5 metastases). Moreover, 75% (6 of 8) patients with 4 to 5 metastases at enrollment eventually developed widespread metastatic progression, compared with 46% (24 of 52) with 1 to 3 metastases. Patients with small cell lung cancer and Ewing sarcoma had markedly inferior PFS, with a median PFS and 1-year PFS of 1.1 months and 0.0%, respectively. For all other patients, these were 6.5 months and 37% (95% CI, 25.6%-50.6%; P < .0001 by log-rank test).

Patient-Based Analysis and Overall Survival

The 1-year and 2-year overall survival (OS) are 81.5% (95% CI, 71.1%-91.1%) and 56.7% (95% CI, 43.9%-68.9%; Fig. 2, Top). Eleven patients had >3-year follow-up; 10 are alive as of this writing. For patients with 1 to 3 metastases, the 2-year OS was 60.3% (95% CI, 46.1%-72.8%) compared with 21.9% (95% CI, 3.3%-68.9%) for patients with 4 to 5 metastases (P = .22, log-rank test). In patients alive with >24 months follow-up, 15 of 16 with control of all protocol metastases were alive, compared with 6 of 12 with progression in any protocol-treated lesion.

Details are in the caption following the image

Patient-based analysis of (Top) control of all protocol treated metastases; (Middle) control of all protocol metastases treated within a patient; and (Bottom) freedom from new metastatic progression (out of stereotactic body radiotherapy [SBRT] field) is shown. In the bottom panel, progression in sites previously involved with cancer and controlled at protocol enrollment (not treated with SBRT) that were first sites of recurrence were scored as progression. Dashed lines represent 95% confidence intervals.

DISCUSSION

We tested the hypothesis that patients with ≤5 metastases in ≥1 organs could be safely treated with SBRT. We found that patients generally tolerated the procedure without undue toxicity and had promising responses. The maximal tolerated dose was not reached in any cohort. Others have reported SBRT dose escalation studies for single12-14, 22, 23 organ sites. Others24, 25 have reported using hypofractionated radiation techniques (4 to 6 Gy/fraction for 10 fractions) to multiple organs. However, our study is unique in using high-dose SBRT (8-16 Gy/fraction) and including patients with metastases in multiple organs treated simultaneously.

Acute and chronic toxicity were relatively limited with 7 patients (11.7%) experiencing grade 3+ toxicity. Although 15 patients received treatment to multiple thoracic metastases, only 1 experienced grade 3 pneumonitis. Currently, no SBRT pneumonitis predictors are known,26 and further investigation into this area is ongoing.27-29 The most concerning late toxicity was hemorrhages, including 1 patient treated to multiple periduodenal lymph nodes. Subsequent to our observation, other reports confirmed the sensitive nature of the duodenum to SBRT.30 A second patient died of unknown causes after an admission for hemoptysis. On the basis of this, and data from others,21 we stopped using 3-fraction SBRT regimens for central lung metastases. Two patients experienced grade 3 neuritis after SBRT to metastases adjacent to or within vertebral bodies, although 1 of these patients had symptoms before protocol treatment.

Perhaps the most interesting finding of this study was that nonsurgical metastasis-directed therapy could render patients free of active measurable tumor. Eleven patients had not progressed at last follow-up. Furthermore, 3 patients progressed only within treated sites, and 2 patients progressed only within previously known sites (controlled at time of protocol enrollment). Therefore, 27% of patients developed no new metastatic sites during follow-up. This rate is similar to long-term disease control after surgical resection of limited metastases.6, 7, 31, 32 This and other reports25, 33 suggest that hypofractionated image-guided radiation therapy may be an alternative to surgery for those with low-volume unresectable metastatic disease.

Another important finding is confirmation of a unique pattern of progression after metastasis-directed therapy for patients with limited metastatic disease. Half of patients had no or limited progression, and many survive with a limited tumor burden, as reflected by the high 2-year survival of 56%. Progression generally occurred in a limited number of metastases amenable to further metastasis-directed therapy. At last follow-up, only 50% had widespread metastases. These findings validate that some patients with limited number and location of metastases will have slow disease progression and SBRT can benefit them if we can identify these patients.

Because 80% (49 of 61) of these patients with tumors of diverse primary origins had systemic treatment before the dose escalation study, it is not possible to separate those patients with de novo oligometastases from those resulting from successful systemic treatment. Now that this dose escalation study is concluded, further study of these different patient groups using clinical and molecular methods should allow the development of guidelines for the identification and potentially curative treatment for appropriate patients.

Investigations are ongoing to identify patients most likely to benefit from metastasis-directed therapies. Our data reveal that simple clinical factors are a first step. Patients with 1 to 3 metastatic sites at enrollment (not cumulative number of metastases) trend to better outcomes than those with 4 to 5 metastases. Furthermore, most patients with 4 to 5 sites of metastases experienced widespread metastatic progression with prolonged follow-up. This is concordant with data suggesting that patients with a lower metastatic burden have better outcomes after metastasectomy.6, 7 In addition, patients with high-risk histologies fared poorly after metastasis-directed therapy. Therefore, patients best suited for SBRT may be those without high-risk histologies and ≤3 metastases. In an effort to identify biological factors of suitability for metastasis-directed therapy, we are currently performing analysis of tumor samples of oligometastatic patients to predict those likely to remain with limited disease compared with those who will experience widespread progression.

We concluded our trial before meeting our primary endpoint of determining the maximum tolerated dose of SBRT in each cohort. Our experience, and that of others, demonstrated that the 3-dose regimen mandated in the protocol (derived from early stage nonsmall cell lung cancer investigations) was not suitable for all patients with limited metastatic disease. Unique to our study, we were able to show that for select abdominal metastases, a 3-fraction regimen to a total dose of 42 Gy was safe as long as normal organ constraints were adhered to.

Although this was not the primary endpoint of our study, the majority of treated metastases were controlled with SBRT. Our data, concordant with others,34, 35 suggests increasing metastasis control with higher radiation doses. Our initial doses were too low. When we initiated our trial, limited data on SBRT doses were available. More recently, phase 1-2 data has elucidated organ-specific dosing schedules for small-volume peripheral lung lesions and limited hepatic metastases with promising control rates.12, 13, 22, 30 In addition, the inclusion of large tumors contributed to our local control rates.

Whether the addition of SBRT or other metastasis-directed therapy contributes to improved PFS or OS is still debatable. Multiple series demonstrate 20% to 25% 5-year to 10-year OS after surgical metastatectomy5-8, 31, 32, 36, 37 or hypofractionated RT.33 Moreover, many series demonstrate that patients with incomplete metastasectomy have inferior survival, suggesting that ablation of all metastatic disease is important.5-7, 36 The only randomized trials showing improved OS with intensified metastasis-directed therapy is in the setting of brain9, 10 and spinal cord38 metastases. Ongoing studies are testing the role of consolidation RT after systemic therapy (NCT00776100) as well as the role of hypofractionated image-guided RT concurrently with systemic therapy in the initial management of patients with limited metastatic nonsmall cell lung cancer (NCT00887315).

In conclusion, these data indicate that a set of clinical criteria derived from published literature based on the number, location, and size of metastatic foci can select for patients with limited metastatic disease. Disease progression in oligometastatic patients occurs most often in a limited number of new metastases. Half of patients remained with limited metastases.

Acknowledgements

We thank Mary Ann Schroeder, Amber Meriwether, Daniel Golden, Karl Farrey, Julian Partouche, and Tianming Wu, as well as the Robert and Valda Svendsen Foundation.

    FUNDING SOURCES

    Supported by the Ludwig Center for Metastasis Research, University of Chicago Research Center Grant 5-30,073, Chicago Tumor Institute, Center for Radiation Therapy and a generous gift from Mr. and Mrs. Vincent Foglia, none of whom had any access to the data or the article.

    CONFLICT OF INTEREST DISCLOSURES

    The authors made no disclosures.