Get 20M+ Full-Text Papers For Less Than $1.50/day. Start a 14-Day Trial for You or Your Team.

Learn More →

A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases

A single-institution study of stereotactic body radiotherapy for patients with unresectable... Purpose: The purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy. Methods and materials: Between July 2007 and June 2010, 90 patients were treated with the CyberKnife SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity. Results: A total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23–84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7–110 mm) for liver and 12.5 mm (range, 5–63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55–81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1–9.5 months). Observed toxicities included grade 1–3 acute toxicities. One grade 3 and no grade 4 toxicity were reported. Conclusion: High-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy. Summary: Stereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients’ life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens. Keywords: SBRT, Liver metastasis, Lung metastasis, Oligometastases, CyberKnife * Correspondence: e-lartigau@o-lambret.fr Radiation Therapy Department, Oscar Lambret Comprehensive Center Lille, 3 rue Combemale, Lille cedex 59020, France Full list of author information is available at the end of the article © 2012 Fumagalli et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fumagalli et al. Radiation Oncology 2012, 7:164 Page 2 of 8 http://www.ro-journal.com/content/7/1/164 Introduction lesions. Clinical data on 90 patients presenting with 113 Over the past decade, stereotactic body radiation therapy hepatic and 26 lung metastases were collected and ana- (SBRT) has emerged as an alternative treatment option lyzed. Patients and tumor characteristics are presented for patients with liver [1,2] and lung [3,4] lesions. The in Table 1. Treatment response was assessed using the term "oligometastases" was first described by Hellman RECIST 1.1 criteria. Toxicity was evaluated with the and Weichselbaum [5] in 1995 as a less-advanced state CTCAE v4.0. Written informed consent was obtained of metastatic disease amenable to and potentially curable from the patient for publication of this report in accord- with local therapy. The term "oligometastases" is most ance with the guidelines of the French National Cancer often used to describe five or fewer metastatic lesions Institute (Institut National du Cancer) required when [6]. Often, this pathology has a slow rate of progression, assessing the efficacy and toxicity of a novel therapy, justifying focal treatments. Main therapeutic options for oligometastases remain Methods surgery or radiofrequency. Due to its high level of preci- SBRT was delivered with Cyberknife, an integrated sion which allows hypofractionnation, SBRT has gained image-guided frameless stereotactic radiation therapy interest as a curative treatment option for inoperable system. It is comprised of a robotic arm coupled with a patients with lung cancer, liver tumors, or oligometas- compact 6-MV X-Ray linear accelerator and a real-time tases. The concept of local treatment for oligometastatic imaging system. Different collimators with diameters lesions exists since only a few years [7-9] Researchers ranging from 5–60 mm are used with the linac. Two X- have reported encouraging data for liver metastases trea- Ray tubes are positioned in the treatment room at a 45° ted with SBRT. Katz et al. [10] have reported a local con- angle. Images created are registered to the treatment- trol rate of 76% and 57% at 10 and 20 months, planning console. This system detects a difference of respectively, with 69 patients. For lung metastases, 0.06 mm in translation and rotation. For liver metasta- Rusthoven et al. have reported local control rates of ses, all patients were treated with the Synchrony Re- 100% and 96% at 1 and 2 years, respectively [11]. SBRT spiratory Tracking System. Four gold fiducial markers can be delivered without tumor tracking using a stereo- were inserted around the lesion 2 weeks before the treat- tactic frame or the breath-hold technique, or most re- ment planning. For lung metastases, patients could be cently, with a real-time tumor tracking system, which is treated with either Xsight Lung Tracking System available with the CyberKnife System (Accuray Incor- (Accuray) or, using an internal target volume (ITV), with porated, Sunnyvale, CA). Most studies have reported Xsight Spine Tracking System (Accuray). These track- results from treatments delivered without tracking [12]. ing methods did not require the implantation of fiducial With real-time tracking, patients can breathe freely dur- markers. For the planning computed tomography (CT) ing treatment sessions. study, patients were immobilized in an external vacuum- Milano reported a study of 121 patients with oligome- type body mold. An abdominal belt could be used for tastases from any site analyzing survival and tumor con- liver lesions in order to decrease respiration amplitudes. trol with encouraging results [6]. Bone metastases A 4D CT-scan was performed for patients with liver appeared to be associated with a fourfold reduced hazard or lung metastases, respectively, with a 1-mm slice thick- of death. To our knowledge, no previous study has been ness and reconstruction in 3-mm slices. For the lung reported with this technique of SBRT for a pooled ana- patients tracked with Xsight Spine, ITV was defined lysis of lung and liver metastases. using the data from the 4D CT-Scan performed for We report a retrospective study of 90 patients with treatment planning. For patients treated with tumor 139 visceral oligometastases (lung or liver), regardless of tracking, GTV was contoured. GTV or ITV was the primary analyzing overall survival, local control and expanded by 5 mm to create the clinical tumor volume relapse free survival. (CTV). CTV was expanded by 3 mm to obtain the plan- ning target volume (PTV). SBRT planning was per- Patients and methods formed with Accuray’s Multiplan treatment planning Patients software. Dose was prescribed to the 80% isodose line Patients treated between July 2007 and June 2010 were and delivered to the target volume over a mean duration included and medical records were retrospectively of 8 days (range, 3–22 days). The median fractionnation reviewed. Patients with oligometastases (1 to 5 lesions) scheme was three fractions of 15 Gy (range, 9–20 Gy). from any primary site and not amenable to surgery, due Critical organ dose constraints are detailed in Table 2. most of the time to anesthesia were eligible. Other inclu- sion criteria were a Performance Status >3 (WHO scale), Follow-up number of hepatic or lung lesions <5, and lesion size All patients were seen every 3 months with a new CT- <100 mm for hepatic metastases and <70 mm for lung Scan. Treatment response was evaluated every 3 months Fumagalli et al. Radiation Oncology 2012, 7:164 Page 3 of 8 http://www.ro-journal.com/content/7/1/164 Table 1 Patient characteristics Table 1 Patient characteristics (Continued) Patients Total (n = 90) % Yes 15 18% Gender: Female 38 42% More than 3 chemotherapy 26,6% regimens before SBRT : Male 52 58% Hepatic lesions (n = 75) 21 28% Age at diagnostic, median (range): 62 years (22–82) Lung lesions (n = 15) 3 20% Age at SBRT, median (range): 65 years (23–84) Primary sites: Digestive 63 70% using the RECIST 1.1 criteria: complete response (CR) Lung 3 3.3% defined as complete disappearance of tumor or only fi- Breast 8 8.9% brosis in the image, partial response (PR) defined as Melanoma 4 4.4% tumor shrinkage of at least 30%, stable disease (SD) Neuro-endocrine 3 3.3% defined as no radiologically measurable difference and Sarcoma 3 3.3% progressive disease (PD) defined as a tumor increase of Other 6 6.7% at least 20%. Local control was defined as CR, PR, or SD during follow-up based on imaging. Acute toxicity was Adenocarcinoma Histology: Hepatic (n = 75) 61 81% evaluated using CTCAE v4. Lung (n = 15) 7 47% Primary for Adenocarcinoma histology 68 Statistics Colorectal 57 84% Descriptive statistics were used for categorical variables Breast 8 12% (frequency and percentage) and continuous variables Gastric 1 1.5% (median and range). The following variables were ana- Lung 1 1.5% lyzed: age, gender, primary site, histology, previous local Kidney 1 1.5% or systemic treatment, time from initial diagnosis to first metastasis, time from the diagnosis of the first metasta- Primary for squamous cell histology : 7 sis to SBRT, total dose received, number of fractions, Esophagus 5 71% dose per fraction, size of the target lesions, and treat- Lung 2 29% ment time. All time to event endpoints were calculated Other histologies : 15 17% from the initiation of treatment. Overall survival Lesions : Lung 15 17% included death from any cause. Disease-free survival Hepatic 75 83% counted events as a progression of an existing target le- sion, appearance of new lesions within the same organ Number of lesions treated by patient : 1 64 71% Table 2 Critical organ constraints 2 19 21% Constraints 34 4% Liver metastases Normal liver V21 < 33% 43 3% V15 < 50% Timing of Metastases: stomach V21 < 5 cm At initial diagnostic 43 49% Spinal cord maximal dose < 22 Gy Within one year 20 23% Kidney V 15 < 33% More than 1 year 25 28% Lung metastases normal lung (= volume of V5 < 50% Time from diagnosis of metastasis to 25.6 months (1.2 – 93.6) right + left lung – PTV) SBRT treatment, median (range) V10 < 30% Previous local treatment : One lung V 20 < 20% Hepatic (n = 75) 53 71% Heart V24 < 15 cm Lung (n = 15) 0 0% Dmax < 30 Gy Prior chemotherapy: 91% trachea and principal bronchi V 15 < 4 cm Hepatic lesions (n = 75) 70 93% V20<1cm Lung lesions (n = 15) 12 92% Dmax < 30 Gy Prior progressive disease with Chemo: esophagus V 21 < 5 cm No 67 82% Dmax < 25 Gy Fumagalli et al. Radiation Oncology 2012, 7:164 Page 4 of 8 http://www.ro-journal.com/content/7/1/164 Table 3 Characteristics and response of metastatic lesions (liver or lung), distant relapse, or death due to cancer, whichever occurred first. Local failure included events Lesions Total (n = 139) % involving pre-existing treated lesions only. Survival rates Number of lesions: were estimated by the Kaplan-Meier method and groups Hepatic metastases 113 81% were compared with the logrank test. P values smaller Lung metastases 26 19% than 0.05 were considered statistically significant. Lesion diameter, median (range): Liver (n = 111) 28 mm (range 7–100) Results Patient characteristics Lung (n = 26) 12.5 mm (range 5–63.5) Ninety patients were treated (52 male and 38 female). Previous local treatment to 68 60% hepatic lesions Median age at diagnosis was 62 (range, 22–82) and me- dian age at the time of SBRT was 65 (range 23–84). Local hepatic treatment: Seventy-one percent of patients had only one metastatic Surgery of same lesion 2 2% lesion. No patient had both liver and lung lesions. Surgery of other lesions 49 44% Histologies of the metastatic lesions were: 68 adenocar- Chemo-embolisation 3 3% cinomas including 57 colorectal tumors, eight breast Radio-frequency 14 12% tumors, one stomach cancer, one lung, and one kidney Response (RECIST) cancer case; seven squamous-cell carcinomas from esophagus and lung; and 15 other histologies [four mela- Hepatic metastases nomas, three neuro-endocrine tumors, three sarcomas, CR 56 51% one GIST (gastro-intestinal stromal tumor), one papil- PR 22 20% lary thyroid tumor, one pneumoblastoma, one adenoid SD 10 9% cystic cancer, two small-cell lung cancers]. Forty-nine PD 22 20% percent of the patients had metastases at the time of ini- Response tial diagnosis. Median time from diagnosis of metastases to start of CyberKnife treatment was 25.6 months Lung metastases (range, 1.2–93.6 months). Eighty-five percent of patients CR 14 58% had received prior chemotherapy; 93% and 92% of liver PR 2 8% and lung patients, respectively. Twenty-seven percent of SD 1 4% patients treated with SBRT had received more than three PD 7 29% cycles of chemotherapy prior to CyberKnife, 28% and Response 21% of liver and lung patients, respectively. No patients had received prior radiotherapy.( Table 1) All lesions There were 113 hepatic and 26 lung metastatic lesions CR 70 52% (Table 3). Median lesion diameter was 28 mm (range, 7– PR 24 18% 100) for liver and 12.5 mm (range, 5–63.5) for lung. CR SD 11 9% rate was 52%, PR 18%, SD 8%, and PD 22%. Except for PD 29 20% one patient, none of the patients with lung metastases had any previous local treatment compared to the 53/75 (71%) patients with 68/113 (69%) hepatic metastases for a liver metastasis for a total dose of 54 Gy due to the who were previously treated locally with surgery to the duodenum proximity. All patients received a total dose treated lesion (2%), surgery to other lesions (44%), chemo- of 27–60 Gy (median dose, 45 Gy). Median treatment embolization (3%), or radio frequency ablation (12%). time was 8 days (range, 3–22) ( Table 4). Treatment was delivered in two weeks, with a session being performed Treatment characteristics every 2 or 3 days. Fifty eight patients were treated with three fractions of 9 Gy (1.1%), 10 Gy (2,2%); 12 Gy (3.3%), 13 Gy (2.2%), 15 Gy (53.3%), or 20 Gy (2.2%) times (Table 4). The Treatment efficacy 20 Gy per fraction regimen was only administered for Median follow up was 17 months ( 95%CI 14-21). The lung metastases. Thirty patients (35.6%), were treated overall response rate was complete for 52% of the with 4 fractions of 10 Gy. One patient was treated with lesions, partial for 20%, stable for 9%, and progressive six fractions of 6 Gy for a total dose of 36 Gy to a lung for 20% of the lesions. Results were similar for hepatic metastasis because of the central localization of the le- and lung lesions. At last follow-up, 21 patients had died sion and one patient was treated with 6 fractions of 9 Gy and 17 patients were disease-free. The local control rate Fumagalli et al. Radiation Oncology 2012, 7:164 Page 5 of 8 http://www.ro-journal.com/content/7/1/164 Table 4 Cyberknife treatment characteristics (by patients) to 89% for other histologies at 1 year and 59% at 2 years Patients Hepatic (n = 75) Lung (n = 15) All Patients compared to 80% for other histologies. Regarding disease- (n = 90) free survival, patients with lung lesions were at a lower Dose per fractions, n (%) risk of failure than patients with hepatic lesions: HR = 0.47 (95% CI: 0.23–0.95, p = 0.02). Patients with a history of re- 6 0 1 1 (1,1%) ceiving chemotherapy were at higher risk of failure com- 9 2 0 2 (2,2%° pared to those without: HR = 4.51 (95% CI: 1.10–18.47, 10 31 (41%) 1 32 (35,6%) p = 0.007) (Table 5). Other factors such as progressive dis- 12 3 0 3 (3,3%) ease following earlier chemotherapy, more than three pre- 13 2 0 2 (2,2%) vious chemotherapy regimens, and time between diagnosis 15 37 (49%) 11 (73%) 48 (53,3%) of the first metastasis and treatment by SBRT were not found to be prognostic for disease-free survival. As far as 20 0 2 2 (2,2%) local control is concerned, female patients had a tendency Total dose, n (%) for lower risk of local failure: HR = 0.48 (95% CI: 0.21–1.10, 27 1 0 1,1% p = 0.07). No factor had any impact on overall survival. 30 2 0 2,2% 36 3 1 4,4% Discussion 39 2 0 2,2% The concept of oligometastasis Oligometastasis is an emerging paradigm in oncology. It is 40 29 (39%) 1 30 (33,3%) described as a distant extension of a primary cancer with 45 37 (49%) 11 (73%) 48 (53,3%) an isolated site or less than five sites of metastases [6]. 54 1 0 1,1% Oligometastases could be seen as clinical manifestations 60 0 2 2,2% of a systemic disease requiring systemic treatment. But Treatment duration, 8 days(3 – 22) they can also be considered as consequences of a slow, median (range) controllable disease progression, curable with local treat- ments. Local treatments include surgery, radiofrequency, at 1 and 2 years were 84.5% and 66.1%, respectively conformal or stereotactic body radiation therapy. The use (Figure 1A). The 1 and 2-year disease-free survival rates of SBRT has seen rapid growth as a noninvasive treatment were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), modality and provides a new treatment alternative for in- respectively (Figure 1B). Median duration of disease-free operable or elderly patients. Salama and al. [13] recently survival was 6.7 months (95% CI: 5.1–9.5 months). The published a dose escalation trial in patients with 1 to 5 2-year overall survival rate was 70% (95% CI: 55–81%) metastases in SBRT. Maximal dose was 48 Gy but the (Figure 1C). maximal dose tolerated was not reached. 2 year overall survival rate was 56.7% and progression free survival rate Toxicity were 33.3% and 22% at one and two years respectively. Side effects were generally mild. Observed toxicites ranged Our progression-free survival rate were lower but we fo- from grade 1 to 2 in the CTCAE v.4. Toxicity for patients cused our study on patients with visceral metastasis, which treated for hepatic lesions consisted mainly of digestive might explain this difference. Indeed in the study pub- adverse events : we recorded 19 nausea (17%), 10 vomiting lished by Salama et al., 13.3% of patients had only bone (9%), three gastritis (2,5%), three anorexia (2,5%), 17 hep- metastases, which could be a factor of better prognosis, as atic pain (15%) and 9 asthenia. (8%) Toxicity for patients Milano et al. have shown [6]. treated for lung lesions was lower, consisting mainly of as- thenia (5 = 19%) radiation pneumonitis (5 = 19%) and Treatment efficacy and predictive factors pleural effusion (3 = 11,5%). We encountered two grade 3 Several studies have been published on different SBRT toxicities : one gastritis in a patient with a hepatic lesion methods. Most of them report about primary and sec- and one epidermitis in a patient treated for two different ondary lesions without distinction [12,14]. Rusthoven hepatic lesions. et al. have reported 47 patients with 63 hepatic lesions. Among the patients, 69% had received at least one prior Univariate analysis systemic therapy regimen for metastatic disease (zero to Regarding local control, neither tumor size nor dose was five regimens) and 45% had extrahepatic disease at study found to be statistically significant. Adenocarcinoma entry. Actuarial in-field local control rates at one and appeared to present a higher risk of failure than other two years after SBRT were 95% and 92%, respectively. histologies: HR = 2.74 (95% CI: 0.95–7.88, p = 0.036). These rates are better than those reported in our study. Control local rate was 82% for adenocarcinoma compared This could be explained by the fact that the Rusthoven Fumagalli et al. Radiation Oncology 2012, 7:164 Page 6 of 8 http://www.ro-journal.com/content/7/1/164 Local Relapse-Free Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Target lesions 139 112 71 37 19 9 4 B Disease free survival Disease-Free Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Patients 90 51 20 6 5 3 2 C Overall survival Overall Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Patients 90 76 60 34 21 14 7 Figure 1 Kaplan-Meier Survival curves. A. Local relapse-free survival. B. Disease-free survival. C. Overall survival. Probability Probability Probability Fumagalli et al. Radiation Oncology 2012, 7:164 Page 7 of 8 http://www.ro-journal.com/content/7/1/164 Table 5 Predictive factors for disease free survival 20 Gy x 3 while only 37/75 patients with liver tumors DFS received 15 Gy x 3 and all the rest received lower doses. Another explanation could be that the lesions' median Patients HR : (95% CI) (p) diameter for lung metastases was 12.5 mm versus Gender: Female 1.17: (0.74 – 1.86) 0.51 28 mm for hepatic lesion. Our univariate analysis did Age at SBRT 65+ 0.72: (0.46 – 1.15) 0.17 not find a difference in local control based on the pri- Adenocarcinoma Histology: 1.28 : (0.75 – 2.19) 0.36 mary tumor site, suggesting that SBRT could be used to Lesions : pulmonary 0.47 : (0.23 – 0.95) 0.02 treat oligometastases from any primary. Still, according Number of lesions : 3+ 1.17 : (0.70 – 1.98) 0.55 to other studies, the role of the primary tumor site in the case of liver metastases remains unclear [18]. Lee Number of hepatic lesions : 3+ 1.40 : (0.79 – 2.48) 0.25 and al. didn't find a difference in overall survival be- Timing of Metastases: < one year 0.67: (0.37 - 1.22) 0.19 tween colorectal, breast and other primaries of metasta- More than 1 year 1.04: (0.60 – 1.79) 0.90 ses treated (respectively 63% (95% CI, 44% to 78%), 79% Prior chemotherapy 4.51: (1.10 – 18.47) 0.007 (95% CI, 36% to 94%), and 38% (95% CI, 14% to 62%). 3+ chemotherapies before SBRT : 1.20: (0.63 – 2.25) 0.59 Dose, within dose range used in this study, did not ap- Prior PD with previous CT 1.31: (0.74 – 2.32) 0.37 pear to be a factor in disease-free or overall survival. Al- though, this result has been confirmed in other studies. study contained only liver patients and 31% of them had McCammon et al. and al [12] found that increased dose not received any chemotherapy before SBRT. There are and smaller gross tumor volume were significant predic- also few data on lung metastases. Studies report local tors of higher local control rates. Their patients treated control rates from 72–100% at 1 year and from 78–96% with 54 Gy or more had a 3-year actuarial local control at 2 years [11,14-16]. rate of 89.3% compared with 59.0% and 8.1% for those Our study evaluated feasibility of SBRT on hepatic and treated with 36–53.9 Gy and less than 36 Gy. The opti- pulmonary oligometastatic lesions from a multitute of mal treatment dose has not been defined yet and should primaries. Local control rates at 1 and 2 years were, re- be the subject of future studies. spectively, 84.5% and 66.1%. These results are similar to other SBRT reports on liver metastases in which 1-year Toxicity local control rates ranged from 71–100% and 2-year In our study, treatment was well tolerated. There were rates from 30–92% [1,17,18]. In our cohort, 49% of the no grade 4 events and only one case of grade 3 gastritis patients had metastases at initial diagnosis. This fact and epidermitis. All of the other events were grades 1 or may have affected our results because of the prognosis 2. The most common acute toxicities were nausea and of such disease that is often considered more aggressive. pain at the time of treatment. None of the toxicities pre- Adenocarcinoma displayed worse prognosis than other vented any patient from completing the treatment and histologies: HR = 2.74 (95% CI: 0.95–7.88), p =0.036. were transitory. Rusthoven et al. have reported similar This could suggest that a more potent dosing regimen results with also one grade 3 event and no grade 4 should be employed when treating metastases with events [17]. Lee et al. have reported two cases of grade 3 adenocarcinoma pathology. Indeed, dose has not been liver enzymes-related toxicities and six acute grade 3 shown as a predictive factor and treatment was well tol- toxicities in the form of two case of gastritis, two cases erated. This is probably also related to the localisation of nausea, one lethargia, and one thrombocytopenia [18]. the treated lesions. Majority of adenocarcinoma metasta- They also had one grade 4 toxicity in the form of ses were hepatic lesions as opposed to being lung thrombocytopenia. A longer follow-up period is neces- lesions. These results were based on a sub-group ana- sary to detect potential long-term toxicities. lysis and care needs to be taken in the interpretation. Regarding disease-free-survival, patients with lung SBRT and previous chemotherapy regimens lesions were at lower risk of failure than those with hep- We wondered whether or not pre-treated patients with atic lesions (HR = 0.47, 95% CI: 0.23–0.95, p = 0.02). As metastatic disease could benefit from SBRT. Most of our there is no previous study comparing lung and hepatic patients had received prior chemotherapy (91%), with a metastases treated with SBRT, this result appears to be a high number of chemotherapy regimens, 27% of them new finding to take into account when considering receiving more than three regimens, which may have SBRT as a treatment option. However, number of lung increased the radioresistance of the metastases. We lesions was lower than number of liver lesions Fur- found that a patient’s history of prior chemotherapy was thermore, the total dose and fractionnation were differ- a major risk factor in recurrence outside the treatment ent between lung and hepatic tumors. 11/15 patients volume (HR = 4.51, 95% CI: 1.10–18.47, p = 0.007). Also, with lung tumors received 15 Gy x 3 and 2/15 received the number of previous chemotherapy regimens Fumagalli et al. Radiation Oncology 2012, 7:164 Page 8 of 8 http://www.ro-journal.com/content/7/1/164 administered or progression while receiving chemother- 10. Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P: Hypofractionated stereotactic body radiation therapy (SBRT) for limited apy significantly correlates with a higher risk of failure. hepatic metastases. International Journal ofRadiation Oncology* Biology* One hypothesis that could explain this finding could be Physics 2007, 67(3):793–798. that the previous chemotherapy regimens, received by 11. Rusthoven KE, Kavanagh BD, Burri SH, Chen C, Cardenes H, Chidel MA, et al: Multi-institutional phase I/II trial of stereotactic body radiation therapy the patients, selected tumoral clones with a lower sensi- for lung metastases. J Clin Oncol 2009, 27(10):1579. tivity to radiation, even if no study has been published 12. McCammon R, Schefter TE, Gaspar LE, Zaemisch R, Gravdahl D, Kavanagh B: to prove it. This suggests that SBRT should perhaps be Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy. Int J Radiation Oncology* used as a local treatment for metastases before the ad- Biology* Physics 2009, 73(1):112–118. ministration of several systemic therapies. 13. Salama JK, Hasselle MD, Chmura SJ, Malik R, Mehta N, Yenice KM, et al: Stereotactic bodyradiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of Conclusion metastatic disease. Cancer 2012, 118(11):2962–2970. Ablative SBRT for liver and lung metastases achieves 14. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M: Stereotactic high 1- and 2-year local control rates, while minimal radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. Int J and invasive. Toxicitiy was very low consisting mainly of Radiat Oncol Biol Phys 2004, 60(1):186–196. grade 1 and 2 nausea. The results indicate that ablative 15. Siva S, MacManus M, Ball D: Stereotactic radiotherapy for pulmonary SBRT is a promising option even for pre-treated patients oligometastases: a systematic review. J Thorac Oncol 2010, 5(7):1091. 16. Ricardi U, Filippi AR, Guarneri A, Ragona R, Mantovani C, Giglioli F, et al: with oligometastases.. Comparative studies are needed to Stereotactic body radiation therapy for lung metastases. Lung Cancer better assess this issue. 2012, 75(1):77–81. 17. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, et Competing interests al: Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy Radiation Therapy Department received a research grant from Accuray. for Liver Metastases. Journal ofClinical Oncology 2009, 27(10):1572–1578. avr 1. 18. Lee MT, Kim JJ, Dinniwell R, Brierley J, Lockwood G, Wong R, et al: Phase I Authors' contributions study of individualized stereotactic body radiotherapy of liver IF, XM and EL conceived the study. IF collected data and drafted the metastases. J Clin Oncol 2009, 27(10):1585. manuscript .JEB, SD, HJ, BP, TL, XM and EL participated in coordination and helped to draft the manuscript. AK performed the statistical analyses. EL doi:10.1186/1748-717X-7-164 provided mentorship and edited the manuscript. All authors have read and Cite this article as: Fumagalli et al.: A single-institution study of approved the final manuscript. stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases. Radiation Oncology 2012 7:164. Author details Radiation Therapy Department, Oscar Lambret Comprehensive Center Lille, 3 rue Combemale, Lille cedex 59020, France. Biostatistics Department, Oscar Lambret Comprehensive Cancer Center, Lille, France. Medical Imaging Department, Oscar Lambret Comprehensive Cancer Center, Lille, France. Received: 12 June 2012 Accepted: 22 September 2012 Published: 27 September 2012 References 1. Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, et al: Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001, 19(1):164. 2. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE: A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J RadiationOncology* Biology* Physics 2005, 62(5):1371–1378. 3. Timmerman R, Papiez L, McGarry R, Likes L, DesRosiers C, Frost S, et al: Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003, 124(5):1946–1955. 4. Schefter TE, Kavanagh BD, Raben D, Kane M, Chen C, Stuhr K, et al: A phase I/II trial of stereotactic body radiation therapy (SBRT) for lung metastases: Initial report of dose escalation and early toxicity. Int J Radiat Submit your next manuscript to BioMed Central Oncol Biol Phys 2006, 66(4):S120–S127. 5. Hellman S, Weichselbaum RR: Oligometastases. JClinOncol 1995, 13(1):8–10. and take full advantage of: 6. Milano MT, Katz AW, Zhang H, Okunieff P: Oligometastases Treated With Stereotactic Body Radiotherapy: Long-Term Follow-Up of Prospective • Convenient online submission Study. Int J RadiationOncology, Biology, Physics 2012, 83(3):878–886. • Thorough peer review 7. Macdermed DM, Weichselbaum RR, Salama JK: A rationale for the targeted treatment ofoligometastases with radiotherapy. J Surg Oncol 2008, • No space constraints or color figure charges 98(3):202–206. • Immediate publication on acceptance 8. Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, et al: • Inclusion in PubMed, CAS, Scopus and Google Scholar Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol 2006, 45(7):808–817. • Research which is freely available for redistribution 9. Kavanagh BD, McGarry RC, Timmerman RD: Extracranial Radiosurgery (Stereotactic Body RadiationTherapy) for Oligometastases. Semin Radiat Submit your manuscript at Oncol 2006, 16(2):77–84. avr. www.biomedcentral.com/submit http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Radiation Oncology Springer Journals

A single-institution study of stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases

Download PDF
8 pages

Loading next page...
 
/lp/springer-journals/a-single-institution-study-of-stereotactic-body-radiotherapy-for-KgWFSWlMNH

References (35)

Publisher
Springer Journals
Copyright
Copyright © 2012 by Fumagalli et al.; licensee BioMed Central Ltd.
Subject
Medicine & Public Health; Oncology; Radiotherapy
eISSN
1748-717X
DOI
10.1186/1748-717X-7-164
pmid
23014094
Publisher site
See Article on Publisher Site

Abstract

Purpose: The purpose of this study is to evaluate the feasibility, efficacy and toxicity of SBRT for treatment of unresectable hepatic or lung metastases regardless of their primary tumor site for patients who received prior systemic chemotherapy. Methods and materials: Between July 2007 and June 2010, 90 patients were treated with the CyberKnife SBRT system for hepatic or pulmonary metastatic lesions. Medical records were retrospectively reviewed. The endpoints of this study were local control, overall survival (OS), disease-free survival (DFS), local relapse free-survival (LRFS), and treatment toxicity. Results: A total of 113 liver and 26 lung metastatic lesions in 52 men (58%) and 38 women (42%) were treated. Median follow-up was 17 months. Median age at treatment was 65 years (range, 23–84 years). Primary cancers were 63 GI, three lung, eight breast, four melanoma, three neuro-endocrine tumors, and three sarcomas. Median diameter of the lesions was 28 mm (range, 7–110 mm) for liver and 12.5 mm (range, 5–63.5 mm) for lung. Local control rates at 1 and 2 years were 84.5% and 66.1%, respectively. Two-year overall survival rate was 70% (95% CI: 55–81%). The 1 and 2-year disease-free survival rates were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), respectively. Median duration of disease-free survival was 6.7 months (95% CI: 5.1–9.5 months). Observed toxicities included grade 1–3 acute toxicities. One grade 3 and no grade 4 toxicity were reported. Conclusion: High-dose SBRT for metastatic lesions is both feasible and effective with high local control rates. Overall survival is comparable with other available techniques. Treatment is well tolerated with low toxicity rates. It could represent an interesting treatment option for oligometastatic patients not amenable to surgery, even when patients had been pre-treated with chemotherapy. Summary: Stereotactic body radiotherapy (SBRT) has previously been successfully used in the treatment of metastatic lesions. It could be considered as a curative option for oligometastatic patients. This retrospective study involved 90 patients, designed to test potential effectiveness of SBRT in the treatment of oligometastases irrespective of primary. Results suggest SBRT could be an effective treatment extending patients’ life span. This treatment appears to be more effective when used prior to multiple systemic treatment regimens. Keywords: SBRT, Liver metastasis, Lung metastasis, Oligometastases, CyberKnife * Correspondence: e-lartigau@o-lambret.fr Radiation Therapy Department, Oscar Lambret Comprehensive Center Lille, 3 rue Combemale, Lille cedex 59020, France Full list of author information is available at the end of the article © 2012 Fumagalli et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Fumagalli et al. Radiation Oncology 2012, 7:164 Page 2 of 8 http://www.ro-journal.com/content/7/1/164 Introduction lesions. Clinical data on 90 patients presenting with 113 Over the past decade, stereotactic body radiation therapy hepatic and 26 lung metastases were collected and ana- (SBRT) has emerged as an alternative treatment option lyzed. Patients and tumor characteristics are presented for patients with liver [1,2] and lung [3,4] lesions. The in Table 1. Treatment response was assessed using the term "oligometastases" was first described by Hellman RECIST 1.1 criteria. Toxicity was evaluated with the and Weichselbaum [5] in 1995 as a less-advanced state CTCAE v4.0. Written informed consent was obtained of metastatic disease amenable to and potentially curable from the patient for publication of this report in accord- with local therapy. The term "oligometastases" is most ance with the guidelines of the French National Cancer often used to describe five or fewer metastatic lesions Institute (Institut National du Cancer) required when [6]. Often, this pathology has a slow rate of progression, assessing the efficacy and toxicity of a novel therapy, justifying focal treatments. Main therapeutic options for oligometastases remain Methods surgery or radiofrequency. Due to its high level of preci- SBRT was delivered with Cyberknife, an integrated sion which allows hypofractionnation, SBRT has gained image-guided frameless stereotactic radiation therapy interest as a curative treatment option for inoperable system. It is comprised of a robotic arm coupled with a patients with lung cancer, liver tumors, or oligometas- compact 6-MV X-Ray linear accelerator and a real-time tases. The concept of local treatment for oligometastatic imaging system. Different collimators with diameters lesions exists since only a few years [7-9] Researchers ranging from 5–60 mm are used with the linac. Two X- have reported encouraging data for liver metastases trea- Ray tubes are positioned in the treatment room at a 45° ted with SBRT. Katz et al. [10] have reported a local con- angle. Images created are registered to the treatment- trol rate of 76% and 57% at 10 and 20 months, planning console. This system detects a difference of respectively, with 69 patients. For lung metastases, 0.06 mm in translation and rotation. For liver metasta- Rusthoven et al. have reported local control rates of ses, all patients were treated with the Synchrony Re- 100% and 96% at 1 and 2 years, respectively [11]. SBRT spiratory Tracking System. Four gold fiducial markers can be delivered without tumor tracking using a stereo- were inserted around the lesion 2 weeks before the treat- tactic frame or the breath-hold technique, or most re- ment planning. For lung metastases, patients could be cently, with a real-time tumor tracking system, which is treated with either Xsight Lung Tracking System available with the CyberKnife System (Accuray Incor- (Accuray) or, using an internal target volume (ITV), with porated, Sunnyvale, CA). Most studies have reported Xsight Spine Tracking System (Accuray). These track- results from treatments delivered without tracking [12]. ing methods did not require the implantation of fiducial With real-time tracking, patients can breathe freely dur- markers. For the planning computed tomography (CT) ing treatment sessions. study, patients were immobilized in an external vacuum- Milano reported a study of 121 patients with oligome- type body mold. An abdominal belt could be used for tastases from any site analyzing survival and tumor con- liver lesions in order to decrease respiration amplitudes. trol with encouraging results [6]. Bone metastases A 4D CT-scan was performed for patients with liver appeared to be associated with a fourfold reduced hazard or lung metastases, respectively, with a 1-mm slice thick- of death. To our knowledge, no previous study has been ness and reconstruction in 3-mm slices. For the lung reported with this technique of SBRT for a pooled ana- patients tracked with Xsight Spine, ITV was defined lysis of lung and liver metastases. using the data from the 4D CT-Scan performed for We report a retrospective study of 90 patients with treatment planning. For patients treated with tumor 139 visceral oligometastases (lung or liver), regardless of tracking, GTV was contoured. GTV or ITV was the primary analyzing overall survival, local control and expanded by 5 mm to create the clinical tumor volume relapse free survival. (CTV). CTV was expanded by 3 mm to obtain the plan- ning target volume (PTV). SBRT planning was per- Patients and methods formed with Accuray’s Multiplan treatment planning Patients software. Dose was prescribed to the 80% isodose line Patients treated between July 2007 and June 2010 were and delivered to the target volume over a mean duration included and medical records were retrospectively of 8 days (range, 3–22 days). The median fractionnation reviewed. Patients with oligometastases (1 to 5 lesions) scheme was three fractions of 15 Gy (range, 9–20 Gy). from any primary site and not amenable to surgery, due Critical organ dose constraints are detailed in Table 2. most of the time to anesthesia were eligible. Other inclu- sion criteria were a Performance Status >3 (WHO scale), Follow-up number of hepatic or lung lesions <5, and lesion size All patients were seen every 3 months with a new CT- <100 mm for hepatic metastases and <70 mm for lung Scan. Treatment response was evaluated every 3 months Fumagalli et al. Radiation Oncology 2012, 7:164 Page 3 of 8 http://www.ro-journal.com/content/7/1/164 Table 1 Patient characteristics Table 1 Patient characteristics (Continued) Patients Total (n = 90) % Yes 15 18% Gender: Female 38 42% More than 3 chemotherapy 26,6% regimens before SBRT : Male 52 58% Hepatic lesions (n = 75) 21 28% Age at diagnostic, median (range): 62 years (22–82) Lung lesions (n = 15) 3 20% Age at SBRT, median (range): 65 years (23–84) Primary sites: Digestive 63 70% using the RECIST 1.1 criteria: complete response (CR) Lung 3 3.3% defined as complete disappearance of tumor or only fi- Breast 8 8.9% brosis in the image, partial response (PR) defined as Melanoma 4 4.4% tumor shrinkage of at least 30%, stable disease (SD) Neuro-endocrine 3 3.3% defined as no radiologically measurable difference and Sarcoma 3 3.3% progressive disease (PD) defined as a tumor increase of Other 6 6.7% at least 20%. Local control was defined as CR, PR, or SD during follow-up based on imaging. Acute toxicity was Adenocarcinoma Histology: Hepatic (n = 75) 61 81% evaluated using CTCAE v4. Lung (n = 15) 7 47% Primary for Adenocarcinoma histology 68 Statistics Colorectal 57 84% Descriptive statistics were used for categorical variables Breast 8 12% (frequency and percentage) and continuous variables Gastric 1 1.5% (median and range). The following variables were ana- Lung 1 1.5% lyzed: age, gender, primary site, histology, previous local Kidney 1 1.5% or systemic treatment, time from initial diagnosis to first metastasis, time from the diagnosis of the first metasta- Primary for squamous cell histology : 7 sis to SBRT, total dose received, number of fractions, Esophagus 5 71% dose per fraction, size of the target lesions, and treat- Lung 2 29% ment time. All time to event endpoints were calculated Other histologies : 15 17% from the initiation of treatment. Overall survival Lesions : Lung 15 17% included death from any cause. Disease-free survival Hepatic 75 83% counted events as a progression of an existing target le- sion, appearance of new lesions within the same organ Number of lesions treated by patient : 1 64 71% Table 2 Critical organ constraints 2 19 21% Constraints 34 4% Liver metastases Normal liver V21 < 33% 43 3% V15 < 50% Timing of Metastases: stomach V21 < 5 cm At initial diagnostic 43 49% Spinal cord maximal dose < 22 Gy Within one year 20 23% Kidney V 15 < 33% More than 1 year 25 28% Lung metastases normal lung (= volume of V5 < 50% Time from diagnosis of metastasis to 25.6 months (1.2 – 93.6) right + left lung – PTV) SBRT treatment, median (range) V10 < 30% Previous local treatment : One lung V 20 < 20% Hepatic (n = 75) 53 71% Heart V24 < 15 cm Lung (n = 15) 0 0% Dmax < 30 Gy Prior chemotherapy: 91% trachea and principal bronchi V 15 < 4 cm Hepatic lesions (n = 75) 70 93% V20<1cm Lung lesions (n = 15) 12 92% Dmax < 30 Gy Prior progressive disease with Chemo: esophagus V 21 < 5 cm No 67 82% Dmax < 25 Gy Fumagalli et al. Radiation Oncology 2012, 7:164 Page 4 of 8 http://www.ro-journal.com/content/7/1/164 Table 3 Characteristics and response of metastatic lesions (liver or lung), distant relapse, or death due to cancer, whichever occurred first. Local failure included events Lesions Total (n = 139) % involving pre-existing treated lesions only. Survival rates Number of lesions: were estimated by the Kaplan-Meier method and groups Hepatic metastases 113 81% were compared with the logrank test. P values smaller Lung metastases 26 19% than 0.05 were considered statistically significant. Lesion diameter, median (range): Liver (n = 111) 28 mm (range 7–100) Results Patient characteristics Lung (n = 26) 12.5 mm (range 5–63.5) Ninety patients were treated (52 male and 38 female). Previous local treatment to 68 60% hepatic lesions Median age at diagnosis was 62 (range, 22–82) and me- dian age at the time of SBRT was 65 (range 23–84). Local hepatic treatment: Seventy-one percent of patients had only one metastatic Surgery of same lesion 2 2% lesion. No patient had both liver and lung lesions. Surgery of other lesions 49 44% Histologies of the metastatic lesions were: 68 adenocar- Chemo-embolisation 3 3% cinomas including 57 colorectal tumors, eight breast Radio-frequency 14 12% tumors, one stomach cancer, one lung, and one kidney Response (RECIST) cancer case; seven squamous-cell carcinomas from esophagus and lung; and 15 other histologies [four mela- Hepatic metastases nomas, three neuro-endocrine tumors, three sarcomas, CR 56 51% one GIST (gastro-intestinal stromal tumor), one papil- PR 22 20% lary thyroid tumor, one pneumoblastoma, one adenoid SD 10 9% cystic cancer, two small-cell lung cancers]. Forty-nine PD 22 20% percent of the patients had metastases at the time of ini- Response tial diagnosis. Median time from diagnosis of metastases to start of CyberKnife treatment was 25.6 months Lung metastases (range, 1.2–93.6 months). Eighty-five percent of patients CR 14 58% had received prior chemotherapy; 93% and 92% of liver PR 2 8% and lung patients, respectively. Twenty-seven percent of SD 1 4% patients treated with SBRT had received more than three PD 7 29% cycles of chemotherapy prior to CyberKnife, 28% and Response 21% of liver and lung patients, respectively. No patients had received prior radiotherapy.( Table 1) All lesions There were 113 hepatic and 26 lung metastatic lesions CR 70 52% (Table 3). Median lesion diameter was 28 mm (range, 7– PR 24 18% 100) for liver and 12.5 mm (range, 5–63.5) for lung. CR SD 11 9% rate was 52%, PR 18%, SD 8%, and PD 22%. Except for PD 29 20% one patient, none of the patients with lung metastases had any previous local treatment compared to the 53/75 (71%) patients with 68/113 (69%) hepatic metastases for a liver metastasis for a total dose of 54 Gy due to the who were previously treated locally with surgery to the duodenum proximity. All patients received a total dose treated lesion (2%), surgery to other lesions (44%), chemo- of 27–60 Gy (median dose, 45 Gy). Median treatment embolization (3%), or radio frequency ablation (12%). time was 8 days (range, 3–22) ( Table 4). Treatment was delivered in two weeks, with a session being performed Treatment characteristics every 2 or 3 days. Fifty eight patients were treated with three fractions of 9 Gy (1.1%), 10 Gy (2,2%); 12 Gy (3.3%), 13 Gy (2.2%), 15 Gy (53.3%), or 20 Gy (2.2%) times (Table 4). The Treatment efficacy 20 Gy per fraction regimen was only administered for Median follow up was 17 months ( 95%CI 14-21). The lung metastases. Thirty patients (35.6%), were treated overall response rate was complete for 52% of the with 4 fractions of 10 Gy. One patient was treated with lesions, partial for 20%, stable for 9%, and progressive six fractions of 6 Gy for a total dose of 36 Gy to a lung for 20% of the lesions. Results were similar for hepatic metastasis because of the central localization of the le- and lung lesions. At last follow-up, 21 patients had died sion and one patient was treated with 6 fractions of 9 Gy and 17 patients were disease-free. The local control rate Fumagalli et al. Radiation Oncology 2012, 7:164 Page 5 of 8 http://www.ro-journal.com/content/7/1/164 Table 4 Cyberknife treatment characteristics (by patients) to 89% for other histologies at 1 year and 59% at 2 years Patients Hepatic (n = 75) Lung (n = 15) All Patients compared to 80% for other histologies. Regarding disease- (n = 90) free survival, patients with lung lesions were at a lower Dose per fractions, n (%) risk of failure than patients with hepatic lesions: HR = 0.47 (95% CI: 0.23–0.95, p = 0.02). Patients with a history of re- 6 0 1 1 (1,1%) ceiving chemotherapy were at higher risk of failure com- 9 2 0 2 (2,2%° pared to those without: HR = 4.51 (95% CI: 1.10–18.47, 10 31 (41%) 1 32 (35,6%) p = 0.007) (Table 5). Other factors such as progressive dis- 12 3 0 3 (3,3%) ease following earlier chemotherapy, more than three pre- 13 2 0 2 (2,2%) vious chemotherapy regimens, and time between diagnosis 15 37 (49%) 11 (73%) 48 (53,3%) of the first metastasis and treatment by SBRT were not found to be prognostic for disease-free survival. As far as 20 0 2 2 (2,2%) local control is concerned, female patients had a tendency Total dose, n (%) for lower risk of local failure: HR = 0.48 (95% CI: 0.21–1.10, 27 1 0 1,1% p = 0.07). No factor had any impact on overall survival. 30 2 0 2,2% 36 3 1 4,4% Discussion 39 2 0 2,2% The concept of oligometastasis Oligometastasis is an emerging paradigm in oncology. It is 40 29 (39%) 1 30 (33,3%) described as a distant extension of a primary cancer with 45 37 (49%) 11 (73%) 48 (53,3%) an isolated site or less than five sites of metastases [6]. 54 1 0 1,1% Oligometastases could be seen as clinical manifestations 60 0 2 2,2% of a systemic disease requiring systemic treatment. But Treatment duration, 8 days(3 – 22) they can also be considered as consequences of a slow, median (range) controllable disease progression, curable with local treat- ments. Local treatments include surgery, radiofrequency, at 1 and 2 years were 84.5% and 66.1%, respectively conformal or stereotactic body radiation therapy. The use (Figure 1A). The 1 and 2-year disease-free survival rates of SBRT has seen rapid growth as a noninvasive treatment were 27% (95% CI: 18–37%) and 10% (95% CI: 4–20%), modality and provides a new treatment alternative for in- respectively (Figure 1B). Median duration of disease-free operable or elderly patients. Salama and al. [13] recently survival was 6.7 months (95% CI: 5.1–9.5 months). The published a dose escalation trial in patients with 1 to 5 2-year overall survival rate was 70% (95% CI: 55–81%) metastases in SBRT. Maximal dose was 48 Gy but the (Figure 1C). maximal dose tolerated was not reached. 2 year overall survival rate was 56.7% and progression free survival rate Toxicity were 33.3% and 22% at one and two years respectively. Side effects were generally mild. Observed toxicites ranged Our progression-free survival rate were lower but we fo- from grade 1 to 2 in the CTCAE v.4. Toxicity for patients cused our study on patients with visceral metastasis, which treated for hepatic lesions consisted mainly of digestive might explain this difference. Indeed in the study pub- adverse events : we recorded 19 nausea (17%), 10 vomiting lished by Salama et al., 13.3% of patients had only bone (9%), three gastritis (2,5%), three anorexia (2,5%), 17 hep- metastases, which could be a factor of better prognosis, as atic pain (15%) and 9 asthenia. (8%) Toxicity for patients Milano et al. have shown [6]. treated for lung lesions was lower, consisting mainly of as- thenia (5 = 19%) radiation pneumonitis (5 = 19%) and Treatment efficacy and predictive factors pleural effusion (3 = 11,5%). We encountered two grade 3 Several studies have been published on different SBRT toxicities : one gastritis in a patient with a hepatic lesion methods. Most of them report about primary and sec- and one epidermitis in a patient treated for two different ondary lesions without distinction [12,14]. Rusthoven hepatic lesions. et al. have reported 47 patients with 63 hepatic lesions. Among the patients, 69% had received at least one prior Univariate analysis systemic therapy regimen for metastatic disease (zero to Regarding local control, neither tumor size nor dose was five regimens) and 45% had extrahepatic disease at study found to be statistically significant. Adenocarcinoma entry. Actuarial in-field local control rates at one and appeared to present a higher risk of failure than other two years after SBRT were 95% and 92%, respectively. histologies: HR = 2.74 (95% CI: 0.95–7.88, p = 0.036). These rates are better than those reported in our study. Control local rate was 82% for adenocarcinoma compared This could be explained by the fact that the Rusthoven Fumagalli et al. Radiation Oncology 2012, 7:164 Page 6 of 8 http://www.ro-journal.com/content/7/1/164 Local Relapse-Free Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Target lesions 139 112 71 37 19 9 4 B Disease free survival Disease-Free Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Patients 90 51 20 6 5 3 2 C Overall survival Overall Survival Cyberknife treatment 1.00 0.75 0.50 0.25 0.00 0 6 12 18 24 30 36 Months Number at risk Patients 90 76 60 34 21 14 7 Figure 1 Kaplan-Meier Survival curves. A. Local relapse-free survival. B. Disease-free survival. C. Overall survival. Probability Probability Probability Fumagalli et al. Radiation Oncology 2012, 7:164 Page 7 of 8 http://www.ro-journal.com/content/7/1/164 Table 5 Predictive factors for disease free survival 20 Gy x 3 while only 37/75 patients with liver tumors DFS received 15 Gy x 3 and all the rest received lower doses. Another explanation could be that the lesions' median Patients HR : (95% CI) (p) diameter for lung metastases was 12.5 mm versus Gender: Female 1.17: (0.74 – 1.86) 0.51 28 mm for hepatic lesion. Our univariate analysis did Age at SBRT 65+ 0.72: (0.46 – 1.15) 0.17 not find a difference in local control based on the pri- Adenocarcinoma Histology: 1.28 : (0.75 – 2.19) 0.36 mary tumor site, suggesting that SBRT could be used to Lesions : pulmonary 0.47 : (0.23 – 0.95) 0.02 treat oligometastases from any primary. Still, according Number of lesions : 3+ 1.17 : (0.70 – 1.98) 0.55 to other studies, the role of the primary tumor site in the case of liver metastases remains unclear [18]. Lee Number of hepatic lesions : 3+ 1.40 : (0.79 – 2.48) 0.25 and al. didn't find a difference in overall survival be- Timing of Metastases: < one year 0.67: (0.37 - 1.22) 0.19 tween colorectal, breast and other primaries of metasta- More than 1 year 1.04: (0.60 – 1.79) 0.90 ses treated (respectively 63% (95% CI, 44% to 78%), 79% Prior chemotherapy 4.51: (1.10 – 18.47) 0.007 (95% CI, 36% to 94%), and 38% (95% CI, 14% to 62%). 3+ chemotherapies before SBRT : 1.20: (0.63 – 2.25) 0.59 Dose, within dose range used in this study, did not ap- Prior PD with previous CT 1.31: (0.74 – 2.32) 0.37 pear to be a factor in disease-free or overall survival. Al- though, this result has been confirmed in other studies. study contained only liver patients and 31% of them had McCammon et al. and al [12] found that increased dose not received any chemotherapy before SBRT. There are and smaller gross tumor volume were significant predic- also few data on lung metastases. Studies report local tors of higher local control rates. Their patients treated control rates from 72–100% at 1 year and from 78–96% with 54 Gy or more had a 3-year actuarial local control at 2 years [11,14-16]. rate of 89.3% compared with 59.0% and 8.1% for those Our study evaluated feasibility of SBRT on hepatic and treated with 36–53.9 Gy and less than 36 Gy. The opti- pulmonary oligometastatic lesions from a multitute of mal treatment dose has not been defined yet and should primaries. Local control rates at 1 and 2 years were, re- be the subject of future studies. spectively, 84.5% and 66.1%. These results are similar to other SBRT reports on liver metastases in which 1-year Toxicity local control rates ranged from 71–100% and 2-year In our study, treatment was well tolerated. There were rates from 30–92% [1,17,18]. In our cohort, 49% of the no grade 4 events and only one case of grade 3 gastritis patients had metastases at initial diagnosis. This fact and epidermitis. All of the other events were grades 1 or may have affected our results because of the prognosis 2. The most common acute toxicities were nausea and of such disease that is often considered more aggressive. pain at the time of treatment. None of the toxicities pre- Adenocarcinoma displayed worse prognosis than other vented any patient from completing the treatment and histologies: HR = 2.74 (95% CI: 0.95–7.88), p =0.036. were transitory. Rusthoven et al. have reported similar This could suggest that a more potent dosing regimen results with also one grade 3 event and no grade 4 should be employed when treating metastases with events [17]. Lee et al. have reported two cases of grade 3 adenocarcinoma pathology. Indeed, dose has not been liver enzymes-related toxicities and six acute grade 3 shown as a predictive factor and treatment was well tol- toxicities in the form of two case of gastritis, two cases erated. This is probably also related to the localisation of nausea, one lethargia, and one thrombocytopenia [18]. the treated lesions. Majority of adenocarcinoma metasta- They also had one grade 4 toxicity in the form of ses were hepatic lesions as opposed to being lung thrombocytopenia. A longer follow-up period is neces- lesions. These results were based on a sub-group ana- sary to detect potential long-term toxicities. lysis and care needs to be taken in the interpretation. Regarding disease-free-survival, patients with lung SBRT and previous chemotherapy regimens lesions were at lower risk of failure than those with hep- We wondered whether or not pre-treated patients with atic lesions (HR = 0.47, 95% CI: 0.23–0.95, p = 0.02). As metastatic disease could benefit from SBRT. Most of our there is no previous study comparing lung and hepatic patients had received prior chemotherapy (91%), with a metastases treated with SBRT, this result appears to be a high number of chemotherapy regimens, 27% of them new finding to take into account when considering receiving more than three regimens, which may have SBRT as a treatment option. However, number of lung increased the radioresistance of the metastases. We lesions was lower than number of liver lesions Fur- found that a patient’s history of prior chemotherapy was thermore, the total dose and fractionnation were differ- a major risk factor in recurrence outside the treatment ent between lung and hepatic tumors. 11/15 patients volume (HR = 4.51, 95% CI: 1.10–18.47, p = 0.007). Also, with lung tumors received 15 Gy x 3 and 2/15 received the number of previous chemotherapy regimens Fumagalli et al. Radiation Oncology 2012, 7:164 Page 8 of 8 http://www.ro-journal.com/content/7/1/164 administered or progression while receiving chemother- 10. Katz AW, Carey-Sampson M, Muhs AG, Milano MT, Schell MC, Okunieff P: Hypofractionated stereotactic body radiation therapy (SBRT) for limited apy significantly correlates with a higher risk of failure. hepatic metastases. International Journal ofRadiation Oncology* Biology* One hypothesis that could explain this finding could be Physics 2007, 67(3):793–798. that the previous chemotherapy regimens, received by 11. Rusthoven KE, Kavanagh BD, Burri SH, Chen C, Cardenes H, Chidel MA, et al: Multi-institutional phase I/II trial of stereotactic body radiation therapy the patients, selected tumoral clones with a lower sensi- for lung metastases. J Clin Oncol 2009, 27(10):1579. tivity to radiation, even if no study has been published 12. McCammon R, Schefter TE, Gaspar LE, Zaemisch R, Gravdahl D, Kavanagh B: to prove it. This suggests that SBRT should perhaps be Observation of a dose-control relationship for lung and liver tumors after stereotactic body radiation therapy. Int J Radiation Oncology* used as a local treatment for metastases before the ad- Biology* Physics 2009, 73(1):112–118. ministration of several systemic therapies. 13. Salama JK, Hasselle MD, Chmura SJ, Malik R, Mehta N, Yenice KM, et al: Stereotactic bodyradiotherapy for multisite extracranial oligometastases: Final report of a dose escalation trial in patients with 1 to 5 sites of Conclusion metastatic disease. Cancer 2012, 118(11):2962–2970. Ablative SBRT for liver and lung metastases achieves 14. Wulf J, Haedinger U, Oppitz U, Thiele W, Mueller G, Flentje M: Stereotactic high 1- and 2-year local control rates, while minimal radiotherapy for primary lung cancer and pulmonary metastases: a noninvasive treatment approach in medically inoperable patients. Int J and invasive. Toxicitiy was very low consisting mainly of Radiat Oncol Biol Phys 2004, 60(1):186–196. grade 1 and 2 nausea. The results indicate that ablative 15. Siva S, MacManus M, Ball D: Stereotactic radiotherapy for pulmonary SBRT is a promising option even for pre-treated patients oligometastases: a systematic review. J Thorac Oncol 2010, 5(7):1091. 16. Ricardi U, Filippi AR, Guarneri A, Ragona R, Mantovani C, Giglioli F, et al: with oligometastases.. Comparative studies are needed to Stereotactic body radiation therapy for lung metastases. Lung Cancer better assess this issue. 2012, 75(1):77–81. 17. Rusthoven KE, Kavanagh BD, Cardenes H, Stieber VW, Burri SH, Feigenberg SJ, et Competing interests al: Multi-Institutional Phase I/II Trial of Stereotactic Body Radiation Therapy Radiation Therapy Department received a research grant from Accuray. for Liver Metastases. Journal ofClinical Oncology 2009, 27(10):1572–1578. avr 1. 18. Lee MT, Kim JJ, Dinniwell R, Brierley J, Lockwood G, Wong R, et al: Phase I Authors' contributions study of individualized stereotactic body radiotherapy of liver IF, XM and EL conceived the study. IF collected data and drafted the metastases. J Clin Oncol 2009, 27(10):1585. manuscript .JEB, SD, HJ, BP, TL, XM and EL participated in coordination and helped to draft the manuscript. AK performed the statistical analyses. EL doi:10.1186/1748-717X-7-164 provided mentorship and edited the manuscript. All authors have read and Cite this article as: Fumagalli et al.: A single-institution study of approved the final manuscript. stereotactic body radiotherapy for patients with unresectable visceral pulmonary or hepatic oligometastases. Radiation Oncology 2012 7:164. Author details Radiation Therapy Department, Oscar Lambret Comprehensive Center Lille, 3 rue Combemale, Lille cedex 59020, France. Biostatistics Department, Oscar Lambret Comprehensive Cancer Center, Lille, France. Medical Imaging Department, Oscar Lambret Comprehensive Cancer Center, Lille, France. Received: 12 June 2012 Accepted: 22 September 2012 Published: 27 September 2012 References 1. Herfarth KK, Debus J, Lohr F, Bahner ML, Rhein B, Fritz P, et al: Stereotactic single-dose radiation therapy of liver tumors: results of a phase I/II trial. J Clin Oncol 2001, 19(1):164. 2. Schefter TE, Kavanagh BD, Timmerman RD, Cardenes HR, Baron A, Gaspar LE: A phase I trial of stereotactic body radiation therapy (SBRT) for liver metastases. Int J RadiationOncology* Biology* Physics 2005, 62(5):1371–1378. 3. Timmerman R, Papiez L, McGarry R, Likes L, DesRosiers C, Frost S, et al: Extracranial stereotactic radioablation: results of a phase I study in medically inoperable stage I non-small cell lung cancer. Chest 2003, 124(5):1946–1955. 4. Schefter TE, Kavanagh BD, Raben D, Kane M, Chen C, Stuhr K, et al: A phase I/II trial of stereotactic body radiation therapy (SBRT) for lung metastases: Initial report of dose escalation and early toxicity. Int J Radiat Submit your next manuscript to BioMed Central Oncol Biol Phys 2006, 66(4):S120–S127. 5. Hellman S, Weichselbaum RR: Oligometastases. JClinOncol 1995, 13(1):8–10. and take full advantage of: 6. Milano MT, Katz AW, Zhang H, Okunieff P: Oligometastases Treated With Stereotactic Body Radiotherapy: Long-Term Follow-Up of Prospective • Convenient online submission Study. Int J RadiationOncology, Biology, Physics 2012, 83(3):878–886. • Thorough peer review 7. Macdermed DM, Weichselbaum RR, Salama JK: A rationale for the targeted treatment ofoligometastases with radiotherapy. J Surg Oncol 2008, • No space constraints or color figure charges 98(3):202–206. • Immediate publication on acceptance 8. Okunieff P, Petersen AL, Philip A, Milano MT, Katz AW, Boros L, et al: • Inclusion in PubMed, CAS, Scopus and Google Scholar Stereotactic body radiation therapy (SBRT) for lung metastases. Acta Oncol 2006, 45(7):808–817. • Research which is freely available for redistribution 9. Kavanagh BD, McGarry RC, Timmerman RD: Extracranial Radiosurgery (Stereotactic Body RadiationTherapy) for Oligometastases. Semin Radiat Submit your manuscript at Oncol 2006, 16(2):77–84. avr. www.biomedcentral.com/submit

Journal

Radiation Oncology – Springer Journals

Published: Sep 27, 2012

There are no references for this article.