Stereotactic body radiotherapy (sbrt) in lung oligometastatic patients: role of local treatments

The management for patients with metastatic disease has always been focused on the use of systemic therapy alone; this potentially allows to treat microscopic metastatic tumor but generally is unable to eradicate gross tumor sites. Local therapies, although effective against single lesion tumors, have been used with palliative intent in these settings of patients. In the recent years a new evidence emerged about the existence of an intermediate condition between localized and widespread systemic disease. In 1995 Hellman and Weichselbaum first proposed the idea of an oligometastatic disease [1], in which metastases are limited in number and site. They suggested that local treatment through reduction of the tumor burden might bring to a better control of disease with consequent lengthening of lifetime. In this “scenario” local approaches, surgery or stereotactic ablative radiation therapy, have been increasingly utilized mostly for the treatment of lung and liver metastases [2, 3]. Although surgery is the main modality used [4, 5], more recently Stereotactic Body RadioTherapy (SBRT) is emerging as an effective alternative for patients unsuitable for surgery. This approach enables the delivery of a limited number of ablative doses with highly conformal techniques and maximum healthy tissue sparing. Retrospective and prospective reports SBRT allowed to achieve excellent local control (LC), more than 90% in some series, to delay progression, and to decrease the subsequent need of further chemotherapy treatments [5‐9]. In this study a set of oligometastatic patients treated with Intensity Modulated Radiation Therapy (IMRT) using Volumetric Modulated Arc Therapy (VMAT) in the RapidArc form (RA) for lung metastases from different solid tumors was reviewed. The aim of this study was to evaluate toxicity, local control and survival.

In Figure 1, an example of dose distribution in one of our patients is shown, providing a qualitative overview of the target coverage and dose fall off outside the PTV. Similar results were obtained for the other patients.

A total of 118 lesions were treated in 76 patients. In 27/76 patients (36%) more than one lung metastases was irradiated. Dose prescription varied according to lesions site, peripheral or central, and volume: 48 Gy/12 Gy fraction in 95 lesions (80.5%); 60 Gy/7.5 Gy fraction in 16 lesions (13.5%), and 60 Gy/20 Gy fraction in 7 lesions (6%) as shown in Table 1. All patients completed the planned treatment. The 6 patients in the cohort who were affected by synchronous metastases in the lung and in other sites, were treated only for the lung lesions because the disease in the other sites (bones and viscera) was stable and/or asymptomatic.

The treatment for metastatic patients mainly consisted in the use of chemotherapeutic agents; the median survival and the treatment choice depend on several prognostic factors: patients age, PS, primary histology, site and number of metastases. The role of radiation therapy in the management of metastatic disease has been principally limited to palliation but we now have an opportunity to challenge this statement. Probably there is an intermediate state defined by a long latent interval between the treatment of the primary tumour and the appearance of metastases. Hellman and Weichselbaum [1] first proposed the idea of an oligometastatic state in 1995. They suggested that for many cancers a few metastases exist at first, before the malignant cells acquire widespread metastatic potential. Theoretically, if ablative hypofractionated radiation therapy could be delivered during the oligometastatic phase, this might modify disease outcome in patients in which up to now radiotherapy was used only with a palliative intent. The role of SBRT for the treatment of oligometastases was investigated also in other sites, often localized in not-accessible sites, Casamassima [10] investigated SBRT in adrenal gland metastases showing in a retrospective analysis on 48 patients an actuarial local control as great as 90%. Bonomo [11] investigated the role of SBRT in paracardiac metastases (on 16 patients) and demonstrated a crude local control of 75% in this challenging localisation. Experimental data from multiple cancer models have provided sufficient evidence to propose a paradigm shift, since some of the effects of ionizing radiation are recognized to give a contribution to systemic antitumor immunity. Recent examples of objective responses achieved by adding radiotherapy to immunotherapy in metastatic cancer patients support this view. Therefore, the traditional palliative role of radiotherapy in metastatic disease is evolving into that of a powerful adjuvant for immunotherapy [12]. Innovative techniques have revolutionized radiation oncology within the last decade. Using IMRT or VMAT the conformity of the dose to the tumor is increased while sparing of healthy tissue is optimized. More recently, in our experience, RA with FFF beams permits a best treatment. In our series oligometastatic patients with lung metastases from different kind of solid tumors underwent SBRT with RA. Using this approach good results were obtained in terms of local response in most patients, local control rate at 1, 2 and 3 years was 95%, 89% and 89% respectively. These results are comparable with other studies in literature. In Table 3 selected trials of stereotactic body radiation therapy for lung metastases are shown [13‐18]. Le [14] reported the results of a phase II trial using SBRT with a dose of 50 Gy in 10 fractions in the treatment of oligometastatic disease resulting in a 2-year local control rate for all treated lesions of 67%. Several recent reports recorded high rate of OS using SBRT in oligometastatic patients. Norihisa [15] treated 35 patients with one or two lung metastases. The primary site was controlled and there were no other organs involved. The original dose of 48 Gy in four fractions was escalated to 60 Gy in five fractions for 16 patients. Two-year results for overall survival, local control and progression-free survival were 84%, 90% and 35%, respectively. Again, Salama [16] treated 61 patients with 113 metastases performing a dose escalation increasing from 24 Gy in 3 fractions to 48 Gy in 3 fractions. One and 2 year progression free survival were 33.3% and 22%, 1-year and 2-year overall survival were 81.5% and 56.7%. Finally, Rusthoven [17] reported a phase I/II prospective study of SBRT for metastatic lung tumors. Thirty-eight patients with 63 lesions were treated and achieved a 2-year local control rate of 96%, but a 2-year overall survival of only 39%. Also in terms of OS at 1 and 2 years our results are comparable with these series with values of 85% and 66% respectively. Despite the heterogeneous characteristics of oligometastatic patients present both in our data and in other published studies, these findings indicate that the use of SBRT gives an advantage in terms of local control, disease free survival and overall survival to a significant percentage of patients: generally ~ 20% of patients remain disease-free 2–4 years after SBRT [13‐23]. Generally SBRT presents negligible toxicity: the ratio of patients with grade 3 acute or late adverse event is less than 10%; in our series no grade 3 or late toxicity was recorded. Different prognostic factors were analysed, in particular age, sex, primary tumor histology, disease free interval, metastases site, size and number and dose prescription. As shown in several series the following factors significantly affect local control, PFS and OS: some histology of primary tumor (i.e. breast cancer) [24], disease-free interval of more than 12 months [25, 26], target position [17, 27‐29], number (≤3) [16, 30‐32] and size of metastases (smaller than 3 cm) [17, 20, 21, 33‐35], and total delivered dose with biological equivalent dose (BED) larger than 100 Gy₁₀[24‐37]. In our experience, however, no factors statistically affected outcome of patients. This finding is probably related to the characteristics of our series: most patients had unfavourable histology (mostly GI tumor and NSCLC), all had primary tumor controlled with disease free interval greater than 12 months.

We have shown that, in oligometastatic patients with lung metastases, SBRT is feasible with limited morbidity. The clinical results obtained are highly satisfactory. Well-designed collaborative trials, including stratification of patients by histology, are necessary to draw final conclusions, in a multidisciplinary perspective, in this field and to determine whether SABR, with it’s lower morbidity, could be a real alternative to surgery in the treatment of oligometastatic patients.