Introduction
Since the formulation of the concept of oligo-metastatic disease by Hellman in 2005, the existence of an intermediate condition between organ-confined and extensively disseminated malignancy has been debated. Indeed, loco-regional treatment by surgery or radiotherapy might be proposed to metastatic cancer patients with limited disease burden (3–5 metastases) [
1] to avoid or postpone the use of chemotherapy [
2]. This new paradigm of treatment integrated clinical practice in a number of different settings, such as limited liver or lung metastatic involvement from operated primary tumors [
3‐
5], but it is unclear whether this policy could be beneficial in all cases. In particular, appropriate management of isolated lymph node metastasis often result in a dilemma for the clinician due to the high risk of subclinical dissemination along the node chain [
6]. In recent years, stereotactic body radiotherapy (SBRT) emerged as a valuable option in the treatment of oligo-metastatic patients, delivering ablative radiation doses with limited toxicity, but the level of evidence for its applicability in the management of lymph node relapse is still poor. Initial reports showed satisfying local control rates with good to excellent survival, but there is a lack of information on the patterns of disease progression following SBRT [
7]. Therefore, the primary aim of the study was to investigate the locoregional relapse-free survival. Secondary objectives were to investigate general outcome and predictors of disease control in a cohort of oligo-metastatic patients undergoing SBRT for lymph node metastases of treated primary tumors.
Discussion
The hypothesis of our study is that focal treatment by SBRT in oligometastatic patients experiencing limited nodal relapse might be effective in arresting spread to the locoregional drainage and ultimately metastatic dissemination, irrespectively of patient baseline characteristics, prior treatments and primary tumor type. To test these hypothesis we reviewed a large consecutive serie of oligometastatic patients receiving SBRT for lymph nodal relapse after discussion at the Multidisciplinary Tumor Board for miscellaneous tumor types at different time points in the treatment sequence.
We reported the patterns of disease progression, in particular, early relapse to neighboring lymph nodes located on the same chain. This event occurred in the majority of patients at the same time of metastatic relapse to one or more extra-node districts, thus conferring theoretically no additional benefit to a more aggressive alternative approach encompassing the whole lymphatic drainage. On the other hand, selected patients who ultimately experience progression in proximity of the treated metastasis could still benefit from repeated SBRT or surgery in 25%. Therefore, onset of loco-regional relapse should not be considered as the result of inappropriate allocation to SBRT of patients that should have received upfront chemotherapy and should not influence the decision to perform further local therapies to prolong the systemic therapy free-interval, whenever feasible.
It is noteworthy that our report shows an impact of response to SBRT on survival in patients receiving SBRT for lymph node metastases, supporting the rationale of reducing the gross disease burden in oligo-metastatic patients by local approaches to improve outcome and alter the natural course of the disease. Most notably, after a median follow up of 23 months, 35% of patients did not experience any disease progression, suggesting that a curative perspective can be undertaken in selected patients in accordance with proposed modeling of oligo-metastatic disease [
17]: future studies should identify this subset of long-lasting responders that might benefit from an exclusive local approach to maximize therapeutic ratio and avoid overtreatment.
In our study, SBRT resulted in durable disease remission, and its use in a strategy encompassing repeated use of local treatments for limited-extent relapse allowed to postpone the administration of systemic therapy in 46% of the patients for 2 years. Analysis of patterns of failure showed the value of target diameter and primary tumor as predictors of early local and distant failure, providing elements for selection of candidate patients for SBRT in the event of oligo-metastatic node involvement.
Lymph node metastases from solid cancers are a frequent occurrence in extensive metastatic dissemination due to the propensity of cancer cells to spread through the lymphatic drainage, often determining in-transit metastases [
6]. However, in case of limited or isolated metastatic lymph-node involvement, therapeutic decision should consider the risk of subclinical invasion of neighboring lymph-nodes. For this reason, treatment options in the event of isolated node metastasis from miscellaneous primary tumors traditionally encompass the entire drainage, ranging from surgical lymphadenectomy to upfront systemic treatment : irradiation of the node chain with or without boost to the macroscopic site of disease has also been proposed [
10‐
14]. However, several limitations must be taken into account: efficacy of chemotherapy can be limited depending on the primary tumor; lymphadenectomy can be contra-indicated due to disease extent, involvement of critical structures and operative morbidity; node chain irradiation may result in over-irradiation of critical structures, chronic lymphedema, and suboptimal efficacy due to the impossibility to the deliver high doses to an extended volume [
10‐
14]. Moreover, according to the oligo-metastatic model, cancer cell spread might occur on a time-dependent, step-wise fashion, thus limited management of the clinically evident metastasis might be sufficient to obtain durable disease control and might exert an effect on overall survival by reducing the amount of actively replicating cells in the metastatic niche [
15].
For these reasons, stereotactic body radiotherapy (SBRT) limited to macroscopic lymphadenopathies has been investigated by a number of authors, reporting promising results in terms of 1-years local control > 90% [
16‐
22], optimal symptom control [
22], long systemic therapy-free interval [
21] and the possibility to iteratively perform SBRT in case of limited secondary relapse [
19,
23]. Nevertheless, toxicity reports and lack of data regarding distant failure and impact on survival, raised doubts about the efficacy of this strategy [
24].
It is noteworthy that in our cohort, following SBRT, disease progression was limited to ≤ 3 metastases in 32 out of 56 patients. This resulted in a further local treatment in almost one-third of these 32 patients as is shown in Table
2. Other authors had similar results [
19,
23]. However, this strategy has been applied only in a minority of patients who maintained an oligo-metastatic pattern after disease progression: therefore patients possibly eligible for further SBRT or surgery might have been prematurely allocated to chemotherapy, which means we probably underestimate the theoretical benefit of a strategy based on multiple local therapy courses.
Local control rates at 2 and 4 years were in line with previously published reports [
16‐
21]. As previously described in liver oligometastases [
25], the main determinant of local efficacy was axial diameter of the metastasis, that is a known surrogate for volume [
26] : this information might provide an useful tool to select patients eligible for SBRT, since according to our logistic regression model the risk of failure increase up to one-third for a diameter > 50 mm, and stresses the importance of timing of SBRT in order to avoid treatment delays that could profit tumor growth. Conversely, no impact of prior treatment (and by consequence of the time of onset of metastases in the natural history of the disease) was observed.
No treatment schedule corresponded to an advantage in terms of local efficacy: it could be argued that the use of high BED
10 ≥ 75 Gy in the majority of cases did not allow a comparison between patient groups [
27].
Toxicity was acceptable, with only one G3 acute event. Hoyer et al. [
28] reported a treatment-related death and two bowel perforations in a mixed cohort of patients treated for abdominal metastases using a three-fraction schedule: in our study the use of 5–6 fractions schedules, predominant para-aortic localization, frequent use of tracking devices and acceptance of rigid dose constraints to the OARs may have contributed to the low toxicity rate.
Our study suffers from the usual limitations of retrospective studies, in particular possible presence of confounders and recall bias in the retrospective collection of outcome and toxicity data. Stereotactic radiotherapy in our cohort was the upfront treatment for metastasis in 52% of cases. Previously published series reported the use of SBRT after a first-line systemic therapy in 38–80% of cases [
16‐
21]: promising outcome data may be influenced by inclusion of patients at an early time point of cancer natural history. Despite significant correlation was found between tumor diameter and risk of local failure, our logistic regression model was based on a small number of events and deserve further validation on larger series. The limited sample and the heterogeneity of treatment at progression do not allow to identify an optimal treatment sequence, in particular for patients with specific tumor types at higher risk of local failure or early distant dissemination. Due to retrospective evaluation of toxicity, underestimation or under-reporting of adverse events might not be excluded.