Oligometastatic disease,the curative challenge in radiation oncology

The concept of oligometastatic disease was first described by Hellman and Weichselbaum in 1995. The mere insight of this concept led to the hypothesis that this disease may be cured using local ablative weapons. Surgery has already demonstrated this hypothesis. Surgery limitations, either technical or due to refusal or associated comorbidity, have led to implement alternative ablative options such as stereotactic body radiation therapy (SBRT). SBRT evolved from (stereotactic radiosurgery) because of the need to irradiate extracranial lesions and has been shown to be safe and effective. SBRT achieves local control rates ranging from 70%-90%, but highly variable survival rates depending on the group analyzed. Series with heterogeneous metastatic sites and tumor origin have reported 20% survival rates at 2-3 years, similar to those achieved with surgery. Despite its excellent results, SBRT still faces significant clinical challenges. Its optimal integration with systemic treatment is unknown, and response assessment is very difficult. However, the greatest challenge lies in selection of patients most likely to remain oligometastatic, those who will most benefit from the technique. Biomarkers, molecular signatures, that accurately predict the biological behavior of malignancy are needed. The expression profile of specific miRNAs has been shown to have a potential in this regard.     

Stereotactic Radiosurgery and Stereotactic Body Radiotherapy in the Management of Oligometastatic Disease

Stereotactic radiosurgery (SRS) and stereotactic body radiotherapy (SBRT) represent non-invasive, efficacious and safe radiation treatments for the ablation of intracranial and extracranial metastases. Although the use of SRS has been established by level 1 evidence for patients presenting with up to three or four brain metastases for at least a decade, the paradigm of ablating a limited number of extracranial metastases (typically up to five, known as oligometastatic disease) has yet to be proven beyond the few reported but highly encouraging phase II randomised trials. In this overview, we summarise the phase III randomised controlled trials evaluating SRS for intact brain metastases and postoperative surgical cavities and introduce the limited literature and future concepts for treating patients with more than five intracranial metastases. Next, we summarise the published phase II randomised controlled trials specific to SBRT and oligometastatic disease, while briefly describing and contrasting the technical principles and biological mechanisms of SBRT versus conventional radiation. Phase III evidence for SBRT is needed, and we summarise ongoing trials in this overview. Ultimately, SRS and SBRT have become cornerstone therapeutic options for patients with oligometastatic disease and the future is bright for these patients, considering that not so long ago they were considered incurable and relegated to palliation alone.     

Stereotactic body radiotherapy for oligometastatic breast cancer: a new standard of care,or a medical reversal in waiting?

Metastases-directed therapy via surgery or stereotactic body radiotherapy (SBRT) has become the de facto standard of care in the United States and abroad despite a lack of high quality prospective, randomized trials. Oligometastatic tumors may behave in an inherently more indolent manner secondary to underlying biologic characteristics, including discrepant microRNA expression patterns. This biologic discrepancy suggests that historic improvements in survival observed in retrospective series may stem from the inherent biology of oligometastases and selection biases as opposed to advances in novel localized treatments. In this review, we discuss the theoretical basis for metastases-directed therapies, retrospective data supporting these approaches, recent advances in oligometastasis biology, and ongoing prospective randomized trials designed to compare SBRT and standard of care systemic therapies. We focus on metastases-directed therapy, primarily SBRT, for oligometastatic breast cancer with references to other tumor types when these other tumor types inform oligometastatic breast cancer treatment.     

GOECP/SEOR radiotheraphy guidelines for non-small-cell lung cancer

Non-small cell lung cancer (NSCLC) is a heterogeneous disease accounting for approximately 85% of all lung cancers. Only 17% of patients are diagnosed at an early stage. Treatment is multidisciplinary and radiotherapy plays a key role in all stages of the disease. More than 50% of patients with NSCLC are treated with radiotherapy (curative-intent or palliative). Technological advances-including highly conformal radiotherapy techniques, new immobilization and respiratory control systems, and precision image verification systems-allow clinicians to individualize treatment to maximize tumor control while minimizing treatment-related toxicity. Novel therapeutic regimens such as moderate hypofractionation and advanced techniques such as stereotactic body radiotherapy (SBRT) have reduced the number of radiotherapy sessions. The integration of SBRT into routine clinical practice has radically altered treatment of early-stage disease. SBRT also plays an increasingly important role in oligometastatic disease. The aim of the present guidelines is to review the role of radiotherapy in the treatment of localized, locally-advanced, and metastatic NSCLC. We review the main radiotherapy techniques and clarify the role of radiotherapy in routine clinical practice. These guidelines are based on the best available evidence. The level and grade of evidence supporting each recommendation is provided.     

The expanding role of stereotactic body radiation therapy in oligometastatic solid tumors: What do we know and where are we going?

The spectrum hypothesis posits that there are distinct clinical states of metastatic progression. Early data suggest that aggressive treatment of more biologically indolent metastatic disease, characterized by metastases limited in number and destination organ, may offer an opportunity to alter the disease course, potentially allowing for longer survival, delay of systemic therapy, or even cure. The development of stereotactic body radiation therapy (SBRT) has opened new avenues for the treatment of oligometastatic disease. Early data support the use of SBRT for treating oligometastases in a number of organs, with promising rates of treated metastasis control and overall survival. Ongoing investigation is required to definitively establish benefit, determine the appropriate treatment regimen, refine patient selection, and incorporate SBRT with systemic therapies.     

乳腺癌寡转移系统治疗联合SBRT的困惑和前景

转移性乳腺癌（metastatic breast cancer，MBC）被认为不可治愈，患者生存预后不佳。但在MBC中存在一部分人群，转移灶的数目和大小较局限，有潜在治愈可能，即寡转移乳腺癌（oligometastatic breast cancer，OMBC）。立体定向放射治疗（stereotactic body radiation therapy，SBRT）联合系统治疗有望延缓OMBC患者的疾病进展，改善生存。如何寻找真正的OMBC患者，SBRT是否覆盖所有转移病灶，联用何种系统治疗方式，都是当下值得探讨的问题。     

Radiation Therapy for Liver Tumors: Ready for Inclusion in Guidelines?

Despite the historically limited role of radiotherapy in the management of primary hepatic malignancies, modern advances in treatment design and delivery have renewed enthusiasm for radiation as a potentially curative treatment modality. Surgical resection and/or liver transplantation are traditionally regarded as the most effective forms of therapy, although the majority of patients with hepatocellular carcinoma and intrahepatic cholangiocarcinoma present with locally advanced or unresectable disease on the basis of local vascular invasion or inadequate baseline hepatobiliary function. In this context, many efforts have focused on nonoperative treatment approaches including novel systemic therapies, transarterial chemoembolization, ethanol ablation, radiofrequency ablation, and stereotactic body radiation therapy (SBRT). This review aims to summarize modern advances in radiotherapy, particularly SBRT, in the treatment of primary hepatic malignancies.     

Traitement des oligometastases et oligoprogression

We propose in this short review to report the impact of stereotactic body radiation therapy (SBRT) in oligometastatic or oligoprogressive cancer patients in terms of metastatic progression-free and global survival, and to identify the place of SBRT in patient's pathway.     

Stereotactic body radiation therapy in patients with hepatocellular carcinoma: A mini-review

Stereotactic body radiation therapy (SBRT) is an emerging treatment for hepatocellular carcinoma. This technique results in excellent local control rates with favorable toxicity profile despite being predominantly used in heavily pretreated patients or those unsuitable for other local therapies. SBRT may be used as a sole treatment or in combination with other local therapies as well as a bridging strategy for patient awaiting liver transplants. This brief review describes current practice of SBRT with respect to radiation technique, patient selection and treatment concepts. It summarizes available evidence from retro- and prospective studies evaluating SBRT alone, SBRT in combination with other treatments and SBRT compared to other local treatment approaches.     

Radiotherapy With Curative Intent in Patients With Early-stage,Medically Inoperable,Non–Small-cell Lung Cancer: A Systematic Review

Patients with early-stage non–small-cell lung cancer (NSCLC) who are unable to undergo surgery can be offered radiation therapy (RT). Previously, conventional RT was offered; however, newer techniques such as stereotactic body RT (SBRT) have become available. The objective of the present systematic review was to investigate the effectiveness of RT with curative intent in patients with early-stage medically inoperable NSCLC. MEDLINE, EMBASE, and the Cochrane Library were searched for studies comparing stereotactic RT with curative intent compared with observation or other types of RT for early-stage, medically inoperable, NSCLC. Comparisons of radiation dosing or fractionation schedules for SBRT were included. We include 4 systematic reviews and 52 observational studies. The evidence suggests that SBRT compared with observation or other forms of RT, such as accelerated hypofractionated RT, 3-dimensional conformal RT, conventional fractionated RT, external beam RT, proton beam therapy, and carbon ion therapy, could have similar or improved results in survival or local control, with similar or fewer adverse effects. Evidence also suggests that local tumor control and survival were associated with the biologically effective dose (BED) for SBRT. Several studies suggested a cutoff of approximately 100 BED correlated significantly with patient outcomes. The presented evidence suggests that SBRT compared with other forms of RT is a reasonable treatment option for patients with medically inoperable early-stage NSCLC.     

Stereotactic body radiation therapy: A good dance partner of oligometastatic non-small cell lung cancer to the sound of SINDAS study

The European Organization for Research on Treatment of Cancer Research published a consensus statement to establish the key criteria to define oligometastatic disease (OMD). According to those criteria, all lesions (both primary and metastatic) should be amenable to radical intent treatment with acceptable toxicity. Several retrospective studies have shown that adding local ablative therapy to the treatment of OMD improves outcomes; however, due to the diverse selection criteria and treatment strategies used in those studies, it is difficult to compare directly results to draw definitive conclusions. In recent years, prospective phase II trials, such as the SABR-COMET and "Oligomez" trials, have shown that stereotactic body radiation therapy (SBRT) improves outcomes in patients with OMD. More recently, interim results of the randomised phase 3 SINDAS trial were reported at the annual meeting of the American Society of Clinical Oncology 2020 demonstrating that upfront SBRT added to systemic treatment with tyrosine kinase inhibitors yielded a significant benefit in both progression-free survival and overall survival in patients with epidermal growth factor receptor-mutant oligometastatic non-small cell lung cancer. In the present editorial, we review the definition and historical context of advanced non-small cell lung cancer with OMD. In addition, we review the scientific evidence for local ablative therapy and SBRT and discuss the results of recently published prospective studies. We also discuss in depth the results of the SINDAS study, including the strengths and weaknesses of the study and the barriers to extrapolating these results to routine clinical practice.     

Fractionated stereotactic body radiotherapy for up to five prostate cancer oligometastases: Interim outcomes of a prospective clinical trial

Stereotactic body radiotherapy (SBRT) can delay escalation to systemic treatment in men with oligometastatic prostate cancer (PCa). However, large, prospective studies are still required to evaluate the efficacy of this approach in different patient groups. This is the interim analysis of a prospective, single institution study of men relapsing with up to five synchronous lesions following definitive local treatment for primary PCa. Our aim was to determine the proportion of patients not requiring treatment escalation following SBRT. In total, 199 patients were enrolled to receive fractionated SBRT (50 Gray in 10 fractions) to each visible lesion. Fourteen patients were castration resistant at enrolment. The proportion of patients not requiring treatment escalation 2 years following SBRT was 51.7% (95% CI: 44.1–59.3%). The median length of treatment escalation-free survival over the entire follow-up period was 27.1 months (95% CI; 21.8–29.4 months). Prior androgen deprivation therapy (ADT) predicted a significantly lower rate of freedom from treatment escalation at 2 years compared to no prior ADT (odds ratio = 0.21, 95% CI: 0.08–0.54, p = 0.001). There was no difference in the efficacy of SBRT when treating 4–5 vs. 1–3 initial lesions. A prostate-specific antigen (PSA) decline was induced in 75% of patients, with PSA readings falling to an undetectable level in six patients. No late grade three toxicities were observed. These interim results suggest that SBRT can be used to treat up to five synchronous PCa oligometastases to delay treatment escalation.     

Spanish Society of Radiation Oncology clinical guidelines for stereotactic body radiation therapy in lymph node oligometastases

Data in the literature support the existence of a state of limited metastases or oligometastases. Favorable outcomes have been observed in selected patients with such oligometastases that are treated with local ablative therapies, which include surgical extirpation, stereotactic body radiation therapy (SBRT), and radiofrequency ablation. The role of SBRT in the setting of lymph node oligometastases is still emerging but the early results for local control are promising. However, the biggest challenge is to identify patients who will benefit from treatment of their oligometastatic disease with local aggressive therapy. Patients are initially categorized based upon examination of the initial biopsy, location, stage, and previous treatments received. Appropriate patient management with SBRT requires an understanding of several clinicopathological features that help to identify several subsets of patients with more responsive tumors and a good tolerance to SBRT. In an effort to incorporate the most recent evidence, here the Spanish Society of Radiation Oncology presents guidelines for using SBRT in lymph node oligometastases.     

Stereotactic body radiation therapy for low and intermediate risk prostate cancer—Results from a multi-institutional clinical trial

BackgroundWe report the outcome of a phase I/II clinical trial of stereotactic body radiation therapy (SBRT) for low (LR) and select intermediate risk (IR) prostate cancer (PCa) patients.Patients and methodsEligible patients included men with prostate adenocarcinoma with Gleason score 6 with PSA ≤ 20 or Gleason 7 with PSA ≤ 15 and clinical stage ≤ T2b. For the phase I portion of the study patients in cohorts of 15 received 45, 47.5, or 50 Gray (Gy) in five fractions. Since the maximally tolerated dose was not met in the phase I study, an additional 47 patients received 50 Gy in five fractions in the phase II study. Toxicity using Common Toxicity Criteria for Adverse Events v. 3.0, quality of life, and outcome data was collected.ResultsA total of 91 patients are included for analysis; 63.7% had NCCN IR and 36.3% had LR PCa. At a median follow up of 54 months the actuarial freedom from biochemical failure was 100% at 3 years and 98.6% at 5 years. Actuarial distant metastasis free survival was 100% at 3 and 5 years. Overall survival was 94% at 3 years and 89.7% at 5 years with no deaths attributed to PCa. Acute and late urinary grade ≥ III toxicity occurred in 0% and 5.5% of patients, respectively. Gastrointestinal (GI) acute and late toxicity of grade ≥ III occurred in 2% and 7% of patients, respectively. A total of four men experienced grade IV toxicity (three GI, one genitourinary).ConclusionSBRT treatment results in excellent biochemical control rates at 5 years for LR and IR PCa patients although doses greater than 47.5 Gy in five fractions led to increased severe late toxicity.     

Management of oligometastatic non-small cell lung cancer patients: Current controversies and future directions

Oligometastatic non-small cell lung cancer (NSCLC) describes an intermediate stage of NSCLC between localized and widely-disseminated disease. This stage of NSCLC is characterized by a limited number of metastases and a more indolent tumor biology. Currently, the management of oligometastatic NSCLC involves radical treatment (radiotherapy or surgery) that targets the metastatic lesions and the primary tumor to achieve disease control. This approach offers the potential to achieve prolonged survival in patients who, in the past, would have only received palliative measures. The optimal therapeutic strategies for the different scenarios of oligometastatic disease (intracranial vs extracranial disease, synchronous vs metachronous) remain undefined. Given the lack of head-to-head studies comparing radiotherapy to surgery in these patients, the decision to apply surgery or radiotherapy (with or without systemic treatment) must be based on prognostic factors that allow us to classify patients. This classification will allow us to select the most appropriate therapeutic strategy on an individualized basis. In the future, the molecular or microRNA profiles will likely improve the treatment selection process. The objective of the present article is to review the most relevant scientific evidence on the management of patients with oligometastatic NSCLC, focusing on the role of radiotherapy and surgery. We also discuss areas of controversy and future directions.     

Long-term Follow-up and Patterns of Recurrence of Patients With Oligometastatic NSCLC Treated With Pulmonary SBRT

IntroductionThis multicenter study aims to analyze outcome as well as early versus late patterns of recurrence following pulmonary stereotactic body radiotherapy (SBRT) for patients with oligometastatic non–small-cell lung cancer (NSCLC).Materials and MethodsThis analysis included 301 patients with oligometastatic NSCLC treated with SBRT for 336 lung metastases. Although treatment of the primary tumor consisted of surgical resection, radiochemotherapy, and/or systemic therapy, pulmonary oligometastases were treated with SBRT.ResultsThe median follow-up time was 16.1 months, resulting in 2-year overall survival (OS), local control (LC), and distant control (DC) of 62.2%, 82.0%, and 45.2%, respectively. Multivariate analysis identified age (P = .019) and histologic subtype (P = .028), as well as number of metastatic organs (P < .001) as independent prognostic factors for OS. LC was superior for patients with favorable histologic subtype (P = .046) and SBRT with a higher biological effective dose at isocenter (P = .037), whereas DC was inferior for patients with metastases in multiple organs (P < .001) and female gender (P = .027). Early (within 24 months) local or distant progression was observed in 15.3% and 36.5% of the patients. After 24 months, the risk of late local failure was low, with 3- and 4-year local failure rates of only 4.0%, and 7.6%. In contrast, patients remained at a high risk of distant progression with 3- and 4-year failure rates of 13.3% and 24.1%, respectively, with no plateau observed.ConclusionSBRT for pulmonary oligometastatic NSCLC resulted in favorable LC and promising OS. The dominant failure pattern is distant with a continuously high risk of disease progression for many years.     

A rationale for the targeted treatment of oligometastases with radiotherapy

An oligometastatic state has been proposed wherein patients with metastases limited in number and location may benefit from local therapy directed at all known sites of metastases. We describe here the clinical and biological basis for the oligometastatic state. We present evidence for a potentially curative approach to patients with oligometastases using stereotactic body radiotherapy (SBRT) and we review the literature for SBRT directed at specific metastatic sites in the lungs, liver and multiple organs.     

Salvage reirradiation for locoregional failure after radiation therapy for prostate cancer: Who,when, where and how?

Even in the current era of dose-escalated radiotherapy for prostate cancer, biochemical recurrence is not uncommon. Furthermore, biochemical failure is not specific to the site of recurrence. One of the major challenges in the management of prostate cancer patients with biochemical failure after radiotherapy is the early discrimination between those with locoregional recurrence only and those with metastatic disease. While the latter are generally considered incurable, patients with locoregional disease may benefit from emerging treatment options. Ultimately, the objective of salvage therapy is to control disease while ensuring minimal collateral damage, thereby optimizing both cancer and toxicity outcomes. Advances in functional imaging, including multiparametric prostate MRI, abdominopelvic lymphangio-MRI, sentinel node SPECT-CT and/or whole-body PET/CT have paved the way for salvage radiotherapy in patients with local recurrence, microscopic nodal disease limited to the pelvis or oligometastatic disease. These patients may be considered for salvage reirradiation using different techniques: prostate low-dose or high-dose rate brachytherapy, pelvic and/or lomboaortic image-guided radiotherapy with elective nodal irradiation, focal nodal or bone stereotactic body radiation therapy (SBRT). An individualized approach is recommended. The decision about which treatment, if any, to use will be based on the initial characteristics of the disease, relapse patterns and the natural history of the rising prostate specific antigen (PSA). Preliminary results suggest that more than 50% of patients who have undergone salvage reirradiation are biochemically relapse-free with very low rates of severe toxicity. Large prospective studies with a longer follow-up are needed to confirm the promising benefit/risk ratio observed with salvage brachytherapy and or salvage nodal radiotherapy and/or bone oligometastatic SBRT when compared with life-long palliative hormones.     

Treatment of Oligometastatic Non-Small Cell Lung Cancer: An ASTRO/ESTRO Clinical Practice Guideline

PurposeThis joint guideline by American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) was initiated to review evidence and provide recommendations regarding the use of local therapy in the management of extracranial oligometastatic non-small cell lung cancer (NSCLC). Local therapy is defined as the comprehensive treatment of all known cancer—primary tumor, regional nodal metastases, and metastases—with definitive intent.MethodsASTRO and ESTRO convened a task force to address 5 key questions focused on the use of local (radiation, surgery, other ablative methods) and systemic therapy in the management of oligometastatic NSCLC. The questions address clinical scenarios for using local therapy, sequencing and timing when integrating local with systemic therapies, radiation techniques critical for oligometastatic disease targeting and treatment delivery, and the role of local therapy for oligoprogression or recurrent disease. Recommendations were based on a systematic literature review and created using ASTRO guidelines methodology.ResultsBased on the lack of significant randomized phase 3 trials, a patient-centered, multidisciplinary approach was strongly recommended for all decision-making regarding potential treatment. Integration of definitive local therapy was only relevant if technically feasible and clinically safe to all disease sites, defined as 5 or fewer distinct sites. Conditional recommendations were given for definitive local therapies in synchronous, metachronous, oligopersistent, and oligoprogressive conditions for extracranial disease. Radiation and surgery were the only primary definitive local therapy modalities recommended for use in the management of patients with oligometastatic disease, with indications provided for choosing one over the other. Sequencing recommendations were provided for systemic and local therapy integration. Finally, multiple recommendations were provided for the optimal technical use of hypofractionated radiation or stereotactic body radiation therapy as definitive local therapy, including dose and fractionation.ConclusionsPresently, data regarding clinical benefits of local therapy on overall and other survival outcomes is still sparse for oligometastatic NSCLC. However, with rapidly evolving data being generated supporting local therapy in oligometastatic NSCLC, this guideline attempted to frame recommendations as a function of the quality of data available to make decisions in a multidisciplinary approach incorporating patient goals and tolerances.     

寡转移瘤患者体部立体定向放疗的疗效及安全性

目的 探讨小体积寡转移瘤患者局部立体定向放疗（SBRT）的疗效及安全性。方法收集2011年6月至2016年12月85例转移灶≤5个、预计生存期＞3个月、一般状况良好的Ⅳ期寡转移瘤患者,采用3个剂量的SBRT,主要研究终点是局部控制率和毒性反应,次要研究终点是总生存期（OS）和无疾病进展生存期（PFS）。疗效评价采用RECIST 1.1版标准;毒副反应采用RTOG评价标准;Kaplan-Meier法计算生存,Log-rank检验生存差异。结果 85例患者共187处转移灶,中位随访时间为25个月,局部控制率为66.8％（125／187）,其中24、30、36 Gy剂量组局部控制率分别为39.0％、79.0％、84.0％,差异有统计学意义（P＜0.05）。全组中位PFS为7.8个月（1～25个月）,1、2、3年无进展生存率分别为33.3％、25.0％、23.0％;中位OS为25个月,1、2、3年生存率分别为80.5％、75.6％、70.6％。4例患者发生3级以上急性毒副反应,其中2例是肺部转移瘤,2个月后证实为放射性肺炎;另外1例是肝脏转移瘤,放疗时发生严重呕吐、转氨酶升高需入院治疗;还有1例肝、肺、骨多发转移患者发生4级骨髓抑制（白细胞减少为主）。结论 寡转移瘤患者在安全治疗范围内可以从局部SBRT放疗中获得较好的局部控制率,不良反应可耐受。