Palliative radiotherapy in oligometastases

Introduction

Halsted et al. theorized that there was an orderly, contiguous, and stepwise mechanism for the spread of cancer within the body, extending from the primary tumor to the lymphatic system, lymph nodes, and ultimately, distant sites. ^, This theory supported the idea that aggressive local treatment, including mastectomy or radiotherapy, can prevent disease spread and improve survival. However, Fisher et al. proposed an alternate theory, in which clinically apparent tumors represent a systemic disease process, which if it has the potential to spread distantly, has already done so. Under this notion, tumors develop early circulating tumor cells, and local treatment should not benefit survival. These two theories, however, fail to consider important intermediate states of tumor progression.

Dr. Samuel Hellman and colleagues developed a theory of cancer progression that incorporates both Halsted’s and Fisher’s theories. Dr. Hellman proposed a spectrum of progression, which included diseases that remained localized as well as those which immediately spread distantly. Notably, he identified an intermediate state that occurs after the initial presentation and before the systemic spread of the disease. In 1995, Hellman and Weichselbaum termed one such intermediate state “oligometastasis,” wherein the tumor involves a limited number of distant metastatic sites. Notably, this state was thought to occur prior to the tumor’s ability for widespread metastatic involvement and thus, had the potential for cure with intense local treatment.

Since then, multiple studies have demonstrated the potential for local curative treatment for this subset of patients with metastatic disease. Surgical resection of metastases to the brain, lungs, and liver have shown the potential for improved outcomes. Other phase II trials have demonstrated the potential for metastasis-directed therapy, including resection or radiotherapy, to prolong progression-free survival (PFS) ^, and overall survival (OS). ^{, ,}

The American Society for Radiation Oncology (ASTRO) and the European Society for Radiotherapy and Oncology (ESTRO) developed consensus guidelines concerning the definition of oligometastatic disease. It is recognized that the oligometastatic state is independent of primary histology and metastasis site, and the identification of this state depends primarily upon a limited disease burden detected by imaging. However, the clinical context for these patients varies significantly, with corresponding heterogeneity in treatment outcomes. Thus, there has been growing interest in the further characterization of the oligometastatic state. ^, The European Organisation for Research and Treatment of Cancer (EORTC) and ESTRO have released a decision tree for more accurate classification of the oligometastatic disease state ( Fig. 23.1 ). They differentiate between induced oligometastatic disease, in which a patient with polymetastatic disease exhibits a partial response to systemic therapy, and genuine oligometastatic disease, in which patients have no history of polymetastatic disease. Within genuine oligometastatic disease, there is differentiation into de-novo, those without a prior diagnosis of oligometastases, and repeat, those with a previous diagnosis of oligometastases. Within de-novo oligometastatic disease, there is a distinction between those with synchronous oligometastases, with a maximum interval of 6 months between the primary diagnosis and the diagnosis of oligometastases; and metachronous oligometastases, with an interval longer than 6 months. Accurately classifying patients with actual oligometastatic disease is crucial, as these patients may have restricted tumor metastatic capacity and may benefit from aggressive local treatment of the metastatic lesions.

Indications for radiotherapy

Traditionally, the role of radiotherapy within metastatic disease has been for palliation of symptoms to improve the quality of life for patients. Identification of the oligometastatic disease state has expanded the role of metastasis-directed therapy for patients with stage IV cancer. As these patients have improved prognoses with potential for long-term survival; there is a greater need for improved local control (LC) of the metastatic lesion via radiotherapy or surgical techniques. Additionally, recent evidence suggests that radiation treatment of all active metastases can be a component of curative treatment, potentially improving PFS and OS. ^{, , , ,}

Identifying patients with oligometastatic disease who may benefit from aggressive metastasis-directed therapy remains challenging. While the potential for biomarkers, such as circulating free DNA, microRNA expression, or tissue-based molecular analysis to improve the definition of the oligometastatic state is promising, these methods are not yet validated for routine clinical use. Therefore, the current definition of the oligometastatic state depends upon the number of lesions identified via imaging, with some trials limiting the number of metastases to 3 ^{6, , ,} and others to 5. ^{, ,} There is broad agreement that aggressive local therapy should be reserved for patients with adequate performance status, ^{, , , ,} with one clinical trial also mandating a life expectancy of at least 6 months. ^, Candidates are typically limited to those who have received systemic therapy or definitive local treatment without progression. ^,

Common histologies

The three primary cancers through which the nature, management, and treatment of the oligometastatic state have been most frequently explored are non-small cell lung cancer (NSCLC), breast cancer, and prostate cancer. ^, With respect to treatment, Flannery et al. found an improvement in 5-year OS of 21% with the use of stereotactic radiosurgery (SRS) for oligometastatic synchronous solitary brain metastasis in patients with NSCLC and good performance status. This initial study indicated that a more aggressive/definitive approach in these patients could improve long-term survival. In the setting of both intracranial and extracranial metastatic disease, a subsequent systematic review of 2176 patients confirmed an OS benefit when aggressive local therapy was employed for NSCLC patients with 1 to 5 metastases. In this analysis, when all sites of disease were treated with either stereotactic body radiotherapy (SBRT), SRS, or metastasectomy, the median OS was 14.8 months and 19 months if the primary site of disease was controlled. Since that time, multiple phase II trials, and the recent phase III SINDAS trial, have shown improved outcomes in key oncologic endpoints such as PFS and OS with the use of consolidative local therapy, individually discussed below. ^{, , , ,}

As noted previously, breast cancer was one of the first disease sites in which concepts of various metastatic states of solid tumors were explored by Hellman et al. ^, It followed initial investigations of consolidative local therapy for limited metastatic disease would involve breast cancer research. Early literature evaluating isolated metastasectomies of breast cancer showed that long-term control could be achieved with an aggressive approach for patients with limited metastases. ^, Subsequent studies showed promising results in terms of long-term PFS and OS for patients with oligometastatic breast cancer receiving SBRT, and recent phase II trials have also shown excellent LC, in addition to PFS and OS, with the use of SBRT. ^, Most recently, NRG-BR001 evaluated the safety of delivering SBRT to either 3 to 4 metastases or two metastases in close proximity (≤5 cm) for patients with primary breast, lung, or prostate cancers and Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. There was minimal toxicity in this study. This approach is being further evaluated currently in phase II trials NRG-BR002 and LU002.

The natural course of prostate cancer, in conjunction with medical advancements, has led to an increasing number of patients living with primary, recurrent, or metastatic disease for years; hence, there is a real opportunity to look at the survival benefits of LC in all disease settings. Furthermore, closer monitoring and improved imaging have allowed for detection of disease earlier than ever before. Historically, when patients had even a small burden of nodal disease, local therapy would be dismissed in favor of androgen deprivation therapy (ADT). ^, Early data have now shown improved survival in patients with the node-positive disease through definitive treatment of the primary tumor. ^, For patients with distant metastatic disease, the management of prostate cancer is continuously shifting towards the investigation of aggressive local therapy in combination with systemic agents. In the current era of personalized oncology, patient selection for local ablative therapy based on molecular and genomic biomarkers is increasingly emphasized. There are now even retrospective data suggesting that specific subsets of patients with oligometastatic prostate cancer may derive a differential benefit from metastasis-directed therapy based on clinical and dosimetric characteristics, such as hormone sensitivity, peri-radiotherapy ADT, and gross tumor volume (GTV).

Tools for prognostication

An integral aspect of personalized medicine for patients with oligometastatic disease is accurate prognostication. A recent clinical trial required that patients have a life expectancy of at least 6 months. ^, However, there is significant heterogeneity in survival for those with oligometastases, with a median OS range of 6 to 52 months, and the identification of those with improved survival remains a challenge. Several favorable prognostic factors have been identified, including female gender, improved performance status, ^, increased disease-free interval between initial diagnosis and metastasis, ^{, ,} fewer metastases, and the absence of intracranial disease ( Table 23.1 ). ^, Certain primary cancers, such as breast, kidney, and prostate cancer, ^, and histologies, such as adenocarcinoma, ^, are associated with improved survival as well. Prognostic models for OS that utilize these factors, such as a nomogram developed by Tanadini-Lang et al. ( Fig. 23.2 A) or the METABANK score (see Fig. 23.2 B), can aid in patient selection for aggressive localized treatment of metastases.

Review of studies

As previously stated, the clinical implication in an oligometastatic setting is long-term survival and quality of life. Initial reports of favorable outcomes in oligometastatic disease largely involved surgical excision of metastatic sites, which is often limited by challenging anatomical location and associated morbidity. Growing evidence of the use of radiation therapy in the treatment of oligometastases accompanied technological advancements in radiation techniques such as SBRT and SRS, which supported the hypothesis of clinical benefits with local therapy ( Table 23.2 ).