Abstract

With the emergence of lung cancer screening programmes and newly detected localised and multifocal disease, novel treatment compounds and multimodal treatment approaches, the treatment landscape of non-small cell lung cancer is becoming increasingly complex. In parallel, in-depth molecular analyses and clonality studies are revealing more information about tumorigenesis, potential therapeutical targets and the origin of lesions. All can play an important role in cases with multifocal disease, oligoprogression and oligorecurrence. In multifocal disease, it is essential to understand the relatedness of separate lesions for treatment decisions, because this information distinguishes separate early-stage tumours from locally advanced or metastatic cancer. Clonality studies suggest that a majority of same-histology lesions represent multiple primary tumours. With the current standard of systemic treatment, oligoprogression after an initial treatment response is a common scenario. In this state of induced oligoprogressive disease, local ablative therapy by either surgery or radiotherapy is becoming increasingly important. Another scenario involves the emergence of a limited number of metastases after radical treatment of the primary tumour, referred to as oligorecurrence, for which the use of local ablative therapy holds promise in improving survival. Our review addresses these complex situations in lung cancer by discussing current evidence, knowledge gaps and treatment recommendations.

Introduction

The treatment landscape of non-small cell lung cancer (NSCLC) is rapidly evolving. Novel treatment compounds and the recent improvements in lung cancer surgery and radiation therapy allow for multimodal treatment approaches and have contributed to the major improvement in survival [1]. In the past years, the implementation of national lung cancer screening programmes has improved the early detection of pulmonary nodules and comprehensive genomic profiling is providing pivotal information for the assessment of early-stage and advanced-stage NSCLC. In view of the increasing complexity of lung cancer treatment, this review aims to address the current evidence and knowledge gaps of frequently encountered complex situations in NSCLC, including multifocal disease, oligoprogression and oligorecurrence.

Search methods

For this narrative review, international guidelines and retrospective and prospective studies published from inception to August 2023 were identified by searches of PubMed, as well as references from relevant articles and reviews. English language was used as a restriction and the PubMed search included the following search terms: “multifocal synchronous lung cancer”, “second primary lung cancer”, “multifocal lung adenocarcinoma”, “pneumonic-type lung adenocarcinoma”, “oligoprogressive disease”, induced oligoprogression”, “oligorecurrence” and “local ablative therapy”.

Multifocal diseaseSummary

The recent advances in imaging techniques such as low-dose computed tomography (CT) and the establishment of lung cancer screening programmes have improved the early detection of pulmonary nodules but also increased the number of patients in whom multiple nodules are synchronously detected [2, 3]. The radiological finding of multiple synchronous lung cancers (MSLCs) can either represent multiple primary NSCLCs that are potentially curable, or locally or haematogeneously spread intrapulmonary metastases. This results in a clinical dilemma, because the relationship between two nodules essentially determines the correct therapeutic approach [4].

Based on clinico-pathological and molecular findings, the International Association for the Study of Lung Cancer (IASLC) proposed revisions in the staging of MSLC and presented four patterns of lung cancer that may synchronously manifest in multiple pulmonary sites [4–7]: 1) second primary lung cancers, 2) separate tumour nodules, 3) multifocal lung adenocarcinoma with ground-glass/lepidic (GG/L) features and 4) pneumonic-type lung adenocarcinoma (figure 1). Each of these patterns require a distinct approach to staging and treatment and further research is required to identify the origin of separate lesions and the role of local treatment approaches.

FIGURE 1

Radiological appearance of the four different patterns of multifocal disease according to the classification proposed by the International Association for the Study of Lung Cancer Multiple Pulmonary Sites Workgroup. a) Second primary lung cancer, b) separate tumour nodules, c) multifocal lung adenocarcinoma with ground-glass/lepidic (GG/L) features (yellow arrows) and d) pneumonic-type lung adenocarcinoma. These different patterns represent different disease stages or different entities that require a distinct approach to staging and treatment. RUL: right upper lobe; RML: right middle lobe. Reproduced and modified from Detterbeck et al. [4], with permission.

Definition

In the past decades, many efforts have been made to distinguish these clinical entities and to determine the adequate treatment. The first empirical criteria were published by Martini and Melamed in 1975 [8] and included clinical characteristics such as the presence of nodal disease, systemic extrapulmonary metastases or a latency of ≥2 years to distinguish primary tumours from intrapulmonary metastases. Together with the American College of Chest Physicians (ACCP) guidelines, these criteria were widely applied in multidisciplinary tumour boards to guide treatment decisions [9]. However, modern pathological and molecular techniques, including targeted sequencing, whole-exome or whole genome sequencing, have recently revealed that many of these synchronous lesions represent multiple different primary tumours rather than metastases [10].

Synchronous second primary lung cancers

If two nodules show different lung cancer histology (including subtype grading and cytological features) in representative tissue specimens, they can easily be distinguished as second primary lung cancers. In contrast, the presence of nodules with identical histomorphological features does not necessarily imply that these are manifestations of the same tumour. The clonal relationships between different tumours in the same patient have recently been investigated by comprehensive genomic profiling of resected nodules. In the study by Liu et al. [10], 15 lung adenocarcinoma cases from six patients showed that all same-patient lung cancers harboured distinct genomic profiles and were classified as second primary lung cancers. Even identical oncogenic driver genes showed different mutations in different tumours from the same patient. Notably, according to the ACCP guidelines, all nodules would have been classified as separate tumour nodules or intrapulmonary metastases [10]. Findings from clonality studies therefore indicate that most nodules with the same histological type are likely to be second primary cancers. The radiological and histological classification should thus always be combined with a detailed genetic assessment to accurately identify the origin of MSLCs [4]. However, defining criteria that conclusively identify two lesions as identical is far more challenging than defining criteria that distinguish two lesions as separate [4]. In the IASLC proposals for revisions in the staging of MSLC, the presence of a different histology, different breakpoints in genomic hybridisation and the simultaneous origin from carcinoma in situ are mentioned as affirmative factors to identify two lesions as separate. Other criteria that speak for a separate origin, e.g. the absence of nodal and systemic metastases, different growth rates, different biomarker patterns and different radiographic appearances, are considered relative criteria and should be used with caution.

In case of second primary lung cancers, both cancers should be classified with a separate tumour, node, metastasis (TNM) staging and treated individually according to the current guidelines [4]. This approach is supported by a recent meta-analysis of the IASLC Multiple Pulmonary Sites Workgroup, which confirmed that the median 5-year survival in patients with synchronous second primary lung cancers treated by definitive local therapy (defined by lobectomy or segmentectomy in stage I tumours) is comparable irrespective of matching histology (45% in patients with same-histology tumours and 46% in patients with different histologies) [6].

Separate tumour nodules (intrapulmonary metastases)

In contrast to second primary lung cancers, which are unrelated tumours, separate tumour nodules are a single tumour with intrapulmonary metastasis. The terminology “satellite nodule” was abandoned in 2010. In the IASLC database for the 8th edition of TNM staging, 3.5% of all patients showed an ipsilateral or contralateral separate malignant nodule of the same histological type. Most commonly, only one separate nodule was present and overall survival (OS) decreased progressively depending on the location of the separate nodule. The best outcomes were for same-lobe nodules (i.e. T3), followed by same lung but different lobe nodules (i.e. T4), with the shortest OS in contralateral nodules (i.e. M1a) [4, 11]. However, OS was primarily confounded by the treatment administered and no survival differences were present among surgically managed and among non-surgically managed patients. Owing to these confounding factors, the TNM classification of the 8th edition for separate tumour nodules was left unchanged: synchronous nodules in the same lobe are classified as T3 and show a median 5-year survival of 38% (52% in N0 disease) and synchronous nodules of the same lung but different lobe are classified as T4 with a median 5-year survival of 30% (43% in N0 disease) [11].

Multifocal lung adenocarcinoma with GG/L features

Radiologically, multifocal adenocarcinoma with GG/L features present with either pure ground-glass morphology or part-solid morphology (figures 1 and 2). They are separate tumours like second primaries, but owing to the distinct clinical, pathological and biological characteristics and similarities, they are considered a separate entity that is associated with an indolent behaviour and a favourable outcome. Patients with multifocal GG/L adenocarcinoma are often female never-smokers and have a reduced risk for nodal or distant metastatic spread, but an increased risk for the development of additional subsolid cancerous lesions [3, 4]. The 5-year survival rates reported in the literature range between 64% and 100% [5]. The radiological GG/L appearance correlates with the pathological subgroups of lepidic-predominant adenocarcinoma, minimally invasive adenocarcinoma, adenocarcinoma in situ or atypical adenomatous hyperplasia. The origin and molecular nature of these lesions are currently not fully understood and clonality studies have shown conflicting results. In a study including targeted sequencing of multiple synchronous multifocal adenocarcinomas with GG/L features, Park et al. [12] showed that while many mutation profiles of paired lesions were different, 68.7% of all patients had lesions that carried mutations in the same genes. This suggests that although these are different tumours, a common molecular abnormality may form the basis of tumorigenesis in these patients [3, 12].

FIGURE 2

Computed tomography (CT) in a 74-year-old female patient with a smoking history of 25 pack-years revealed multiple ground-glass lesions in the right upper (a and b) and lower lobe, as well as the left lower lobe but without signs of enlarged mediastinal lymph nodes. Follow-up CT after 6 months revealed the growth of a lesion in the right lower lobe (c) with a new solid component of 3 mm diameter, while all other lesions remained stable. After multidisciplinary tumour board discussion, a wedge resection of the lesion in the right lower lobe was performed. The histological and genetic analysis revealed a well-differentiated lepidic adenocarcinoma harbouring a Kirsten rat sarcoma virus (KRAS) G12C mutation. The Tumour, Node, Metastasis (TNM, 8th edition) staging was considered pT1b cN0 cM0. The patient made an uneventful recovery and in the latest follow-up 2 years after surgery, all remaining ground-glass lesions were stationary. The patient was treated at the University Hospital Zurich.

Regarding the treatment of synchronous second primary lung cancers, many questions remain unanswered. To date, there are no uniform recommendations. A multidisciplinary team approach is essential. According to the recent guidelines of the American College of Radiology, GG lesions that remain stable in size or do not exceed the threshold of >1.5 mm growth per year are classified as Lung Imaging Reporting and Data System (RADS) 2 (<30 mm) or Lung-RADS 3 (>30 mm) and can thus be followed-up by low-dose CT in 6- or 12-month intervals, respectively [13]. By contrast, for lesions that show accelerated growth or develop a solid component, treatment should be considered [13]. Parameters that determine the treatment modality include the location (peripheral versus central, unilateral versus bilateral, single or multiple lobes involved), the morphology of each lesion (size, growth rate, solid areas), the patient's functional reserve to tolerate surgical resection and the patient's treatment preference. The ACCP guidelines recommend sublobar resection of all lesions if feasible [13]. However, these cases must be evaluated individually by a multidisciplinary tumour board [14]. Most centres follow a “whack-a-mole” strategy, in which the largest growing lesion is anatomically resected by segmentectomy or lobectomy to obtain a definitive histological diagnosis and perform molecular analyses [15]. If ipsilateral lesions are increasing in size or density as well, synchronous limited resection of these lesions may provide valuable additional information, especially when considering targeted systemic treatment [3]. Further lesions that are suspected to be malignant and are located contralaterally or difficult to access surgically, or that require large parenchymal resections, are commonly treated by stereotactic body radiation therapy (SBRT), as are patients who do not have sufficient functional reserve to undergo surgery [16].

Pneumonic-type adenocarcinoma

Typically, CT of patients with pneumonic-type adenocarcinoma shows a diffuse consolidative pattern that includes ground-glass as well as solid components [17]. Histologically, these findings commonly correspond to mucinous adenocarcinoma with highly heterogeneous areas. The IASLC Multiple Pulmonary Sites Workgroup proposes that the staging in these patients is performed according to the TNM classification. Tumours confined to one lobe are thus staged as T3, tumours involving multiple lobes of one side as T4 and tumours with bilateral spread as M1a [4]. While the rate of progression is usually slow and nodal or systemic metastases are rare, the prognosis is significantly poorer than in patients with multifocal GG/L adenocarcinoma [4]. Owing to the rare occurrence of this disease entity, treatment recommendations are mainly based on expert opinions and individual decision-making by a multidisciplinary tumour board is essential. Because of the diffuse spread of the disease, surgery is commonly only performed if a single lobe is affected. In selected patients, the use of double-lung transplantation is reported in the literature with a 5-year survival rate of 39% [18].

Conclusion

Implementation of low-dose CT screening for lung cancer is increasing the diagnosis of numerous pulmonary nodules, ranging from preinvasive to invasive types. Future studies including pathological and molecular assessment of matched tissue samples from multiple lesions may hopefully elucidate the lineage connections of these lesions and thereby offer valuable understanding into their development as cancers. This knowledge will help to guide multidisciplinary tumour board decisions on well-informed treatment strategies for this increasingly common clinical scenario. With regards multifocal lung adenocarcinoma with GG/L features, parenchymal-sparing surgical resection of the lesions with accelerating growth or solid components remains the gold standard in patients who are eligible for a definitive local treatment.

Induced oligoprogressionSummary

With the current standard-of-care systemic treatments, many patients with widespread stage IV NSCLC show disease control and partial or complete responses, but a majority will face disease progression [19]. However, a significant proportion of the latter will present with induced oligoprogressive disease (OPD), which describes cancer progression in a limited number of sites with otherwise controlled disease (figure 3). Currently, there are many knowledge gaps in the definition and treatment of OPD. Based on the evidence available, local ablative therapy (LAT) by minimally invasive surgery and/or SBRT to moderate doses are promising options to address localised treatment resistance. The ideal time for a switch in systemic treatment currently remains uncertain, but treatment continuation beyond progression is often recommended in OPD because it preserves further treatment options.

FIGURE 3

Chest computed tomography (CT) was performed in a 75-year-old female patient owing to a persistent cough and elevated inflammatory markers. The CT showed a large tumour in the right upper lobe and multiple bilateral pulmonary lesions. A subsequent bronchoscopy and endobronchial ultrasound-guided biopsy confirmed a thyroid transcription factor-1 (TTF-1)+ adenocarcinoma with hilar lymph node metastases. Next-generation sequencing revealed an epidermal growth factor receptor (EGFR) exon 19 mutation. The subsequent fluorodeoxyglucose positron emission tomography-CT (PET-CT) showed the primary tumour in the right upper lobe with pulmonary metastases (a). A brain magnetic resonance tomography (MRT) showed no intracranial metastases. Therefore, a clinical Tumour, Node, Metastasis (TNM, 8th edition) stage cT4 cN1 cM1a was assumed. The patient underwent targeted treatment with osimertinib and, after 3 months, a metabolic and morphologic partial response was seen (b). The patient continued osimertinib and, after another 3 months, oligoprogression occurred in the left upper lobe (upper panel, c). A robotic-assisted wide wedge resection was performed (lower panel, c) and histological analysis confirmed that the adenocarcinoma metastasis maintained the identical EGFR exon 19 mutation without additional resistance mutations. Targeted therapy with osimertinib was thus continued and, after another 6 months, a follow-up PET-CT showed oligoprogression at the site of the primary tumour in the right upper lobe (upper panel, d). The patient then underwent stereotactic body radiation therapy of the progressive lesion in the right upper lobe with eight fractions of 6 Gy (65% isodose) using a volumetric modulated arc therapy technique (lower panel, d). Osimertinib was again continued beyond progression and, to date, regular clinical and radiological follow-up 5 years after initial diagnosis has not shown any signs of relapse. The patient was treated at the University Hospital Zurich.

Definition

Over the course of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) treatment, an oligoprogressive pattern is seen in 15–47% of all patients [20–22]. OPD is less common under immune checkpoint inhibitor (ICI) treatment when compared to TKI treatment, with an approximate incidence of 20% [23]. The initial state of disseminated or polymetastatic disease is what sets apart the concept of induced OPD from the better-established concept of oligometastatic disease (OMD). A European Society for Radiotherapy and Oncology and European Organisation for Research and Treatment of Cancer consensus report recently defined the scope of OMD and distinguished the state of induced OPD (discussed within this review) from metachronous oligoprogression [24]. The latter was defined by new appearance of oligometastases >6 months after systemic treatment for a non-metastatic disease and its treatment goes beyond the scope of this review [24]. The concept of induced OPD is supported by multiple studies that assessed the genetic evolution of tumours at sites of localised progression by re-biopsy: once treatment resistance is acquired in a tumour subpopulation, this subpopulation is selected in a Darwinian manner and may systemically re-seed to cause widespread disease progression [21, 25, 26].

The development of localised treatment failure and acquired resistance to systemic treatment is believed to involve diverse mechanisms that depend on the tumour's genetic profile and the applied treatment modalities. In patients with acquired resistance to TKI treatment, a re-biopsy should thus be performed whenever possible to identify the molecular driver of resistance [27]. Under ICI treatment, different mechanisms, e.g. tumour-associated loss of neoantigens, expression of alternate immune checkpoints, defective interferon-receptor signalling or antigen presentation pathway, and changes in the tumour microenvironment are assumed to induce treatment resistance [28–30]. From a clinical perspective, the induced OPD setting offers the meaningful opportunity to regain short- or even long-term control of a disseminated disease by the use of local treatments [31]. The local eradication of de-differentiated subclones in this intermediate stage of disease aims to restore the status of treatment sensitivity that subsequently enables re-initiation of the previous systemic treatment [26]. In various retrospective analyses, the oligoprogressive state was associated with a favourable prognosis with significantly improved progression-free survival (PFS) and OS when compared to multi-progressive disease (defined as more than five metastases) [30, 32, 33]. Different oncogenic driver mutations result in a distinctive pattern of metastatic spread, with a higher incidence of liver and brain metastases in EGFR-mutant NSCLC and an increased risk of liver, pleural and pericardial metastases in anaplastic lymphoma kinase (ALK)-mutant NSCLC [26, 34, 35]. Nevertheless, the most common site of treatment failure remains the lung itself [26, 34].

Currently, there is very limited evidence to guide local salvage therapies and systemic treatment decisions for induced OPD. And while several prospective phase 2 and 3 trials, including local, systemic and combined approaches, are ongoing (ClinicalTrials.gov: NCT03256981, NCT04405401, NCT04892953, NCT04549428, NCT04767009, NCT02759835, NCT03410043), the recommendations discussed here are based primarily on low-quality evidence and expert opinions.

Systemic treatment for induced OPD

In patients under TKI treatment presenting with OPD in the follow-up, the options are either to switch to a next-generation TKI (e.g. osimertinib after first-line erlotinib or afatinib after first-line gefitinib) or to continue the established treatment beyond radiological progression until clinical progression occurs [26]. If no further targeted treatment option is available, a switch to conventional chemotherapy can be performed. However, the termination of TKI treatment in oncogene-addicted NSCLC may result in a rapid disease flare and hyperprogression within a short time after discontinuation [36]. In addition, each change in treatment means that further treatment options become more and more limited and, based on current data, an established TKI treatment should be continued beyond radiological progression [26]. The results of the ASPIRATION phase 2 study confirm that a continuation of erlotinib despite radiological progression is feasible and associated with a potential improvement in OS [37]. However, in contrast, the IMPRESS phase 3 study assessed the efficacy of continuing gefitinib with platinum-based chemotherapy for gefitinib-resistant NSCLC and did not find significantly prolonged PFS when compared to platinum-based chemotherapy alone [38]. Unfortunately, there are currently no robust clinical data about the management of OPD after ICI therapy. However, there are several ongoing clinical phase 2 studies that evaluate a continuation of ICI beyond progression (UMIN-CTR: UMIN000041778; ClinicalTrials.gov: NCT04767009) or an ICI switch to atezolizumab (ClinicalTrials.gov: NCT04549428) in combination with local treatment. Considering the remaining uncertainty about the ideal time for a treatment switch, the decision about continuing an established treatment should always be discussed individually by a multidisciplinary tumour board.

Local therapy for induced OPD

While there are a few prospective trials assessing the application of local treatment options in oncogene-addicted NSCLC and induced OPD, there are currently no prospective data evaluating the addition of local treatments in patients with non-oncogene-addicted NSCLC under ICI [39, 40]. Based on the available evidence, the current guidelines of the European Society of Medical Oncology (ESMO), as well as the current guidelines of the National Comprehensive Cancer Network, suggest LAT to the oligoprogressive sites as a reasonable treatment option that may extend the duration of benefit of the current line of systemic therapy [39–41]. However, due to the lack of evidence there are no specific recommendations concerning the modality of LAT (surgery versus radiotherapy) [39–41].

Surgical treatment

In a selected group of patients with either induced OPD or residual disease after first-line systemic treatment, surgical resection within a salvage concept is under evaluation as an additional treatment option. Currently, clinical data on the outcome of this approach are scarce and candidate selection remains a central challenge. In case of OPD at the site of the primary tumour and especially after ICI treatment or in patients with central tumours, hilar dissection may be complicated and extended resections including sleeve-resections or intrapericardial resections are common. Prospective, randomised trials are thus necessary to evaluate the benefit of this approach. At the University Hospital Zurich (Switzerland), the salVage trial, an investigator-initiated randomised phase 3 trial comparing maintenance with the addition of LAT in stage IV NSCLC and induced oligopersistence after standard-of-care first-line systemic treatment, started recruiting in February 2024 (ClinicalTrials.gov: NCT06114108). The trial features two co-primary end-points in a predefined hierarchy, first PFS and second quality of life as measured by patient-reported outcome measures.

Radiotherapy

The use of SBRT in induced OPD is supported by several retrospective cohort analyses. Qiu et al. [42] report a retrospective series of 46 patients with oligoprogressive EGFR-mutant NSCLC under TKI treatment who underwent LAT (radiotherapy in 44 patients, radiofrequency ablation of lung metastases in two patients). All patients continued the established TKI treatment and median PFS and OS were 7.0 and 13.0 months, respectively. Grade 3 pneumonitis was encountered in two patients (4.3%). A retrospective analysis by Rossi et al. [20] reported on 13 patients with induced OPD during first-line afatinib or gefitinib. LAT was performed by SBRT and TKI treatment was continued in 30 patients. Median OS was longer in the group receiving LAT compared to patients who continued TKI beyond progression without LAT (37.3 months versus 20.1 months, p<0.001) [20].

To date, there is evidence on local therapy for induced OPD from four prospective phase 2 or 3 trials (table 1). In the multi-institutional phase 2 trial by Iyengar et al. [43], 24 patients with OPD NSCLC under conventional chemotherapy received SBRT and concurrent erlotinib. Notably, none of the tumours tested harboured an EGFR mutation. With a median PFS of 14.7 months, and median OS of 20.4 months, the survival was longer than historical values for patients who received systemic agents only [43]. Kim et al. [44] conducted a single-arm phase 2 trial in oligoprogressive EGFR-mutant NSCLC in the era of osimertinib. All 24 patients received LAT by different modalities, including SBRT and/or surgery, and osimertinib was continued beyond progression. PFS was 11.2 months, and ever longer in a cohort of T790M-positive cases (15.8 months) [44]. Another phase 2 study on oligoprogressive EGFR-mutant NSCLC was conducted by Weiss et al. [45]. Patients who showed OPD under treatment with erlotinib underwent LAT by SBRT and osimertinib was continued beyond progression. After SBRT, the median PFS was 6 months. Owing to poor accrual with upcoming third-generation TKI alternatives, the trial was closed early [45]. An interim analysis of the only randomised trial in OPD to date, the CURB trial, showed a significantly longer PFS in the cohort of NSCLC patients treated by SBRT (median PFS of 44 weeks versus 9 weeks with standard of care) [46]. Unfortunately, the interim analysis does not provide insights into the administered systemic treatment that may fundamentally influence the outcome. In the population of induced OPD, there are currently several trials underway that assess different LAT approaches, such as the randomised NORTHSTAR (ClinicalTrials.gov: NCT03410043) and HALT (ClinicalTrials.gov: NCT03256981) trials. In general, when planning SBRT in patients under TKI treatment, the risk for flare-up of the disease when stopping the TKI should be balanced against the risk of toxicity. And last but not least, prognostic factors in the setting of advanced malignancies such as fat-free mass index or handgrip strength can provide help in the decision-making process for LAT [47].

TABLE 1

Clinical phase 2 and 3 trials on induced oligoprogression in NSCLC

Conclusion

Currently, the knowledge gaps in the definition and treatment of OMD and OPD do not allow clinical decisions to be based on high-level evidence. In view of the many uncertainties, minimally invasive surgery and/or SBRT to moderate doses are reasonable options as LAT in OPD. Cases of induced OPD should be discussed by a multidisciplinary tumour board to find a personalised treatment approach. In parallel, the currently ongoing clinical trials on different LAT approaches will help to guide treatment decisions in the future. Finally, in the population of OPD with extensively pretreated patients, quality-of-life considerations should play a central role in the multidisciplinary decision-making.

OligorecurrenceSummary

Another subgroup of OMD is oligorecurrence, marked by a disease-free interval (DFI) of ≥6 months and a controlled primary lesion. This subgroup comprises patients with markedly superior survival in comparison to synchronous OMD. While evidence strongly suggests the application of LAT to all metastatic sites, the treatment modality is still subject of ongoing discussions and thus far both surgery and SBRT, and potentially microwave ablation therapy, appear to be suitable therapeutic approaches.

Definition

Oligorecurrent NSCLC is a distinct clinical entity, limited to metastatic sites suited for localised treatment. Oligorecurrence and OMD share similarities, both describing a state of limited distant relapse confined to specific locations (figure 4) [48]. However, oligorecurrence differs by having a controlled primary lesion [48, 49]. This classification stems from the prognostic significance of the primary lesion's status, creating a favourable OMD subgroup [50]. Subsequently, patients with oligorecurrence exhibit better prognosis compared to synchronous oligometastatic or poly-recurrent cases [48, 51–53]. For instance, He et al. [54] observed a significant difference in OS, with oligorecurrent NSCLC patients experiencing an OS of 41.5 months compared to 21 months for sync-oligometastases. Similar results emerged from a larger study by Yamashita et al. [53], reporting median OS of 66.6 months for oligorecurrence and 23.9 months for sync-oligometastases across various primary tumours, including NSCLC, colorectal cancers, head and neck cancers, uterine cancers and others. It is common to differentiate synchronous from metachronous disease based on a DFI of 6 months [54, 55]. This differentiation is pivotal to discern between progression and true recurrence. Similar to OMD, the absence of a clear consensus on the definition of oligorecurrent NSCLC limits the comparison of outcomes from literature and the formation of treatment guidance. Therefore, establishing a uniform definition is crucial. While most authors have used three metastatic lesions as the threshold for oligorecurrence [51, 56], Sonoda et al. [57] proposed two metastatic lesions as the preferred threshold, given the notably better prognosis for one to two recurrences compared to three or more. In the context of oligorecurrence, it is important to mention that metachronous disease should be defined as a DFI of a minimum of 6 months [53]. The topic of oligorecurrence assumes high relevance, because with advances in postoperative surveillance tools an increasing number of patients is being detected with limited recurrence [58]. For instance, Zhang et al. [59] reported 60% of locally advanced NSCLC cases with disease progression displaying oligorecurrence. In summary, based on current evidence and expert opinions, we suggest defining oligorecurrence as one to three metachronous metastases in one organ, with a DFI >6 months, that can be treated by LAT, with the condition of a controlled primary lesion [24, 51, 52, 56, 60].

FIGURE 4

Computed tomography (CT) in a 73-year-old male patient revealed a 19 mm pulmonary nodule in the right lower lobe (a, yellow arrow). A video-assisted thoracoscopic surgery (VATS) right lower lobectomy was performed, and histological analysis revealed an adenosquamous carcinoma staged pT2a pN0. An R0 resection was achieved, the programmed cell death ligand-1 (PD-L1) status was negative (<1%) and no targetable mutation was present. Adjuvant therapy with tegafur/uracil followed. After 18 months, a 7 mm nodule was detected in the left upper lobe (b, yellow arrow), initially visible as a small nodule 6 months postoperatively. Both systemic therapies (chemotherapy, immunotherapy and tyrosine kinase inhibitors) and local ablative therapies (surgical resection, stereotactic body radiation therapy and radiofrequency ablation) were discussed. A VATS wedge resection was performed and histology confirmed squamous cell carcinoma without a driver mutation, suggestive of metastasis. The nodule measured 11 mm, and surgical margins were negative. Remarkably, even 2 years and 6 months after the oligo-metastasectomy, the patient remains disease-free. The patient was treated at Kyoto University Hospital.

LAT for oligorecurrent NSCLC

LAT has gained significant attention owing to their potential benefits on post-recurrence PFS and even OS [52, 54, 58–61]. However, despite several retrospective analyses suggesting an improvement in OS with LAT, its direct correlation has not yet been proven [61]. Research by Sonoda et al. [62] illustrated a significantly higher 5-year post-recurrence survival (PRS) rate of 55.6% for patients undergoing LAT versus 31.1% without, underlining LAT's efficacy. Although some prospective trials exist for OMD, evidence for oligorecurrence mainly relies on retrospective studies, demonstrating the need for more prospective trials (table 2) [51, 52, 60, 66]. A recent prospective observational study by Yano et al. [51] included 17 postoperative oligorecurrent NSCLC cases. Their findings aligned with prior retrospective research, indicating that LAT should be considered for managing oligorecurrence.

TABLE 2

Retrospective and prospective analyses of oligorecurrence in NSCLC

The choice of treatment modality for oligorecurrent NSCLC remains a subject of ongoing discussion and may vary based on the metastatic site and patient factors. In a retrospective study with 97 patients with oligorecurrent pulmonary NSCLC, surgical resection trended towards improved 5-year PRS and post-recurrence PFS compared to radiation therapy, although this was not statistically significant [62]. Additionally, significantly longer PRS for surgical resection has been reported when compared to nonoperative therapy with a similar cohort [54, 67].

Surgical treatment

Surgical resection offers the advantage of providing tissue samples for analysis, which is vital for distinguishing pulmonary oligorecurrence from secondary tumours [10, 68]. In a retrospective study involving a small cohort of 11 patients, He et al. [54] demonstrated a significantly longer OS and 5-year survival for patients with oligorecurrent pulmonary NSCLC who received combined surgical treatment and chemotherapy, compared to those who underwent chemotherapy alone. Additionally, the study findings supported the notion that pulmonary wedge resection and segmentectomy should be considered the preferred surgical approaches. Conversely, the authors cautioned against the use of lobectomy owing to its relatively higher operation risk and greater trauma [54]. This aligns with results from Aoki et al. [55], which indicated a better prognosis for patients who underwent sublobar resection instead of lobectomy or pneumonectomy. However, secondary surgery for oligorecurrent lesions in the chest may be challenging because of anatomical changes, higher complication rates and patient surgery-fatigue [58]. Furthermore, some patients may not be eligible for surgery owing to poor general condition or limited respiratory function [62]. In such cases, local radiotherapy with or without chemotherapy is an alternative treatment option [58]. Regarding surgical treatment for metastatic s