Evolving concepts in oligometastatic head and neck cancer

Characterised by an uncommon, indolent, and low-volume pattern of malignant dissemination to distant organs, the term oligometastatic has been used with the intent of local ablation and possibly improved overall survival in certain tumour types. But how uncommon is this phenomenon in head and neck cancer? What are the current treatment options and what the future directions of research? These and other questions will be addressed in this article.

Being linked to the history of local ablation of distant metastases, our understanding of oligometastatic disease has evolved over time, and its definition has thus been a continuous matter of debate (Tab. 1).^1–9 Clinical trials have usually adopted diagnostic criteria relying on the maximum number of metastases not surpassing three to five lesions, which has also been proposed in a recently published European Society for Radiotherapy and Oncology/American Society for Radiation Oncology (ESTRO/ASTRO) consensus document.¹⁰

Nevertheless, mounting evidence suggests that a definition based primarily on a therapeutic opportunity has several shortcomings, particularly in that it does not exclude patients with a widespread subclinical dissemination. In this respect, disease biology and the role of the immune system seem to play a key role in the development of oligometastatic disease. This situation should therefore be considered a distinct clinical stage with intermediate aggressivity ranging between locoregionally advanced and widespread polymetastatic disease (Fig. 1), albeit more data being needed to draw definitive conclusions.

Epidemiology

In squamous cell carcinoma of the head and neck (SCCHN), the most common malignancy arising from the upper aerodigestive tract, reports on oligometastatic manifestation have been scarce and mostly limited to small retrospective studies.¹¹ This scarcity can partially be attributed to an overall low prevalence of this condition.

Illustrative to that are the results of a large retrospective analysis: The investigators found that out of 934 patients with locoregionally advanced oropharyngeal cancer and known human papillomavirus (HPV) status, there were 15% presenting with distant recurrence after initial management with radiotherapy or chemoradiotherapy. Only 4% of the 934 patients met criteria for oligometastatic disease defined by the presence of one to five lesions in not more than one organ. These patients were treated, and 10 (i.e., 1% of the initial population) were probably cured with no evidence of disease at the last follow-up visit (between 1.9 and 7.7 years after distant recurrence). All of the long survivors had lung disease, and the majority of them had HPV-positive disease treated with local ablation.¹²

These results have two important implications for clinical practice. The first is for patient follow-up, the latter for treatment, and both will be discussed here below.

Post-primary treatment surveillance

Early detection of recurrences, second primary tumours, and late toxicities in order to improve quality of life is the main objective of an active patient follow-up after completion of potentially curative treatment of the primary tumour with or without regional lymph node involvement (i.e., surgery, radiotherapy or chemoradiotherapy). Because of limited evidence and lacking predictive factors, the impact of post-treatment surveillance on overall survival has not been unequivocally demonstrated.¹³ Therefore, apart from few specific situations, periodic imaging is not routinely recommended in SCCHN survivors. However, HPV-positive oropharyngeal carcinoma patients presenting with metachronous oligometastases in the lungs (i.e., more than 3–6 months after primary diagnosis) may be an exception because they can be cured; this should be kept in mind in daily practice.

Of note, dissemination in the lungs is typically asymptomatic, and in comparison with HPV-negative SCCHN, it may appear over a longer period of time and also later during the post-treatment follow-up, even after five years. In addition, multiple organ sites are often involved including unusual localisations (e.g., muscle, kidney, pancreas). Hence, if radiology surveys are carried out, they should cover extrapulmonary regions as well.

Local treatment

As evident from Table 1, surgical resection has been supported by the largest body of evidence. In a meta-analysis of eleven studies retrospectively evaluating pulmonary metastasectomy in 387 SCCHN patients, 5-year overall survival rate reached up to 29%. The most common clinical manifestation was a single metachronous lung nodule, although patients with up to six of them were included. Noteworthy, the included individual studies identified the following poor prognostic factors: primary tumour in the oral cavity, initial regional lymph node positivity, short disease-free interval after primary treatment, incomplete resection, and multiple nodules.¹⁴

Due to the encouraging results and non-invasive nature, stereotactic (ablative) body radiotherapy (SABR/SBRT) has emerged as a viable alternative, particularly in non-operable cases, however, a direct comparison with surgery has been lacking.¹¹ Other, less frequently used methods of local ablation in SCCHN are mentioned in Table 1.

Systemic approaches

Systemic approaches are considered the current standard of care in recurrent and/or metastatic disease not amenable to curative local therapy. The latter condition varies according to institutional expertise and patient preferences. First-line palliative treatment options can be summarized as chemotherapy with or without cetuximab and immunotherapy with or without chemotherapy. They improve median overall survival to more than 1 year, but the outcomes strongly depend on used agents and patient and tumour characteristics.¹⁵ The information on the proportion of oligometastatic patients in the large phase III trials is missing, although it was probably low.

Nevertheless, similarly to local ablation, some patients receiving immune checkpoint inhibitors may experience long-lasting remission and this even if they initially presented with polymetastatic disease. Despite still limited long-term data, 5-year overall survival may be ranging from 10 to 30%.^16,17 However, the major drawback is a lack of validated predictive markers, currently represented only by programmed cell death ligand 1 (PD-L1) expression.¹⁵

Further options

Combination of systemic and local approaches and their sequencing have been gaining growing interest of healthcare professionals. As an example, if systemic therapy decreases tumour burden down to several persisting lesions (oligopersistence), local ablation at the next step may be used for oligoconsolidation of these remaining metastases. Analogously, if few metastases start progressing in a patient with an otherwise controlled polymetastatic disease, local ablation may be used to selectively target this so-called oligoprogression. On the other hand, selected cases may benefit from local ablation in order to postpone the initiation of systemic treatment or a change thereof.^11,18

Finally, keeping in mind that tumour doubling time is usually in the order of several months, treatment deferral may sometimes be preferred, especially in asymptomatic cases with known growth kinetics. The objective is to avoid jeopardizing quality of life or to verify if some micronodules develop in overt metastatic disease or not.^11,19,20

Future directions and conclusions

Despite the long history of clinical experience with patients presenting with an oligometastatic phenotype, our knowledge of its different underpinnings is far from being complete. Thus, ample opportunities arise to conduct research in the areas of preclinical studies, diagnostic workup, and treatment. In particular, a better insight into its biological basis together with fine-tuning its clinical determinants is indispensable for developing reliable composite prognostic and predictive models.

The concept of oligometastatic disease pertains to many cancer types, especially lung cancer, where it became part of the latest TNM staging system, colorectal cancer, renal cell carcinoma, prostate and breast cancers, and sarcomas. Therefore, while some advances in this field are common to all entities, such as technological advances (e.g., improvements in external and internal radiotherapy) or innovative approaches to clinical trial design (e.g., adjusted endpoints, patient-reported outcomes), other advances are specific only to certain tumour types. These include PSMA-targeted PET/CT in prostate cancer, new drugs (e.g., epigenetic modifiers reversing a polymetastatic to an oligometastatic phenotype), combinations of local and systemic therapies (especially with immune checkpoint inhibitors), treatment sequencing, or liquid biopsy to monitor residual disease and detect early recurrence.¹⁸ The latter holds great promise also in HPV-related oropharyngeal carcinoma, where cell-free plasma HPV DNA has been in the forefront of experimental studies.²¹

In conclusion, a great leap forward in the management of recurrent and/or metastatic SCCHN has been made in the past 20 years. In the continuous process of improvement, research of oligometastatic disease occupies an important place, pursuing cure as the ultimate goal of oncology.

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