Role of Radiotherapy in the treatment of Metastatic Head and Neck Cancer

Different prognostic factors have been studied in patients with SBRT-treated metastasis. Rusthoven et al²³ showed a significant difference in 5-year survival for differently sized SBRT-treated metastases, with a 5-year local control rate of 100% for smaller lesions compared to 77% for those >3 cm. Other authors have shown a very low rate of 2-year progression-free survival in cases with fewer than three metastases.²⁷

There are some theoretical advantages to SBRT over surgery, with good immediate tolerance and ambulatory treatment, no need for anesthesia, and lower morbidity.²⁸ Furthermore, SBRT has the potential to be combined with new systemic therapies, such as immunotherapy. It has been shown that hypofractionated RT with doses of 10 Gy or 20 Gy sensitize antigen tumors to T-cell-mediated rejection through loading of tumor stroma with tumor antigens,²⁹ as well as enhanced functioning of effector T cells, inducing an abscopal effect at distance.³⁰ Moreover, different preclinical studies have suggested that hypofractionated treatment with doses of 10 Gy ×5 fractions and 8 Gy ×3 fractions plus CTLA4-blocking antibodies induces a higher abscopal response than conventional fractionation.^31,32 In addition, the combination of PDL1 inhibitors and SBRT has shown long survival in preclinical models.³³ Finally, necrosis after ablative doses has been associated with liberation of more neoantigens, in contrast to the mitotic catastrophe induced by conventional fractionation.³⁴ Different phase III studies are investigating the role of immunotherapy with CRT in HNC. The role of SBRT combined with immunotherapy in recurrent or mHNC cancer should be investigated. In summary, the treatment of metastasis with SBRT in oligometastatic disease is a safe procedure that offers the possibility of controlling the disease or delaying its progression, likewise delaying the need for further treatment.

Patients with HPV⁺ tumors with local or regional recurrence

Some studies have suggested that locoregional control is an important prognostic factor for survival in patients with already established DM,³⁵ supporting the concept that complete removal of the index primary tumor might be appropriate to achieve locoregional control, as long as this can be achieved with minimal morbidity.

Head and neck tumors associated with human papillomavirus (HPV) infections have been shown to follow a different natural course than HPV⁻ ones. Huang et al³⁶ compared the natural course of DM in 624 HPV⁺ (p16⁺) and HPV⁻ (HPV⁻/p16⁻) patients for whom HPV status was available and who had metastatic oropharyngeal cancer treated with chemoradiotherapy (CRT). The authors found a higher proportion of disseminating phenotypes and multiple organs affected among HPV⁺ patients compared to those who were HPV⁻, with DM as the predominant site of metastasis in these patients. Moreover, the subset of patients with HPV⁺ tumors and oligometastatic disease presented prolonged survival times, even with palliative treatment. McBride et al³⁷ investigated predictive factors for long-term survival in 25 patients with oropharyngeal cancer who developed metastases and had previously received radical approach treatment. Most of the patients (84%) had DMs at the time of distant failure with a controlled primary tumor, and seven had limited disease (one or two adjacent lesions in a single organ). Fifteen patients (78.9%) had undergone radical treatment for their DMs with surgery and/or RT, with or without systemic chemotherapy. HPV status was available for 54% of the patients, of whom 95% were HPV⁺. The authors reported a global rate of 2-year OS of 40.8% after the development of metastases. Limited DM and Karnofsky PS (KPS) were independent prognostic factors for survival, showing a very favorable outcome in the low-risk patients (limited DM and KPS ≥80), as 100% of the patients within this group survived >2 years after diagnosis of DM, whereas intermediate-risk (limited DM or KPS ≥80) and high-risk patients (extensive disease and KPS <80) presented 2-year survival after metastasis of 45.8% and 0, respectively. It should be noted that four of the five patients in the low-risk group were also HPV⁺. Finally, Sinha et al³⁵ studied the clinical outcomes of 66 patients with metastasis from an oropharynx carcinoma, of whom 38% were HPV⁻ and 62% HPV⁺. Locoregional disease was present in 52% of the HPV⁻ group compared with 25% in the HPV⁺ patients (P=0.022). A curative approach to the metastasis was performed in three HPV⁺ patients (12%) and eleven HPV⁻patients (27%). However, all p16⁻ patients either suffered progression or died within 24 months of DM detection; 2-year post-DM progression-free survival in the p16⁺ patients was 20%. Multivariate analysis identified that p16 negativity, no treatment/palliative treatment vs curative treatment of the metastasis, and presence of locoregional disease were associated with reduced post-DM disease-specific survival (Table 3).

(To view a larger version of Table 3, click here.)

Patients with metastatic nasopharyngeal carcinoma and local or regional recurrence

Recent research has investigated prognostic factors associated with long-term survival in patients with metastatic nasopharyngeal cancer (mNPC). A retrospective study of 263 patients diagnosed with mNPC identified two different prognostic groups of patients: patients with single-organ metastases or one to five lesions who presented a 5-year OS of 38.7% and patients with multiple-organ metastases or more than five lesions whose 5-year OS was 7%. In this study, treating the primary tumor with RT was a favorable prognostic factor for OS (HR 1.57, 95% CI 1.10–2.25).³⁸ In a recent study, Shen et al³⁹reported the results of a retrospective study of 312 patients with mNPC and bone-only metastases to identify which patients might benefit from combined CRT. In a multivariate analysis, the number of metastatic lesions (more than three vs three or fewer), spine involvement, and primary tumor-treatment modality (CRT vs chemotherapy or RT only) were independent prognostic factors for OS. Patients that were treated with CRT presented a 5-year OS of 57.3% compared with 11.2% in those that received palliative treatment with RT or chemotherapy. Cao et al⁴⁰ analyzed 221 patients who developed single type DM after primary treatment. Multivariate analysis showed that age >40 years, local recurrence, disease-free interval ≤24 months, and treatment with chemotherapy alone were independent negative prognostic factors. Moreover, CRT on the primary tumors was associated with longer survival in patients who presented up to two negative prognostic factors, with a median OS of 49.5 compared with 19.4 months.

Different clinical models are being investigated to better identify metastatic patients who may benefit from a curative approach. A recent report studied a prognostic classifier with support-vector-machine techniques to stratify mNPC in different prognostic groups. A ten-signature classifier was developed: three clinical variables (presence of oligometastases, N stage, and extraregional lymph-node metastasis) and seven hematological variables (Epstein–Barr virus viral capsid-antigen IgA, neutrophil count, monocyte count, platelet count, hemoglobin, glutamic–pyruvic transaminase, and glutamyl transpeptidase). Patients classified as low risk presented different survival after treatment of the primary tumor with CRT compared with chemotherapy alone, with 5-year OS of 47% and 10%, respectively (P>0.001).⁴¹ Investigation is needed to select precisely which patients with mNPC may benefit from a more radical approach.

Future perspectives

One of the key issues in the treatment of oligometastatic disease is how to identify accurately which tumors have true oligometastatic disease and which patients will benefit from a radical approach. Clinical factors have been shown to be ineffective for accurate prediction of which patients are at the oligometastatic stage and may be candidates for a radical approach. Different molecular approaches are being tested to correlate biological markers with clinical outcomes and improve the ability to predict oligometastatic disease. Lussier et al⁴² analyzed miRNA expression from lung metastases in patients with fewer than five metastases treated with curative intent. Stratification with miRNA expression identified two groups of patients with different rates of progression and survival. Further, the existence of circulating tumor cells has been shown to be predictive of response to systemic therapy in metastatic breast cancer.⁴³ Theoretically, circulating tumor cells may help to identify patients with a true oligometastatic state that will facilitate accurate selection of patients for a radical approach,⁴⁴ increasing the therapeutic ratio of patients.

Finally, recent data from immunotherapy trials performed on recurrent and mHNC patients have suggested that a subgroup of patients may present a considerable increase in long-term survival after treatment with checkpoint inhibitors.³ The role of radical treatment with RT in this clinical setting should be studied in future.