Radiation therapy for synchronous oligometastatic Nasopharyngeal cancer in a low-middle-income country

Introduction

Nasopharyngeal cancer ranks 23rd globally in terms of occurrence. In North Africa, its prevalence is significant, with an annual incidence rate of 24 cases per 100,000 inhabitants.¹ In Tunisia, it is the second most common head and neck cancer, following laryngeal tumors.² Due to its location within the nasopharynx and the often-non-specific nature of its early symptoms, diagnosis frequently occurs late, leading to a poorer prognosis.³ Metastases are present at the time of diagnosis in 4 to 10% of cases.⁴

For localized tumors, radiotherapy is the standard treatment, which may or may not be combined with chemotherapy.⁵ For metastatic tumors, polychemotherapy is often recommended.⁵

Indeed, the concept of oligometastasis has revolutionized the treatment of many solid tumors; it describes a state between localized disease and disseminated cancer, characterized by a limited number of metastases.⁷ Numerous studies have demonstrated that aggressive treatment, including curative intent therapy for the primary tumor, can significantly improve survival rates in cancers such as prostate, colorectal, and lung cancer.^8,9

Given the promising outcomes observed in other cancers with oligometastasis, we hypothesized that a similar approach could be beneficial for patients with oligometastatic nasopharyngeal cancer. Therefore, we conducted a retrospective study on patients with oligometastatic nasopharyngeal cancer treated with curative intent radiotherapy to analyze survival outcomes and identify prognostic factors.

Materials and methods

Results

Between January 2015 and December 2021, 70 patients were diagnosed with oligometastatic nasopharyngeal cancer at our institution. After excluding 11 patients who received palliative radiotherapy and 9 others who experienced disease progression after primary chemotherapy, a total of 50 patients were deemed eligible for inclusion in our study. The mean age of the patients was 49.6 years, with a male predominance (male-to-female ratio of 2:1). The median delay in consultation was 4 months. Presenting symptoms included rhinologic symptoms in 38% of patients and the presence of lymphadenopathy in 34% of cases. All patients presented with undifferentiated carcinoma nasopharyngeal type. The basic clinical data of the patient cohort are shown in Table 1.

Ninety-four percent of patients completed 3 to 6 cycles of palliative chemotherapy, including a platinum-based regimen. Eighty-four percent of patients achieved a partial response in the primary tumor, while 42% achieved a partial response in metastatic sites. All patients underwent curative radiotherapy to the primary tumor with a dose of 70 Gy delivered in 35 fractions, and 49 patients received concurrent chemotherapy during radiotherapy. Forty-six percent of patients received curative treatment for metastases, with 6 patients undergoing surgery and 17 receiving radiotherapy. The surgical treatments included 3 wedge resections of pulmonary masses, 1 laminectomy, and 2 axillary dissections for nodal metastases. Twenty-four percent of patients received maintenance chemotherapy with capecitabine. Table 2 summarizes the treatment modalities administered to our patients.

During a median follow-up of 39.9 months, we found that 52% of patients with disease progression, and 39 patients died. Median PFS was 14 months (95% CI: 7-24.5 months) and Median OS was 32 months (95% CI: 23.5-49.5 months). The 1-year PFS rate was 56% and the 3-year PFS rate was 18% (Figure 1). The 1-year OS rate was 92% and the 3-year OS rate was 44% (Figure 2).

Figure 1. Progression free survival of the entire patient cohort.

Figure 2. Overall survival of the entire patient cohort.

Univariate analysis indicated that several factors were significantly associated with improved OS: female gender (p=0.046), early-stage tumors (T1-T2, p=0.028), metastases in sites other than bone (p=0.023), treatment with intensity-modulated radiation therapy (IMRT) (p=0.03), and maintenance chemotherapy following radiotherapy (p=0.047).

Additionally, factors associated with improved PFS included female gender (p=0.008), early-stage tumors (T1-T2, p=0.021), absence of RT interruption (p=0.043), and maintenance chemotherapy following radiotherapy (p=0.04). Table 3 summarizes the results of the univariate analysis.

As for the multivariate analysis, no prognostic factors were associated with progression-free survival. However, T1-T2 stage and metastases to sites other than bone were independent prognostic factors for overall survival with p=0.024 and 0.001, respectively.

Discussion

The concept of oligometastatic cancer was introduced by Hellman and Weichselbaum in 1995,⁷ and since then, its definition has varied across different studies. Recently, the WHO published the 9th edition of the nasopharyngeal carcinoma classification, introducing a new subgroup, M1a, for patients with 3 or fewer metastases.¹¹ In our study, we considered patients with fewer than 5 metastases and a maximum of two affected organs as oligometastatic.

Numerous retrospective studies have demonstrated improved OS in metastatic nasopharyngeal carcinoma (mNPC) patients treated with palliative chemotherapy combined with curative radiotherapy compared to those receiving only palliative chemotherapy.^12–17

A large series from the National Cancer Database (NCDB), which included 718 patients newly diagnosed with mNPC, further corroborated these findings. This analysis revealed a significant improvement in OS for patients receiving radiotherapy (median OS: 21.4 months) compared to those who did not receive it (median OS: 15.5 months). Moreover, the study showed a positive correlation between increasing radiotherapy doses and improved OS.¹⁶

A phase 3 prospective study involving 126 patients with mNPC evaluated the impact of curative radiotherapy following palliative chemotherapy. After a median follow-up of 26.7 months, the 24-month OS was significantly higher in patients receiving radiotherapy (76.4%) than in those treated with chemotherapy alone (54.5%). The study also demonstrated an improvement in PFS in patients receiving curative RT (p < 0.01). However, it is important to note that only a limited proportion of patients (19–20%) had oligometastatic disease.⁶

A recent phase 2 prospective study by Huang et al. involving 69 patients investigated the efficacy of locoregional RT in patients with oligometastatic nasopharyngeal carcinoma. With a median follow-up of 60 months, the study demonstrated a median PFS of 24.23 months, suggesting a promising role for locoregional RT in this setting. Furthermore, it reported a median OS of 53.87 months in patients treated with chemoradiotherapy, indicating a significant improvement in long-term survival outcomes.¹⁸

In our study, the median OS and PFS were 32 and 14 months, respectively. The 3-year OS and PFS rates were 44% and 18%, respectively. While these results compare favorably with some previously reported outcomes, they fall below those observed in the phase 2 study by Huang et al. Several factors may have contributed to this discrepancy. Firstly, our study included a relatively small patient population. Secondly, the limited availability of initial 18F-FDG PET/CT imaging may have impacted patient selection and treatment planning, potentially influencing overall outcomes.

The impact of gender on OS and PFS in mNPC remains controversial, with conflicting findings in the literature. Some retrospective studies reported no significant OS or PFS differences between genders, while others suggested a survival advantage for either men or women.^14,19,20 Notably, our study found a statistically significant improvement in OS (p=0.046) and PFS (p=0.008) for women.

The number of affected organs has been identified as an important factor influencing OS and PFS in several retrospective studies.^14,21 This was further confirmed in the study by Huang et al., which found significantly better OS (p = 0.001) and PFS (p = 0.037) in patients with only one affected organ. Additionally, it showed that among oligometastatic patients, the exact number of metastases (1, 2, or 3–5) had no impact on survival.¹⁸

The site of metastasis also impacts survival outcomes. The literature suggests that hepatic metastases are associated with poorer survival.^15,21 However, our findings differed, showing better survival in patients with visceral metastases (other than bone). These unexpected results may be explained by the limited number of patients with hepatic metastases in our study.

The analysis of the NCDB highlighted the importance of the RT dose in the treatment of mNPC, showing that a dose greater than 50 Gy is beneficial, with an optimal dose of 70 Gy or higher.¹⁶

The optimal fractionation schedule for RT remains uncertain. A prospective phase 2 study found no significant difference between normofractionated treatment (70 Gy in 33 fractions) and hypofractionated treatment (60 Gy in 25 fractions).²²

It has been shown that interruptions in RT negatively impact local control, even if the delay is brief (>2 days).²³ Our study further confirmed these findings from the literature.

The RT technique was established based on studies of localized NPC, with IMRT being the standard of care.^24,25 However, no studies have directly compared the impact of different RT techniques on survival in mNPC. Notably, our results showed that patients treated with IMRT had better OS and PFS than those treated with 2D RT.

A phase 3 clinical study demonstrated that maintenance chemotherapy with capecitabine improves survival; however, none of these patients received RT.²⁶ Similarly, in the study conducted by Huang et al., patients receiving maintenance chemotherapy had better PFS.¹⁸ The limited number of patients receiving this adjuvant chemotherapy in our cohort may explain the lack of long-term survival benefits.

The value of local treatment for metastases remains controversial. Most retrospective studies suggest that combining systemic therapy with local treatment in mNPC may improve survival outcomes.^27,28 One study involving 105 patients with oligometastatic mNPC with a single lung lesion found that combining local treatment - either stereotactic RT or surgery - with chemotherapy significantly improved OS and PFS compared to chemotherapy alone.²⁹ Furthermore, Huang et al. confirmed the importance of local treatment in improving OS (p = 0.05).¹⁸ In our study, most patients received radiotherapy, but primarily at a palliative dose, which may explain the absence of improved survival rates.

The addition of anti-PD-1 therapy to chemotherapy (gemcitabine-cisplatin) has shown promising results in mNPC, with a significant improvement in survival.^30,31 Several ongoing studies are evaluating the combination of chemotherapy, immunotherapy, locoregional RT, and local metastasis-directed treatment with SBRT in oligometastatic nasopharyngeal cancer (NCT05385926, NCT05431764, NCT05290194). A more aggressive treatment approach may further enhance survival and quality of life for these patients.

Our study has several limitations. First, its retrospective design inherently restricts its value. Second, the absence of PET-CT FDG for initial staging and the lack of circulating EBV DNA assessment hindered our ability to perform accurate initial stratification. Finally, treatment heterogeneity over time, including variations in chemotherapy regimens and radiotherapy techniques, adds another limitation.

Nevertheless, it is important to note that, to our knowledge, this is the first north-African study reporting results for this specific patient population.

Conclusion

Our study examined the treatment outcomes for patients with newly diagnosed oligometastatic nasopharyngeal cancer. It demonstrates that an optimal treatment approach combining chemotherapy, high-dose radiotherapy, and curative local treatment of metastases can improve overall survival and progression-free survival.

Further prospective studies evaluating the addition of immunotherapy are needed in order to determine the best treatment strategy for these patients, who have a better prognosis.

Ethics statement

This study was approved by the ethical committee of Salah Azaiez Institute, on January 9^th, 2025 (Approval N0: ISA/2025/1). The study was conducted in accordance with the ethical principles of the Declaration of Helsinki. Patient data anonymity and confidentiality were ensured throughout the data collection process.