In 2018, approximately 572 000 new cases of oesophageal cancer were diagnosed worldwide, and this was the seventh most common cancer diagnosed in South Africa.^1,2,3 Approximately 70% of cases in England, Scotland and Northern Ireland in 2014 were diagnosed at a late stage.¹ Although definitive data are lacking for South Africa, most new cases follow a similar trend, with a high percentage of patients presenting with locally advanced or metastatic disease. One retrospective study conducted in South Africa by Dandara et al.⁴ examining all patients presenting with oesophageal cancer over a 30-year period reported that 76% of patients presented with advanced disease and poor clinical condition requiring palliative care.⁴ In those patients receiving palliative care, the average survival was approximately 4–6 months.^4,5

Dysphagia is documented as the most common presenting symptom, prompting patients with oesophageal cancer to seek medical care and has a substantial impact on quality of life which becomes more significant in advanced disease.^6,7 One large study conducted by the American College of Surgeons⁸ reported dysphagia in 74% of the 5044 patients enrolled. Palliation of this symptom is crucial to maintain an acceptable quality of life in these patients.^9,10,11

Currently no consensus guidelines are available for the optimal management of dysphagia in patients with locally advanced and metastatic oesophageal cancer. Options for palliation include stent placement, dilatation, external beam radiotherapy (RT), brachytherapy, chemotherapy, laser treatment, and photodynamic therapy or ablation.^12,13 Various studies have been carried out comparing the benefit of RT, both external beam radiotherapy (EBRT) and brachytherapy to endoscopic stenting while evaluating various end points to determine the efficacy of treatment. Retrospective studies demonstrated that endoluminal stenting that provided earlier and more rapid relief of symptoms, however, was associated with recurrent dysphagia in the long-term¹¹ while RT provides more durable response.¹⁴ These studies suggested the optimal management for palliation of dysphagia in these patients is a combination of endoluminal stenting and RT or brachytherapy.^13,14,15,16 Palliative chemoradiation shows a modest but not significant benefit over RT alone¹⁷; and considering the increased toxicity associated with concurrent chemoradiation, it is not considered a viable option in palliation. Although previous data suggest effective relief of dysphagia in patients with locally advanced and metastatic oesophageal cancer treated with palliative RT,⁵ only limited data are available to suggest the duration of this response. One retrospective study of the use of RT in palliation of dysphagia conducted in the Netherlands by Caspers et al.¹⁸ reports improvement in dysphagia score (DS) in 70.5% of patients with a median dysphagia-free interval of 3.7 months. Another retrospective study conducted in Germany by Welsch et al.¹⁹ between 1994 and 2004, analysing 139 patients with advanced or incurable oesophageal cancer treated with palliative RT, that is, with EBRT, brachytherapy or a combination of both EBRT and brachytherapy, reported subjective symptom relief in 72% of patients with a median response duration of five months.¹⁹ Our study was primarily aimed at examining the overall duration of response to RT in our clinical setting and to identify the contributing factors that may affect the overall response to palliative RT.

A total of 84 patients presenting to the gastro-oesophageal carcinoma clinic between the period January 2015 and December 2016 met the inclusion criteria for the study. The patient- and disease-specific factors were grouped by variables such as gender, age group, PS (ECOG), histological subtype and location of primary tumour are provided in Table 1.

A slight predominance of male patients 46 (54.8%) versus female patients 38 (45.2%) was observed. The mean age was 59 years and the modal age group was 51–60. More than 50% of all patients were between 50 and 70 years. No patients in our study population were younger than 31 years of age. Most patients were observed to have a PS (ECOG) 2 or 3. Regarding the duration of symptoms, most patients had symptoms for > 3–6 months prior to presentation; and the mean duration of symptoms was 6.1 months before seeking medical attention. The most common presenting symptoms were dysphagia and weight loss. More than 85% of patients had reported weight loss as shown in Table 1; of these > 75% reported losing more than 10% of their baseline body weight.

The most common histological subtype was squamous cell cancer (78 patients; 92.9%) versus adenocarcinoma (6 patients; 7.1%). The most common subsite among all patients was the middle third of the oesophagus (46 patients; 54.8%) followed by the lower third of the oesophagus (16 patients; 22.6%). The least common subsite was the gastro-oesophageal junction (6 patients; 7.1%).

More than 90% of the patients had a DS ≥ 2 at presentation. Approximately half of the patients had insertion of oesophageal stent (43 patients, 51.2%). Most patients presenting with DS ≤ 2 did not have oesophageal stent insertion. Of the patients with grade 4 dysphagia who were referred for stent insertion, one failed to have the procedure because of poor PS (ECOG) (Table 2). After stent insertion, 100% of patients had an improvement in DS by ≥ 1 point.

For the delivery of palliative RT, three fractionation regimens were used, namely, 18 (21%) of patients received 20.0 Gy in 5#, 60 (71%) received 18.4 Gy in 4# and 6 (7%) received 30.0 Gy in 10#.

The DS as assessed prior to starting RT, after RT and at the time of progression of dysphagia is shown in Figure 1. One patient was lost to follow-up and hence the data for the remaining 83 patients were analysed. Prior to RT, the majority of patients (94%) had DS of grade 2 or 3. Our study did not include any patients with grade 4 dysphagia at the time of RT as all patients seen post-stent insertion with DS of grade 4 either did not meet the inclusion criteria or died prior to receiving RT. At the post-RT review, 58 patients (68.9%) had DS of grade 2 or 3. One patient (1.2%) had a deterioration in DS to grade 4 following RT.

The duration of DPFS is represented in the column chart (Figure 2) and scatter plot (Figure 3). The median DPFS calculated using the ungrouped data was 73 days (IQR: 35–145) (Figure 4). Simple and multiple linear regression analyses were performed to assess the association between DPFS and several variables. The median DPFS appeared to have a numerically significant difference between those with and without stent insertion, with patients with a stent having a shorter duration of DPFS (median 54 days; [IQR: 31–98]) than those without a stent (median 83 days; [IQR: 45.5–176.5]) (Figure 5). However, this result in conjunction with the log-rank test (p = 0.224) confirmed no statistical significance between DPFS in patients who were stented and those who were not.

A simple regression analysis showed the median duration of DPFS significantly differed by DS at presentation (p = 0.045), DS after RT (p < 0.0001) and PS (ECOG) (p = 0.036) (Table 3). Using multiple linear regression, only the DS after RT (p < 0.0001) was found to be significantly associated with DPFS. From this analysis, for every 1 point increase in DS, the DPFS decreased by 61 days.

The objective changes in DS when reassessed at six weeks after palliative RT were as follows: 4 (4.8%) of patients had worsening of DS, 48 (57.8%) of patients had no change in DS from baseline; however, 31 patients (37.3%) had an improvement in DS following RT; 21 patients (25.3%) reported an improvement in DS by 1 point, 8 patients (9.6%) reported an improvement by 2 points and 2 patients (2.4%) reported an improvement by 3 points. The mean objective change in DS was 0.45 ± 0.89 points in all patients at six weeks post-RT treatment and 0.28 ± 0.80 points in stented and 0.63 ± 0.95 points in non-stented patients. Independent t test showed that the difference in mean objective change in DS between the stented and non-stented groups was not statistically significant (p = 0.0757).

Simple regression analysis showed DS at time of RT was the only variable significantly associated with the mean objective change in DS (p = 0.001) (Table 4). Using multiple linear regression, only the DS at the time of RT (p = 0.001) was found to be significantly associated with DS. From this analysis, for every 1 point increase in DS at the time of RT, the mean objective change post RT decreased by 0.56 points.

The median OS of patients receiving RT was 150 days (IQR: 131–169). The median OS in the RT patients without stents was 154 days (IQR: 99–211) while the median OS in the RT patients with stents was 136 days (IQR: 71–206). The difference between these values compared by Mann–Whitney U test was not statistically significant (p = 0.387).

The median survival following RT in the study population was 95 days (IQR: 41–154). In the stented group of patients, the median survival was 81 days (IQR: 30–135) compared to 123 days (IQR: 58–181) in the non-stented group of patients. The Mann–Whitney U test was used to assess the correlation between post-RT OS and stent insertion and showed that median survival post-RT was significantly shorter in patients who had a stent insertion (p = 0.0482).

Simple regression analysis showed that the only variables which significantly affected post-RT OS were DS at presentation (p = 0.027), change in DS post RT (p = 0.006) and PS (ECOG) (p = 0.031) (Table 5). Using multiple linear regression, DS at presentation (p = 0.002) and change in DS post RT (p < 0.0001) were found to be significantly associated with post-RT OS. From this analysis, for every 1 unit increase in DS at the time of RT, the duration of post-RT survival decreases by 75 days, holding other variables constant and for every 1 unit increase in the change in DS, the duration of post-RT survival increases by 56 days, holding other variables constant.

From our study, the median DPFS after palliative RT was 73 days; the median DPFS in patients without stent insertion was approximately 1 month longer than that in the stented subgroup of patients (83 days vs 54 days); however, this result was not statistically significant between the two groups (p = 0.224). Patients having DS 1 or 2 at presentation or post-RT or PS (ECOG) ≤2 had significantly better DPFS. No other variables were associated with DPFS.

Because of the assumption that patients who died were considered to have had dysphagia progression at the time of death, the estimated value for median DPFS in our study represents the worst-case scenario and is most likely to represent a minimum value as the cause of death may not directly be related to failure to swallow in these patients.

Following palliative RT, the median change in DS was 0, with most patients (57.8%) remaining unchanged following treatment. The mean objective change in DS was calculated as 0.45 ± 0.89 points. This value is much lower than that described in studies examining the impact of stent insertion as the sole intervention⁵ which suggests that patients receiving RT have a less dramatic improvement in dysphagia than patients who have stent insertion. Existing literature reports approximately 60% – 70% of patients have improvement in DS immediately following stent insertion.^14,21,22 The relief of dysphagia following RT is slower usually taking approximately 4–6 weeks to improve post RT.^11,23 From our data, at 6 weeks post RT, only 37.5% of patients reported improvement in DS, thus supporting previous data that stenting provides a more rapid relief of dysphagia than RT.

In our study population, the median OS was 150 days, the median OS in the RT patients without stents was 154 days while the median OS in the RT patients with stents was 136 days. Previous data suggested the median OS to be 62 days in patients with only covered stent insertion.¹⁰ Thus, our data suggest that the RT with or without stenting leads to an improved median OS.

The median post-RT survival in the study population was 95 days. The post-RT survival was significantly longer in the non-stented group than in the stented group of patients (123 vs. 81 days; p = 0.0482). Both PS (ECOG ≤ 2) and DS ≤ 2 at presentation and after RT were significantly associated with improved median post-RT survival on simple linear regression analysis. Using the DPFS curve for all patients who received radiation, at the time of 95 days (median post-RT survival), 40% of patients still did not have any progression of dysphagia. This validates the use of RT as an effective method of palliation of dysphagia to ensure that most patients are able to swallow at least liquids and soft diet until the time of death.

Most patients who had stents inserted had worse DS at presentation which can be attributed to more advanced disease and possibly more aggressive tumour biology. Cumulatively, these factors could lead to decreased tumour response and control following palliative RT and hence account for the poorer response in all measured outcomes in the stented subgroup of patients in our study population. Other than DS and PS (ECOG), no other patient or tumour factors significantly affected the outcomes in our patients treated with palliative RT. As such, PS and DS at presentation can be used to guide patient selection for those who will benefit the most from palliative RT, which can be useful in the setting of limited resources. Additionally, the DS and mean objective change in DS after RT can also be used to determine which patients are likely to have a longer survival and hence may benefit from further palliative therapies.

A major problem in the developing countries such as our setting revolves around access to care and health education, resulting in a high proportion of patients presenting late with advanced stage disease.²⁴ In our study, approximately 75% of patients reported having symptoms for more than three months and almost 10% of patients had symptoms for more than a year. Approximately 70% of patients presented had PS (ECOG) ≥ 2 and more than 80% of patients presented had significant weight loss of more than 10% baseline body weight. This can be attributed to the advanced DS at presentation, with more than 90% of patients having a DS of at least grade 2. This affects nutritional status and PS (ECOG) and contributes to the poor general physical condition that precludes many oesophageal cancer patients from receiving radical treatment.^6,7

When examining patient and disease characteristics, a male predominance is seen in our study (54.8%), with a higher incidence of squamous cell cancer (92.9%) and a predominance of tumours on the upper and middle oesophagus (70.3%). Previous data report oesophageal cancers located in the upper oesophagus are primarily squamous cell cancers and are associated with lifestyle and cultural factors such as diet, smoking and heavy alcohol consumption²⁵ and generally tend to be more prevalent in lower socio-economic populations.² These factors are also noted in a large proportion of our study population.

At our centre, the standard fractionation schedule used is 18.4 Gy in four fractions, which has the same EQD2 as 20 Gy in five fractions, a frequently used palliative fractionation schedule.²⁶ Notably, the fractionation schedule did not impact the objective response to RT. This is of significance in low- and middle-income countries where resources are scarce as a shorter fractionation schedule (i.e. 18.4 Gy in four fractions) can improve the workflow. The acute toxicity and complication associated with this regimen from our experience are tolerable, however were not described in the study; and hence, further research is necessary for comparison in this regard to other fractionation schedules.

A limitation of our study was that the impact of RT on the other symptoms associated with locally advanced oesophageal cancer such as odynophagia, pain and regurgitation was not assessed. Existing data suggest benefits of radiation for palliation of these symptoms but the duration of response is unknown.²⁷ In addition, an objective assessment of the DS was involved following RT; however, the impact on nutritional status and weight gain was not assessed. These represent areas requiring further work in locally advanced and metastatic oesophageal cancer.

Radiotherapy is beneficial to palliation of dysphagia associated with locally advanced and metastatic squamous cell cancer of the oesophagus with respect to DPFS and improvement in DS. The median duration of DPFS following RT was 73 days; in relation to the post-RT survival, this was effective in palliating dysphagia in approximately 60% of patients until the time of death. Patients who have stent insertions had a shorter duration of response compared to patients without stent insertions. In the setting of patients with locally advanced and metastatic oesophageal cancer who are receiving palliative treatment, PS (ECOG) and DS at presentation can be used as a surrogate to determine which patients will benefit the most from RT. A short course of RT can be an effective method of palliation in these patients in a limited resource setting. Additional investigations on the quality of life and impact of RT on relief of other symptoms may be beneficial to further quantify the magnitude of benefits in these patients.