Neoadjuvant chemoradiation in older Irish adult patients with oesophageal cancer: A retrospective institutional review of clinical outcomes and hematological toxicity

doi:10.21203/rs.3.rs-4864633/v1

Background and Objectives:

Neoadjuvant chemo-radiotherapy improves survival compared with surgery alone in locally advanced oesophageal cancer. In the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) randomised controlled trial (RCT), the median age was 60. However, one third of patients diagnosed with oesophageal cancer are aged ≥70 years. The reported outcomes and toxicities from the CROSS RCT are therefore limited in their application to older adult patients. The proportion of older patients with oesophageal cancer is increasing globally due to prolonged life expectancy and an aging population. The aim of this study was to investigate the clinical outcomes and toxicity reported in older patients (≥70 years) treated with neoadjuvant chemo-radiation for oesophageal cancer compared with those aged < 70 years in a tertiary Irish cancer centre.

Methods:

A retrospective cohort of patients treated with neoadjuvant chemo-radiation for oesophageal cancer was identified between 1^st January 2015 and 1^st January 2021. Eligible patients with cT1-4aNxM0 oesophageal cancer were identified in the Beaumont RCSI Cancer Centre database. Baseline characteristics and haematological toxicities were reported. Pathological response was reported. Chemotherapy toxicity was reported using the CTCAE Version 5.0. Survival was estimated using the Kaplan-Meier method. Survival between groups was compared using the log-rank test, and the Cox proportional hazards model was used to identify factors associated with overall survival (OS).

Results:

In total 105 patients with potentially curable oesophageal cancer were included. One third (n=35) of patients were ≥70 years (older cohort) and 70 (67%) aged <70 years (younger cohort). In the older cohort, the median age was 75 (range: 70-86) and the younger cohort median age was 60 (29-69). The majority in both cohorts were male (73%). In 5 (14%) of the older and 7 (10%) younger cohort, individuals experienced ≥ grade 3 neutropoenia. In total, 80% of the older and 86% of the younger cohort proceeded to surgery. There was no difference in OS between the cohorts. There was also no difference in disease free survival (DFS) between the cohorts.

Conclusion:

In conclusion, in patients aged ≥ 70 years compared to those aged < 70 years, we confirm that neoadjuvant chemoradiation is tolerable. There was no evidence to suggest any differences in OS and DFS between the cohorts. Neoadjuvant therapy in appropriately selected patients aged ≥ 70 years with oesophageal cancer is a reasonable treatment choice.

Ireland

Older Adult

Oesophageal Cancer

Chemoradiation

Oesophagostomy Surgery

Tolerability

Outcomes.

Oesophageal cancer is one of the most common cancers worldwide. The Global Cancer Statistics report estimated that 604,100 people were diagnosed with oesophageal cancer in 2020, and 544,076 people died of the disease in the same year(1). The proportion of older patients with oesophageal cancer is estimated to increase in the future due to longer life expectancy(2). For patients with locally advanced, but potentially curable disease, preoperative therapy is recommended based on the Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) (3). In this pivotal phase III randomised controlled trial (RCT), the median age of patients treated with carboplatin, paclitaxel and radiotherapy was 60 years and only patients aged 18 to 75 were eligible. However, the peak age of oesophageal cancer diagnosis is between 60 and 70 years and approximately 30% of all newly diagnosed patients with oesophageal cancer are older than 70 years (4). Hence, evidence concerning treatment strategies in older patients is still sparse (5).

In common with many clinical trials, prospective studies in oesophageal cancer have tended to enrol younger patients (6). Therefore, clinical trial experience may not translate into standard clinical practice as older patients tend to have poorer performance status, more comorbidities, and shorter life expectancy compared to younger individuals(5). Moreover, older patients might be less tolerant to trimodally therapy(7, 8, 9). Although some series have demonstrated favourable outcomes with preoperative chemo-radiotherapy in well-selected older patients, these have often focused on patients over 65 years of age(10, 11). In other cancers such as non-small cell lung cancer, outcomes have been specifically assessed in patients aged ≥ 70 years(12, 13). Therefore, we retrospectively sought to evaluate outcomes for older patients (aged ≥ 70 years) with oesophageal cancer who underwent neoadjuvant chemoradiation followed by surgery for locally advanced disease at an academic tertiary referral centre for oesophageal cancer in Ireland.

Patients diagnosed between 1^st January 2015 and 1^st January 2021 and treated with neoadjuvant chemoradiotherapy followed by surgery were identified from the prospectively maintained upper-gastrointestinal cancer database at the Beaumont Royal College of Surgeons of Ireland (RCSI) Cancer Centre in Dublin. Patients with histologically confirmed oesophageal or gastro-oesophageal junction (GEJ) carcinoma, T1-T4a, any nodal status and M0 disease per American Joint Committee on Cancer 8th edition were included. Data on cancer diagnosis, staging, treatment and outcomes were extracted from the database. All patients were planned to receive weekly chemotherapy with carboplatin at an area under the curve of 2 mg per millilitre per minute, paclitaxel 50 mg/m² with 41.4 Gray radiotherapy in 23 fractions. Data on chemotherapy doses administered, haematological toxicity, hospitalisation and length of stay, pathological response, disease free survival (DFS) and overall survival (OS) were collected from retrospective chart review. Haematological toxicity was graded using the CTCAE version 5.0 criteria from the start of treatment and for 6 weeks after completion of concurrent chemoradiation(14).

Baseline characteristics were compared between the two cohorts using frequency (%) for categorical data. Chi-square statistics are used for categorical comparisons between the groups and Fisher’s exact test is used for 2 by 2 group comparisons where the cell frequencies were small. Median length of hospital stay was presented and comparisons between cohorts using non-parametric Mann-Whitney U test were made.

Outcomes (recurrence and survival) were compared between patients in two cohorts: younger cohort (age < 70 years) and older cohort (age ≥ 70 years). DFS and OS were estimated using the Kaplan-Meier method, and the log-rank test was used to compare outcome survival curves with a data cut-off of December 1^st, 2022. One-, two- and three-year OS rates are provided with 95% confidence intervals (CIs) (Table 4). Cox proportional hazards (PH) regression analysis was performed to identify whether age (<70 vs ≥ 70 years), tumour stage and number of cycles of neoadjuvant therapy were associated with survival. Hazard ratios (HRs) and 95% CIs were presented. Patients with missing or incomplete data on treatment information or survival status were excluded. Stata (v17.0) was used for analysis and significance at p<0.05 was assumed throughout. Ethical approval was granted from the Beaumont RCSI ethics committee to conduct this retrospective review.

Patient Baseline Characteristics:

In total 105 patients were included. One third of patients (n=35) were aged ≥ 70 years and 70 patients (67%) were aged < 70 years (Table 1). In the older cohort, the median age was 75 (range: 70-86) and in the younger cohort the median age was 60 (range: 29-69). The majority (73%) of patients in each cohort were male. Similar numbers of patients in each cohort had adenocarcinoma (80% versus 74%) and squamous cell carcinoma (20% versus 26%). Tumour stage was comparable between cohorts.

In total 19 (54%) of older patients completed all five planned doses of chemotherapy concurrently with their radiotherapy (Table 1). In comparison 52 (74%) of younger patients completed the entire course of concurrent chemotherapy (p=0.026). The commonest reason for early discontinuation of chemotherapy was haematological toxicity. Anaemia was more common in the older cohort (88% versus 64.8%; p=0.01). 18(51%) and 33(47%) older and younger patients respectively experienced any grade of neutropoenia (p=0.68). In total, 15(43%) and 43(61%) of older and younger patients respectively experienced any grade of thrombocytopaenia (Table 2).

Five patients (14%) in the older cohort and 16 (23%) in the younger patient cohort were admitted to hospital with a treatment-related toxicity. The median length of hospital stay was 28 days (range 2-41) and 7.5 days (1-96) for the older and younger cohorts respectively.

In total, 28 (80%) of the older and 60 (86%) of the younger cohort proceeded to surgery. An R0 resection was achieved by 10 (36%) older and 29 (48%) younger patients. A complete pathological response was achieved by 3 (11%) and 17 (28%) patients in the older and younger cohorts respectively.

Survival results:

DFS was analysed across the entire population in our study, demonstrating 42% (44/105) patients had disease recurrence. There was no significant difference in recurrence between the cohorts < 70 years or ≥ 70 years was identified (figure 1).

At study cut-off 45 (43%) patients had died at median follow up of 19.1 months. The median OS was 31.5 months for those < 70 years of age and 41 months for those ≥ 70 years of age (Figure 2). Hazard ratios (HR) and 95% confidence interval (CI) for OS are presented in Table 3. Survival probabilities at 1, 2 and 3 years (with 95% CI) are shown in Table 4. In a Cox PH regression model, age ≥70 years was not significantly associated with OS after adjustment for tumour stage and cycles of chemotherapy administered (HR=0.79; 95% CI 0.37, 1.65; p=0.53).

Although the standard of care for potentially resectable locally advanced oesophageal cancer is neoadjuvant chemoradiotherapy followed by surgery, the efficacy and tolerability in older patients are unclear(6). This current study suggests that older patients are less likely to get an R0 resection and obtain a complete response, but side-effects and survival are comparable to younger patients.

Baseline clinical characteristics in this retrospective study are similar to the CROSS RCT and are comparable between both older and younger cohorts. On younger patient with Stage I disease was treated after multidisciplinary meeting discussion. This study highlights a real-world analysis in the Irish population of the clinical outcomes as it included many patients with more advanced disease e.g. T4 and N2 disease that the CROSS RCT excluded. Similar retrospective studies that have focused on elderly cohorts, typically aged 65 to 70 years and upwards(10, 11, 15, 16), including a review of several retrospective studies have reported on the toxicities and survival outcomes across the world(16, 17). In that systematic review, despite favourable survival outcomes, a higher incidence of toxicities was noted in older cohorts than we report within our study(17). Our retrospective analysis identified only one patient who experienced ≥ grade 3 anaemia,5 (14%) older and 7 (10%) younger patients who experienced ≥ grade 3 neutropoenia and 15 (43%) and 43 (61%) of older and younger patients who experienced any grade of thrombocytopaenia. Despite few patients completing the planned 5 cycle of neoadjuvant chemotherapy in the older cohort compared with the younger group it did not result in difference in survival outcomes. These real-world outcomes are comparable both in terms of efficacy and safety to those treated in the CROSS study, confirming that chemoradiation followed by surgery is a reasonable option for elderly patients with a good performance status who are planned to receive radical treatment (3, 17). A recent Japanese retrospective systemic review of 149 patients evaluated outcomes in elderly patients with a higher age threshold of > 75 years and similarly found good oncologic outcomes. In that study the authors report that patients older than 80 years demonstrated decreased tolerance for concurrent chemotherapy, were less likely to receive chemotherapy, and still demonstrated a higher incidence of grade 3 toxicities compared with the younger elderly patients (17).This retrospective study only included 6 patients ≥ 80 years of age, however some retrospective studies have suggest decreased tolerance/survival benefit of chemotherapy in patients over 80, unlike younger cohorts(18, 19). In our study, we report a higher incidence of patient who did not complete all 5 doses of chemotherapy in the older cohort versus the younger cohort, 54% versus 74% respectively (p = 0.026). Despite this, there did not appear to be increased toxicity, possibly owing to planned rather than reactive dose omissions.

Within our study, 80% of the older and 86% of the younger cohort proceeded to surgery. In total, 3 (11%) and 17 (28%) of the older and younger cohorts respectively who underwent surgery achieved a complete pathological response. Comparing these outcomes with the larger studies, our study contains real-world patients in an Irish population proceeding to surgery in the older cohort of patients. In total, 163 (94%) of patients within the CROSS RCT proceed to surgery and 47 (29%) achieved an ypCR. The ypCR rate reported within our study is much higher in the younger cohort than the older cohort, but overall much less than in the reported RCT CROSS results and in keeping with the CROSS arm of the NEO-AGIES trial ypCR results (3, 20).The fact that our study included many patients with more advanced disease may account for this; also this may also be due to statistical variability due to small sample size and known underperformance of real-world patients compared to clinical trials. The number of patients achieving a R0 resection across both cohorts in our study is less than in the CROSS RCT reported outcomes and indeed less than in the larger retrospective analyses. Again, our cohorts containing more locally advanced disease may explain this observation, given patients included here often presented with more advanced tumour size and greater degrees of nodal involvement. These results illustrate that carefully selecting appropriate older patients with this disease can result in better outcomes and they are able to tolerate such an intense treatment plan.

Older randomised trials demonstrated 2-year OS ~ 35–40% for all-comers treated with definitive chemoradiotherapy, typically in cohorts with a median age in the mid-60s (21, 22). The CROSS trial reported 3-year OS ~ 60% in patients who underwent trimodality treatment, with a median OS of approximately 50 months(3). The 3-year OS in this study was 47% in the younger cohort and 65% in the older cohort. This is comparable to the CROSS results for older patients, however the lower 3-year OS in the younger cohort and a lower median OS overall in these results may reflect patients with more advanced disease being included in the current real-world experience.

Our study has the following strengths. Firstly, this study used a population-based database within a tertiary cancer centre and benefitted from long-term follow-up. This is the first reported study in Ireland of the outcomes and toxicities in patients across all age groups treated with neoadjuvant chemoradiation and the first which has compared a real-world Irish population to the original internationally accepted toxicity and survival profiles. Secondly, it is a comprehensive analysis of primary treatment patterns and wide-ranging subgroup baseline characteristics and analysis by age, which made the conclusion reliable and stable in this study. This makes it applicable to our patients in the future. Our study population was balanced between both cohorts of patients; however, our inclusion criteria was slightly broader than the CROSS-inclusion criteria(3), reflective of a more real-world patient population. We included patients who had up to and including T4 and N2 disease whereas CROSS had excluded these patients (3). This may account for some differences in our outcomes however, our study population is more representative of real-world clinical experience and certainly more applicable to clinical practice. However, this study also has several limitations. First, this is a retrospective, single centre study, limited by selection bias and other confounding variables. Second, data were missing on performance status and granulocyte stimulating factor therapy use. There was inconsistent documentation regarding posttreatment PET/CTs and endoscopies. Furthermore, the effect of treatment on patient-reported toxicity and quality of life was not collected. This study was conducted prior to the routine use of adjuvant immunotherapy in patients who did not obtain a complete pathological response (23). A comprehensive geriatric assessment (CGA) was not included, but there is growing global evidence suggesting that these assessments allow oncologists to deliver optimal care to older patients and minimise toxicity(24). A further weakness in this retrospective review is the omission of postoperative surgical complications as these were not recorded in the medical oncology database. In a similar study with a larger number of cases has been reported that deals with the impact of complications/survival on the elderly. In that study patients with anastomotic leakage, pneumonia, and infectious complications showed significantly worse overall survival. Anastomotic leakage served as a negative prognostic factor of OS and recurrence-free survival, and its negative prognostic impact was more evident in older patients > 75 years (25).

These results reported in this study remain relevant, even if the standard of care may shift, as we await the longer-term results from the recently reported initial analysis of the prospective randomized multicentre phase III trial comparing perioperative chemotherapy (FLOT protocol) to neoadjuvant chemoradiation (CROSS protocol) in patients with adenocarcinoma of the oesophagus (ESOPEC trial) (26). While this study includes patients up to aged 86, it is unclear if older patients will tolerate the more toxic triplet combination of FLOT protocol, and CROSS may remain a standard of care in this group.

In this single institution retrospective study from an Irish tertiary cancer centre, curative-intent neoadjuvant chemoradiation was feasible in selected patients ≥ 70 years with oesophageal cancer. After adjusting for other variables, OS was similar in older compared to younger patients with acceptable haematological toxicity. Longer hospital admissions were seen in the older patient cohort, but this difference was not statistically significant. Given the natural limitations of retrospective studies, these findings should be interpreted with caution and clinical decisions should comprehensively assess comorbidities in older patients. In future, focussed clinical trials in older patients, encompassing multidisciplinary care and comprehensive geriatric assessments are needed.

CI = Confidence Interval

CROSS = Chemo-Radiotherapy for Oesophageal cancer followed by Surgery Study

DFS = Disease Free Survival

GEJ = Gastro-oesophageal Junction

OS – Overall survival

RCT = Randomised Controlled Trial

RCSI = Royal College of Surgeons of Ireland

Declaration of interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Ethical Approval:

Ethical approval was granted from the Beaumont RCSI ethics committee to conduct this retrospective review.

Consent for publication: N/A

Availability of data and materials:

Eligible patients with cT1-4aNxM0 oesophageal cancer were identified in the Beaumont RCSI Cancer Centre database.

Competing Interests:

There are no conflicts of interests or disclosure to be made with regards to this article from any of the authors.

Funding:

There was no funding required for the retrospective review.

Authors' contributions:

RMcL and PM wrote the article and completed the analysis with KB. All other authors reviewed the article.

Acknowledgements:

The authors acknowledge all patients and their families who were included in this retrospective analysis.

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Table 1: Baseline Characteristics

Characteristic	Older Cohort (Age ≥ 70) (n=35)	Younger Cohort (Age <70) (n=70)
Age- years
Range	70-86	26-69
Median	75	60
Gender – no. (%)
Male	27 (73)	51 (73)
Female	8 (27)	19 (27)
Tumour Type – no (%)
Adenocarcinoma	28 (80)	52 (74)
Squamous cell carcinoma	7 (20)	18 (26)
Tumour Location – no (%)
Oesophagus	25 (71)	43 (61)
Gastroesophageal Junction	10 (29)	27 (39)
Clinical T Stage – no. (%)
T1	0 (0)	1 (1)
T2	2 (6)	8 (12)
T3	30 (85)	55 (79)
T4	2 (6)	1 (1)
Unknown	1 (3)	5 (7)
Clinical N stage – no. (%)
N0	13 (37)	17 (24)
N1	14 (40)	26 (37)
N2	6 (17)	15 (21)
Undetermined	1 (3)	12 (18)
AJCC Staging (8^th Edition)
I	0 (0)	1 (1)
II	1 (3)	0 (0)
IIB	0 (0)	3 (4)
III	24 (69)	48 (69)
IVA	7 (20)	13 (19)
Undetermined	3 (8)	5 (7)
Cycles of Chemotherapy – no (%)
5	19 (54)	52 (74)
4	10 (29)	12 (17)
≤3	6 (17)	6 (9)

Table 2: Hematological Toxicity.

Characteristic	Older Cohort (Age ≥ 70) (n=35)		Younger Cohort (Age < 70) (n=70)
	Any grade no. (%)	Grade ≥III no. (%)	Any grade no. (%)	Grade ≥III no. (%)
Anemia	31 (89)	1 (3)	45 (64)	1 (1)
Neutropaenia	18 (51)	5 (14)	33 (47)	7 (10)
Thrombocytopaenia	15 (43)	0 (0)	43 (61)	0 (0)

Table 3: Hazard ratios (HR) and 95% confidence interval (CI) for Overall Survival

HR

95% CI

p value

Age:

70+ years vs <70 years

0.79

0.37, 1.65

0.53

Tumour T stage:

Code 3 vs <3

Code 4 vs <3

3.85

10.93

0.89, 16.62

1.68, 71.22

0.071

0.012

Number of Chemotherapy cycles:

4 vs <4

5 vs <4

0.46

0.19

0.15, 1.40

0.07, 0.53

0.172

0.001

Table 4: Survival probabilities at 12, 24 and 36 months (with 95% CI)

	< 70 years	≥ 70 years
12 months	0.89 (0.78, 0.95)	0.80 (0.61, 0.91)
24 months	0.63 (0.48, 0.74)	0.65 (0.41, 0.81)
36 months	0.47 (0.32, 0.61)	0.65 (0.41, 0.81)

No competing interests reported.

Neoadjuvant chemoradiation in older Irish adult patients with oesophageal cancer: A retrospective institutional review of clinical outcomes and hematological toxicity

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Abstract

Figures

Introduction

Methods

Results

Discussion

Conclusion

Abbreviations

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References

Tables

Additional Declarations

Status:

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