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Article

The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center

by
Philipp Linde
1,2,*,
Markus Mallmann
1,2,
Anne Adams
3,
Simone Wegen
1,2,
Jiaqi Fan
1,2,
Johannes Rosenbrock
1,2,
Maike Trommer
1,2,
Simone Marnitz
1,2,
Christian Baues
1,2 and
Eren Celik
1,2
1
Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital of Cologne, University of Cologne, Kerpener St 62, 50937 Cologne, Germany
2
Center for Integrated Oncology (CIO), University Hospital of Cologne, Faculty of Medicine and University of Cologne, Kerpener St 62, 50937 Cologne, Germany
3
Institute of Medical Statistics and Computational Biology, Faculty of Medicine and University of Cologne, Kerpener St 62, 50937 Cologne, Germany
*
Author to whom correspondence should be addressed.
Cancers 2023, 15(1), 106; https://doi.org/10.3390/cancers15010106
Submission received: 12 November 2022 / Revised: 12 December 2022 / Accepted: 22 December 2022 / Published: 23 December 2022
(This article belongs to the Special Issue Current Status and Future Prospects for Oesophageal Cancer)
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Abstract

:

Simple Summary

Esophageal cancer (EC) is one of the most common cancers worldwide, with over 1.6 million new cases and 1.2 million deaths each year. There is insufficient data on management of elderly and frail EC patients. It is important to explore how elderly EC patients benefit from definite and neoadjuvant chemoradiation regimens. The choice of a schedule and the chemotherapy components in regard of age, comorbidities and several influencing risk factors remains challenging. In our retrospective analysis, combination of carboplatin and paclitaxel shows the benefits of preventing progressive disease and prolonging survival without increasing adverse reactions. Furthermore, trimodal treatment seems to be feasible and effective in the group of the elderly. We discuss current knowledge and the results of studies on the role of chemoradiation in frail elderly EC patients.

Abstract

Elderly patients > 70 years of age with esophageal cancer (EC) represent a challenging group as frailty and comorbidities need to be considered. The aim of this retrospective study was to evaluate the efficacy and side effects of curative chemoradiation therapy (CRT) with regard to basic geriatric screening in elderly patients in order to elucidate prognostic factors. Thirty-four elderly patients > 70 years with EC treated at our cancer center between May 2014 and October 2018 fulfilled the selection criteria for this retrospective analysis. Treatment consisted of intravenous infusion of carboplatin/paclitaxel or fluorouracil (5-FU)/cisplatin with the intention of neoadjuvant or definite chemoradiation. Clinicopathological data including performance status (ECOG), (age-adjusted) Charlson comorbidity index (CCI), Frailty-scale by Fried, Mini Nutritional Assessment Short Form, body mass index, C-reactive protein to albumin ratio, and treatment-related toxicity (CTCAE) were assessed. Data were analyzed as predictors of overall survival (OS) and progression-free survival (PFS). All patients (ten female, 24 male) received combined CRT (22 patients in neoadjuvant, 12 patients in definite intent). Median age was 75 years and the ECOG index between 0 and 1 (52.9% vs. 35.3%); four patients were rated as ECOG 3 (11.8%). Median follow-up was 24 months. Tumors were mainly located in the lower esophagus or esophagogastric-junction with an T3 stage (n = 25; 75.8%) and N1 stage (n = 28; 90.3%). 15 patients (44.1%) had SCC, 19 patients (55.9%) AC. 26 of the patients (76.5%) were scored as prefrail and 50% were in risk for malnutrition (n = 17). In relation to the BMI, ten patients (29.4%) were ranked as overweight, and 15 patients were presented in a healthy state of weight (44.1%). Grade 3 acute toxicity (or higher) occured in nine cases (26.5%). Most of the patients did not show any late toxicities (66.7%). Trimodal therapy provides a significant prolonged OS (p = 0.049) regardless of age, but without impact on PFS. Our analysis suggests that chemoradiation therapy is feasible for elderly patients (>70 years) with tolerable toxicity. Trimodal therapy of EC shows a positive effect on OS and PFS. Further studies are needed to elucidate benefitting subgroups within the elderly. In addition to age, treatment decisions should be based on performance status, nutritional condition and multidisciplinary validated geriatric screening tools.

1. Introduction

Esophageal cancer (EC) is the second most common tumor of the gastrointestinal organ besides cancer of the stomach [1].Squamous cell carcinomas (SCC) of the esophagus are the most common histology in Asian countries, while in Western regions adenocarcinomas (Adeno) occur with increasing incidence [2,3]. Since life expectancy will also continue to increase over time, the number of elderly patients with EC is likely to rise in the future [4].
A person is often defined as “elderly” once that person is 65 years of age or older [5,6]. Elderly patients are often excluded from clinical trials or are at least underrepresented as a group [7,8,9]. Biological age as a prognostic factor is the focus of current discussions, but several studies have shown no prognostic impact of age [10,11].
Semrau et al. contrasted 152 patients with EC aged < 70 years treated with definite chemoradiation (dCRT; cisplatin/5-fluorouracil) with 51 patients aged ≥ 70 years [12]. Progression-free survival (PFS) showed a significant benefit in favor of the group ≥ 70 years, with no difference in overall survival (OS) in the two groups. In contrast, an analysis by Takeuchi et al. showed significantly lower efficacy and more severe toxicities (cisplatin/5-fluorouracil protocol) in selected elderly patients [13].
In the last decade, a landmark study by van Eyck et al. has significantly reduced chemotherapy-related toxicities using carboplatin/paclitaxel (Carb/Tax) [14]. The combination of Carb/Tax with simultaneous 41.4 Gy radiotherapy before surgery appears to be safe in the long term, even in patients over 75 years of age, and does not significantly increase the risk of toxicity-related deaths or postoperative mortality [15]. Based on their study, Haefner et al. stated that age and comorbidities should not be the main factors in the decision for dCRT or neoadjuvant chemoradiation therapy (nCRT) followed by surgical treatment [16]. The Charlson comorbidity index (CCI) ≤ 2 seems to be an (age-)independent prognostic factor associated with survival for elderly patients [17,18].
Due to the special characteristics of elderly patients, nomograms, geriatric assessment tools and established preoperative screening tools are applied to determine the performance status of the oldest patients prior to therapy decisions and initiation [19,20,21].
We here present a retrospective single-center analysis including trimodal therapy and definite CRT regimes in patients > 70 years with EC. We focus on acute and late toxicities, overall and progression free survival and try to elucidate the relevance of comorbidities in regard of therapy choice, and to identify explanatory variables.

2. Patients and Methods

2.1. Patient Cohort

We identified 34 patients aged > 70 years with EC (cT1-4, any N, any M) treated with either neoadjuvant or definitive CRT at our tertiary cancer care centre between May 2014 and October 2018. Due to the time period covered by this study and changing clinical practice, chemotherapy regimens and radiation techniques vary. Inclusion criteria were age > 70 years, newly diagnosed histologically proven AC or SCC of the esophagus and definite or neoadjuvant CRT using conventional (anterior-posterior (APPA)fields, 3D-conformal multi-field or intensity-modulated radiotherapy (IMRT)) techniques. We excluded patients who were treated for recurrent disease, who had previously received CRT or had received definitive treatment without chemotherapy. A systematic audit of patients’ charts and reports was performed to identify patient and treatment characteristics, reported acute and late toxicities, and treatment-related outcomes.

2.2. Radiotherapy

All patients were simulated in supine position in a universal/wing board for mid to distal esophageal tumors or immobilized using a customized long thermoplastic mask for upper EC. Once contraindications (e.g., risk of aspiration, allergy, renal insufficiency) had been discounted, the contrast medium was administered in a standardized manner both intravenously and orally. The gross tumor volume (GTV) was identified on the pre-chemotherapy extent of the disease using the endoscopy report and initial positron emission tomography in combination with a computed tomography (PET/) CT scan. The entire esophageal wall, including any disease extending through the wall, was contoured as GTV, as were any (PET/) CT-avid or pathologically enlarged lymph nodes. The clinical target volume (CTV) encompassed mediastinal lymph nodes, the peri-esophageal lymph nodes, and the submucosal spread longitudinally along the esophagus. This required a 1.0–1.5 cm radial expansion on the GTV and a 3–4 cm expansion superiorly and inferiorly. The planning target volume (PTV) was uniformly generated with the addition of 0.7 cm.
Radiotherapy was provided once a day, five times a week, except weekends and holidays, with a daily dose of 1.8 Gy. The total doses administered on the PTV were 50.4 Gy and a subsequent boost of 9 Gy on the GTV for dCRT, and 41.4 Gy for nCRT.

2.3. Chemotherapy

Patients received chemotherapy according to a treatment plan based on ECOG performance status, comorbidity, and the presence of specific contraindications to the planned agents. All patient cases were discussed in a multidisciplinary tumor board (both pre and post) and the concomitant chemotherapy was finally prescribed by the treating radiation oncologist. Intravenous chemotherapy consisted of either two courses of cisplatin/5-fluorouracil (cisplatin [75 mg/m2 body-surface area] on the first day combined with 5-fluorouracil [1000 mg/m2] continuous infusion daily for four days) or cycles of carboplatin/paclitaxel (Carb/TAX; carboplatin [AUC 2 mg/mL per min] combined with paclitaxel [50 mg/m2 body-surface area], weekly). Patients who were to receive taxane-based dCRT were planned for five to six administrations; four applications were targeted in the neoadjuvant setting.
Treatment with Carb/TAX was given alongside premedication to avoid hypersensitivity reactions (dexamethasone, dimetinden maleate and H2 antagonists). The platinum-containing regimen was applicated after adequate i.v. prehydration, mannitol and i.v. antiemetics (5HT3 antagonists and dexamethasone), followed by i.v. posthydration. If necessary, additional antiemetics (5HT3 antagonists, corticosteroids, dimenhydrinate and metoclopramide) were used to treat prolonged nausea after other causes of nausea had been ruled out (e.g., hyponatremia). A complete blood count and serum chemistry test, including creatinine clearance, were performed at least once a week.
Dose reduction or de-escalation of chemotherapy was considered if grade 3 to 4 hematological toxicity emerged. If severe radiation-related toxicity occurred, a patient-centred decision on dose reduction or discontinuation of chemotherapy was considered.

2.4. Monitoring under Chemoradiation and Associated Supportive Measures

Treatment toxicity was assessed daily during chemotherapy and weekly during radiotherapy. If clinically indicated, toxicity was monitored more frequently. The documentation was standardised (Common Terminology Criteria for Adverse Events (CTCAE)). Supportive care included symptom management, e.g., nutritional counselling, enteral or parenteral nutrition, pain anamnesis and therapy according to the WHO standard, and supportive hospitalisation if needed.

2.5. Aftercare

All patients were offered structured follow-up in our department in addition to the primary medical-oncological follow-up. It took place for the first time 8–10 weeks after the end of treatment and then at intervals of three to six months during the first year. The follow-up included a medical history, an orienting clinical examination, and anamnesis in accordance with the LENT/SOMA criteria [22]. Chest-abdomen-pelvis CT scans for staging and evaluation of the former radiation region and an endoscopy ordered and provided by the primary care provider (usually an oncologist) were reviewed, and in individual cases, scheduled for the patient. In the second year of follow-up, patients were regularly visited at least every 6–12 months until progression of disease or death. Patients and their primary care physicians were encouraged to report complications occurring after chemoradiation immediately to our department. If a scheduled follow-up appointment was missed, patients were contacted (by phone or by letter) by our patient management. Relapse of disease was documented by histological biopsy when possible. In case of missing information, the database of the University Hospital of Cologne was checked for information on the current status of the patient.

2.6. Evidence-Based Definitions, Statistical Analysis, and Ethical Considerations

Acute and late toxicity was scored retrospectively according to CTCAE v5.0 [23]. Acute toxicities were defined as occurring during radiotherapy and 90 days after the start of radiotherapy; from day 91 onwards they are late side effects. Performance status was scored according to the ECOG index [24]. The (age adjusted) Charlson comorbidity index was used to analyze the comorbidity burden of our cohort [25,26]. Patients were assessed using the Frailty scale [27]. With this criterion, in many clinical situations patients have a less favorable course of treatment and disease [28]. It is used for integrated assessment and in shared decision making. Nutritional status and body composition were determined using the short-form Mini Nutritional Assessment (MNA-SF) scale and body mass index (BMI) [29,30]. To independently assess the prognosis of EC patients, serum C-reactive protein (CRP) and albumin concentrations were collected, and the CRP/albumin ratio (CAR) was calculated [31,32,33]. The standard values were used on the basis of the reference standard of the central laboratory of the University Hospital of Cologne: CRP < 3 μg/L; albumin 35–52 g/L). Categorization was set CAR > 0.5 vs. <0.5. Here, we were interested in the fact that patients with high CAR usually have severe tumor-related inflammatory responses or are in poor nutritional status and therefore may benefit from anti-inflammatory therapy and nutritional support [34,35].
Survival data were calculated according to the Kaplan-Meier method [36]. OS was defined as the interval from the first day of treatment to death or to the last follow-up time point still alive. PFS was calculated from the first day of treatment until death or diagnosis of relapse (local or distant metastases) or last follow-up alive. Univariate analyses were performed using log rank testing and Cox regression [37]. A p-value of <0.05 was defined as statistically significant. Calculations and data management were performed with SPSS®-statistics software v.28.0.1.0.
The study was conducted in accordance with the Declaration of Helsinki in its latest version. All patients gave written informed consent before the start of treatment. Due to the retrospective nature, from the point of view of the local ethics committee, there is no professional consultation obligation for the North Rhine physicians according to § 15 para. 1 of the professional code of conduct.

3. Results

Median follow-up for the entire cohort was 24 months. Radiotherapy was completed by all of the patients and all patients received initially prescribed dose (Gy).
Median age of the 34 patients in our cohort at the start of therapy was 75 years (range 71–82), ten patients were female, 24 were male. 15 patients (44.1%) had SCC, 19 patients (55.9%) AC. The majority presented with an ECOG index between 0 and 1 (52.9% vs. 35.3%), T3 stage (n = 25; 75.8%) and N1 stage (n = 28; 90.3%). The majority of patients were treated with nCRT (n = 22; 64.7%) and received surgery. Myocardial infarction, congestive heart failure, peripheral vascular disease, chronic obstructive pulmonary disease, and uncomplicated diabetes were the most common comorbidities and therefore included in the Charlson index scores. 26 of the patients (76.5%) were scored as prefrail and 50% were in risk for malnutrition (n = 17). In relation to the BMI, ten patients (29.4%) were ranked as overweight and 15 patients were presented in a healthy state of weight (44.1%).
For detailed patient, scoring and treatment characteristics see Table 1 and Table 2.

3.1. Chemotherapy

29 of our 34 patients received concurrent Carb/Tax chemotherapy, one was treated with cisplatin/5-fluorouracil, two patients received Tax monotherapy. Two patients did not receive any chemotherapy based on the interdisciplinary assessment of the treatment team.

3.2. Toxicities

For detailed analysis of acute and late toxicity see Table 3 and Table 4.

3.2.1. Acute

Grade 3 acute toxicity (or higher) was found in nine cases (26.5%). Generally, maximum acute toxicity during or after CRT was grade 0 to 1 in 12 patients (35.3%), grade 2 in 13 patients (38.2%), grade 3 in seven (20.6%), grade 4 in one (2.9%), and grade 5 in one patient (2.9%); mainly hematotoxicity, (odyno-)dysphagia, nausea, loss of appetite, and fatigue. The patients with grade 5 toxicity presented as follows: 80 years, female, ECOG 3, CCI 2, cT3, SCC, and dCRT (Tax mono). Grade 5 toxicity was related to hematotoxicity.

3.2.2. Late

Most of the patients did not show any late toxicities (66.7%). Grade 3 late toxicity (or higher) was found in two of 30 evaluable cases. Maximum late toxicity after CRT was grade 1 in seven patients (23.3%), grade 2 in one (3.3%), grade 3 in one (3.3%), grade 4 in one (3.3%), and grad 5 in one (3.3%); solely (odyno-)dysphagia. The patient with grade 5 toxicity presented as follows: 67 years, male, ECOG 2, CCI 5, cT3, SCC, and dCRT (Carb/TAX). Grade 5 toxicity was related to fistula.

3.3. Survival Analysis

The median OS of all patients > 70 years was 32 months and the median PFS was 16 months, see Figure 1 and Figure 2, respectively. The median OS for SCC patients was 43 months vs. 21 months for AC (p = 0.008).
In the univariate Cox regression model, treatment regimen (nCRT vs. dCRT) significantly affected OS, but not PFS, see Figure 3 and Figure 4, respectively. The trend shown is independent of age. Pre-therapeutic ECOG PF of 0–1 was one parameter significantly affecting OS and PFS, too. An elevated CAR > 0.5 seems to be a predictor of PFS without being statistically significant.
Detailed results of univariate Cox regression analysis are demonstrated in Table 5.

4. Discussion

This study assessed the OS, PFS and treatment-related toxicities of patients older than 70 years with EC treated with nCRT and dCRT in relation to comorbidities and common baseline performance scores. Biological age has been addressed as a prognostic parameter in previous RT studies on EC [38,39]. With the increase in average life expectancy, the number of elderly EC patients is steadily increasing year by year [40,41].
In our small but representative cohort of patients over 70 years, a significant advantage in terms of OS and PFS was seen in the nCRT group and concomitant Carb/TAX chemotherapy was well-tolerated in both treatment groups. Herskovic et al. were able to remarkably demonstrate the therapeutic benefit of concurrent chemotherapy in definite treatment using radiotherapy [42]. Ji et al. were able to show a clear improvement in efficacy with the 5-FU prodrug Tegafur in a cohort of elderly patients aged 70 to 85 years who were randomized to RT alone and simultaneous dCRT [43]. High-grade toxicities (grade 3) with leukopenia occurred in the combination arm (9.5% vs. 2.7%). Two-year overall survival (OS) was significantly improved (p = 0.002) demonstrating the feasibility and tolerability with higher efficacy, substantially improving treatment options for elderly patients [44,45,46].
Surgical treatment of EC is increasingly accepted for elderly people defined as aged over 70 years. Not differing outcome and long-term results in the selected elderly from those reported for younger patients offer the possibility of risk/opportunity stratification and assessment [47,48,49,50]. Here, based on a comparison of the CROSS trial with historical controls (e.g., RTOG 8501 and Intergroup [INT] 0123) and retrospective studies, radiosensitizing with Carb/TAX seems more tolerable than cisplatin/5-fluorouracil [51,52,53].
The retrospective comparisons by Munch et al. between the two established chemotherapy regimens (cisplatin/5-fluorouracil or Carb/TAX) are in line and highlight the results concerning the moderate acute and late toxicities due to chemotherapy in our cohort [54,55].
Our data confirm that risk factors in the group of elderly should never be considered in absolute order to avoid selection bias. Special attention should be given to the fact that the “advanced age” factor is associated with lower referral of older patients to specialists, increased administration of suboptimal therapies and increased rejection of therapy by the patients themselves [56,57,58,59].
In addition to the experienced clinician’s view, validated screening and geriatric assessment tools are needed in order to achieve an objective patient selection [60,61,62,63]. Screening tools such as O-POSSUM and predictive models such as those published by Steyerberg et al. and the International Esodata Study Group should generally be considered when stratifying elderly patients for more intensive or less intensive therapy [64,65,66,67,68]. More recent data highlights the critical role of rigorous supportive care [69]. For example, integrating prophylactic intravenous hydration, nutritional counselling and more frequent treatment visits towards the end of treatment could reduce emergency department visits and treatment interruptions in this vulnerable population of the elderly. Recently, prehabilitation has emerged as a way to prepare a patient for any major surgery [70,71]. If patients can be prevented from worsening their physical and nutritional condition, this could have a significant impact on overall cancer treatment [72,73].
Of course, the patient’s wish for therapy, quality of life (QOL) scoring, and the involvement of his or her relatives should also be emphasized here [74,75]. Specific radiooncological screening, prehabilitation, and assessment tools are rare; here, interdisciplinary exchange and the development of valid instruments are to be wished and must set as a goal for the future [76,77].
We observed that ECOG performance status (0–1) is an age-independent predictor of survival. Recently, Hulshof et al. showed within their prospective ARTDECO trial that escalating the radiation dose (DE) does not improve local tumor control or survival [78]. Interestingly, the majority of patients were elderly (mean 71 years) and mainly had an ECOG-PS of 0 or 1. The results may therefore not be applicable to younger patients (around 50 years of age), who may represent a beneficial subgroup of a DE. Consistent with our retrospective data, there were no significant differences in overall toxicities between the 1:1 randomized arms of elderly patients (DE vs. standard dose). With modern staging and (pre-)treatment approaches, similar outcomes appear to be achievable for the elderly as in younger cohorts with EC. [16,79,80,81]. Esophagectomy in the elderly is also less used and is associated with a potential increase in peri- and postoperative complications but is performed in selected patients with acceptable outcomes [82,83,84,85,86]. Minimally invasive esophagectomy may minimize mortality in elderly patients [87]. Vlacich et al. presented a review of the National Cancer Database [45]. Patients ≥ 80 years were more likely to receive no treatment in the non-definite setting and less likely to receive trimodal therapy and esophagectomy alone in the definite setting. Considering individual comorbidities and the known pharmacokinetic properties and modes of action in the elderly, they should be treated as younger patients [88,89]. Adjuvant immunotherapy, for example, should complement the curative treatment approach in the case of pathologically incomplete response after trimodal therapy, even in older patients [41,90]. The median age in the CheckMate 577 registration trial was 62 years (PD-1 inhibitor arm) vs. 61 years (placebo arm) in an ECOG of 0–1, too and well tolerated.

5. Limitations

Our retrospective analysis comes with limitations. Treatment compliance is one of the most important endpoints in the treatment of frail elderly patients. All patients who started chemoradiation with curative intent should be included and e.g., shown within a CONSORT flow chart. As this is a retrospective cohort study, the design may be prone to sampling bias, which we must cite as our major limitation. The results should therefore be interpreted with caution.

6. Conclusions

The data support the supposition that chemoradiation therapy is feasible for the elderly patient group (>70 years) with tolerable toxicities. Trimodal therapy shows a positive effect on OS and PFS. Further studies are needed to elucidate benefitting subgroups within the elderly. Treatment decisions should no longer be based solely on chronological age, but should include performance status, nutritional condition and validated geriatric screening tools. With modern treatment approaches and well-tolerated cytostatic agents, similar results seem to be achievable as in younger patients.

Author Contributions

Conceptualization, P.L.; Data curation, P.L., M.M. and E.C.; Formal analysis, A.A.; Investigation, P.L.; Methodology, P.L., E.C. and A.A.; Project administration, P.L. and E.C.; Resources, C.B. and S.M.; Supervision, P.L., M.M., A.A., S.W., J.F., J.R., M.T., S.M., C.B., E.C.; Visualization, P.L. and E.C.; Writing–original draft, P.L.; Writing–review and editing, all authors. All authors have read and agreed to the published version of the manuscript.

Funding

The authors acknowledge support for the Article Processing Charge from the DFG (German Research Foundation, 491454339). No other funds, grants, or other support was received.

Institutional Review Board Statement

The study was conducted according to the guidelines of the Declaration of Helsinki in its latest version.

Informed Consent Statement

Patient consent was waived because this study is retrospective, and the Ethics Committee of the University of Cologne, Faculty of Medicine states in the reference 19-1160 that ethical approval is not required. This is according to § 15, Abs. 1 “Berufsordnung für die Nordrheinischen Ärztinnen und Ärzte”; consent to participate: § 6, Abs. 1 Satz 1 GDSG NRW.

Data Availability Statement

The data are included in the article. Further details can be obtained from the corresponding author via e-mail.

Acknowledgments

Special thanks to Fabia Bertram for her support in proofreading as a native speaker.

Conflicts of Interest

The authors declare that they have no competing interests.

Abbreviations

3D-CRT3-dimensional conformal radiotherapy
ACAdenocarcinoma
Carb/TAXCarboplatin and paclitaxel
dCRTDefinite chemoradiation therapy
ECEsophageal cancer
GTVGross target volume
GyGray
IMRTIntensity-modulated radiotherapy
nCRTNeoadjuvant chemoradiation therapy
OSOverall survival
PET/CTPositron emission tomography/computed tomography
PFSProgression-free survival
PTVPlanning target volume
SCCSquamous cell carcinoma
QOLQuality of life

References

  1. Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2021, 71, 209–249. [Google Scholar] [CrossRef] [PubMed]
  2. Ajani, J.A.; D’Amico, T.A.; Bentrem, D.J.; Chao, J.; Corvera, C.; Das, P.; Denlinger, C.S.; Enzinger, P.C.; Fanta, P.; Farjah, F.; et al. Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology. J. Natl. Compr. Cancer Netw. 2019, 17, 855–883. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Arnal, M.J.D.; Arenas, Á.F.; Arbeloa, Á.L. Esophageal cancer: Risk factors, screening and endoscopic treatment in Western and Eastern countries. World J. Gastroenterol. 2015, 21, 7933–7943. [Google Scholar] [CrossRef] [PubMed]
  4. Various: Bevölkerungsvorausberechnung–Annahmen zur künftigen Entwicklung der Lebenserwartung, Statistisches Bundesamt (Destatis). 2021. Available online: https://www.destatis.de/DE/Themen/Gesellschaft-Umwelt/Bevoelkerung/Bevoelkerungsvorausberechnung/Methoden/Erlaeuterungen/Sterblichkeit.html (accessed on 27 October 2022).
  5. OECD. Elderly Population (Indicator). Available online: https://www.oecd-ilibrary.org/social-issues-migration-health/elderly-population/indicator/english_8d805ea1-en (accessed on 3 September 2022).
  6. Orimo, H.; Ito, H.; Suzuki, T.; Araki, A.; Hosoi, T.; Sawabe, M. Reviewing the definition of “elderly”. Geriatr. Gerontol. Int. 2006, 6, 149–158. [Google Scholar] [CrossRef]
  7. Chen, R.C.; Royce, T.J.; Extermann, M.; Reeve, B.B. Impact of age and comorbidity on treatment and outcomes in elderly cancer patients. Semin. Radiat. Oncol. 2012, 22, 265–271. [Google Scholar] [CrossRef]
  8. Singh, H.; Kanapuru, B.; Smith, C.; Fashoyin-Aje, L.A.; Myers, A.; Kim, G.; Pazdur, R. FDA analysis of enrollment of older adults in clinical trials for cancer drug registration: A 10-year experience by the U.S. Food and Drug Administration. J. Clin. Oncol. 2017, 35 (Suppl. 15), 10009. [Google Scholar] [CrossRef]
  9. Daste, A.; Chakiba, C.; Domblides, C.; Gross-Goupil, M.; Quivy, A.; Ravaud, A.; Soubeyran, P. Targeted therapy and elderly people: A review. Eur. J. Cancer 2016, 69, 199–215. [Google Scholar] [CrossRef]
  10. Lagarde, S.M.; Kate, F.J.W.T.; Reitsma, J.B.; Busch, O.R.C.; Van Lanschot, J.J.B. Prognostic factors in adenocarcinoma of the esophagus or gastroesophageal junction. J. Clin. Oncol. 2006, 24, 4347–4355. [Google Scholar] [CrossRef]
  11. Eloubeidi, M.A.; Desmond, R.; Arguedas, M.R.; Reed, C.E.; Wilcox, C.M. Prognostic factors for the survival of patients with esophageal carcinoma in the U.S.: The importance of tumor length and lymph node status. Cancer 2002, 95, 1434–1443. [Google Scholar] [CrossRef]
  12. Semrau, R.; Herzog, S.; Vallböhmer, D.; Kocher, M.; Hölscher, A.; Müller, R.-P. Radiotherapy in elderly patients with inoperable esophageal cancer. Is there a benefit? Strahlenther. Onkol. 2012, 188, 226–234. [Google Scholar] [CrossRef]
  13. Takeuchi, S.; Ohtsu, A.; Doi, T.; Kojima, T.; Minashi, K.; Mera, K.; Yano, T.; Tahara, M.; Muto, M.; Nihei, K. A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer. Am. J. Clin. Oncol. 2007, 30, 607–611. [Google Scholar] [CrossRef]
  14. van Hagen, P.; Hulshof, M.C.; van Lanschot, J.J.; Steyerberg, E.W.; Henegouwen, M.V.B.; Wijnhoven, B.P.L. Preoperative chemoradiotherapy for esophageal or junctional cancer. N. Engl. J. Med. 2012, 366, 2074–2084. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Verma, V.; Haque, W.; Zheng, D.; Osayande, F.; Lin, C. Patterns of Care and Outcomes of Elderly Esophageal Cancer Patients Not Meeting Age-based Criteria of the CROSS Trial. Am. J. Clin. Oncol. 2019, 42, 67–74. [Google Scholar] [CrossRef]
  16. Haefner, M.F.; Lang, K.; Verma, V.; Koerber, S.A.; Uhlmann, L.; Debus, J.; Sterzing, F. Neoadjuvant versus definitive chemoradiotherapy for locally advanced esophageal cancer: Outcomes and patterns of failure. Strahlenther. Onkol. 2018, 194, 116–124. [Google Scholar] [CrossRef]
  17. Tougeron, D.; Hamidou, H.; Scotte, M.; Di Fiore, F.; Antonietti, M.; Paillot, B.; Michel, P. Esophageal cancer in the elderly: An analysis of the factors associated with treatment decisions and outcomes. BMC Cancer 2010, 10, 510. [Google Scholar] [CrossRef] [Green Version]
  18. Go, S.-I.; Lee, W.S.; Kang, M.H.; Song, H.-N.; Kim, M.J.; Lee, M.J.; Kim, H.-G.; Lee, G.W.; Kang, J.H.; Lee, J.-H.; et al. Response to concurrent chemoradiotherapy as a prognostic marker in elderly patients with locally advanced esophageal cancer. Tumori J. 2012, 98, 225–232. [Google Scholar] [CrossRef]
  19. Won, E.; Ilson, D.H. Management of localized esophageal cancer in the older patient. Oncologist 2014, 19, 367–374. [Google Scholar] [CrossRef] [Green Version]
  20. Molena, D.; Stem, M.; Blackford, A.L.; Lidor, A.O. Esophageal cancer treatment is underutilized among elderly patients in the USA. J. Gastrointest. Surg. 2017, 21, 126–136. [Google Scholar] [CrossRef] [Green Version]
  21. Lin, S.H.; Wang, J.; Allen, P.K.; Correa, A.M.; Maru, D.M.; Swisher, S.G.; Hofstetter, W.L.; Liao, Z.; Ajani, J.A. A nomogram that predicts pathologic complete response to neoadjuvant chemoradiation also predicts survival outcomes after definitive chemoradiation for esophageal cancer. J. Gastrointest. Oncol. 2014, 6, 45–52. [Google Scholar]
  22. Rubin, P.; Constine, L.S.; Fajardo, L.F.; Phillips, T.L.; Wasserman, T.H. Late effects of normal tissues (LENT) scoring system. Int. J. Radiat. Oncol. 1995, 31, 1041–1042. [Google Scholar] [CrossRef] [PubMed]
  23. US Department of Health and Human Services. Common Terminology Criteria for Adverse Events (CTCAE) Version 5; National Institutes of Health, National Cancer Institute: Bethesda, MD, USA, 2009.
  24. Oken, M.M.; Creech, R.H.; Tormey, D.C.; Horton, J.; Davis, T.E.; McFadden, E.T.; Carbone, P.P. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am. J. Clin. Oncol. 1982, 5, 649–655. [Google Scholar] [CrossRef] [PubMed]
  25. Charlson, M.E.; Pompei, P.; Ales, K.L.; MacKenzie, C.R. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J. Chronic Dis. 1987, 40, 373–383. [Google Scholar] [CrossRef] [PubMed]
  26. Charlson, M.; Szatrowski, T.P.; Peterson, J.; Gold, J. Validation of a combined comorbidity index. J. Clin. Epidemiol. 1994, 47, 1245–1251. [Google Scholar] [CrossRef] [PubMed]
  27. Fried, L.P.; Tangen, C.M.; Walston, J.; Newman, A.B.; Hirsch, C.; Gottdiener, J.; Seeman, T.; Tracy, R.; Kop, W.J.; Burke, G.; et al. Frailty in older adults: Evidence for a phenotype. J. Gerontol. Ser. A Biol. Sci. Med. Sci. 2001, 56, M146–M157. [Google Scholar] [CrossRef] [PubMed]
  28. Eriksen, G.F.; Šaltytė Benth, J.; Grønberg, B.H.; Rostoft, S.; Kirkhus, L.; Kirkevold, Ø. Geriatric impairments are prevalent and predictive of survival in older patients with cancer receiving radiotherapy: A prospective observational study. Acta Oncol. 2022, 61, 393–402. [Google Scholar] [CrossRef]
  29. Rubenstein, L.Z.; Harker, J.O.; Salvà, A.; Guigoz, Y.; Vellas, B. Screening for Undernutrition in Geriatric Practice: Developing the Short-Form Mini-Nutritional Assessment (MNA-SF). J. Gerontol. 2001, 56, M366–M377. [Google Scholar] [CrossRef] [Green Version]
  30. Keys, A.; Fidanza, F.; Karvonen, M.J.; Kimura, N.; Taylor, H.L. Indices of relative weight and obesity. J. Chronic Dis. 1972, 25, 329–343. [Google Scholar] [CrossRef]
  31. Borda, F.; Borda, A.; Jimenez, J.; Zozaya, J.M.; Prieto, C.; Gomez, M. Predictive value of pre-treatment hypoalbuminemia in prognosis of resected colorectal cancer. Gastroenterol. Hepatol. 2014, 37, 289–295. [Google Scholar] [CrossRef]
  32. Crumley, A.B.; Stuart, R.C.; McKernan, M.; McMillan, D.C. Is hypoalbuminemia an independent prognostic factor in patients with gastric cancer? World J. Surg. 2010, 34, 2393–2398. [Google Scholar] [CrossRef]
  33. Liu, Z.; Shi, H.; Chen, L. Prognostic role of pre-treatment C-reactive protein/albumin ratio in esophageal cancer: A meta-analysis. BMC Cancer 2019, 19, 1161. [Google Scholar] [CrossRef]
  34. Velissaris, D.; Pantzaris, N.; Koniari, I.; Koutsogiannis, N.; Karamouzos, V.; Kotroni, I.; Skroumpelou, A.; Ellul, J. C-Reactive Protein and Frailty in the Elderly: A Literature Review. J. Clin. Med. Res. 2017, 9, 461–465. [Google Scholar] [CrossRef] [PubMed]
  35. Park, J.E.; Chung, K.S.; Song, J.H.; Kim, S.Y.; Kim, E.Y.; Jung, J.Y.; Kang, Y.A.; Park, M.S.; Kim, Y.S.; Chang, J.; et al. The C-Reactive Protein/Albumin Ratio as a Predictor of Mortality in Critically Ill Patients. J. Clin. Med. 2018, 7, 333. [Google Scholar] [CrossRef] [Green Version]
  36. Kaplan, E.L.; Meier, P. Nonparametric estimation from incomplete observations. J. Am. Stat. Assoc. 1958, 53, 457–481. [Google Scholar] [CrossRef]
  37. Cox, D.R.; Oakes, D. Analysis of Survival Data; Chapman Hall: London, UK, 1984. [Google Scholar]
  38. Zhang, P.; Xi, M.; Zhao, L.; Shen, J.-X.; Li, Q.-Q.; He, L.-R.; Liu, S.-L.; Liu, M.-Z. Is there a benefit in receiving concurrent chemoradiotherapy for elderly patients with inoperable thoracic esophageal squamous cell carcinoma? PLoS ONE 2014, 9, e105270. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  39. Jingu, K.; Takahashi, N.; Murakami, Y.; Ishikawa, K.; Itasaka, S.; Takahashi, T.; Isohashi, F.; Sakayauchi, T.; Ogawa, K. Is Concurrent Chemotherapy with Radiotherapy for Esophageal Cancer Beneficial in Patients Aged 80 Years or Older? Anticancer Res. 2019, 39, 4279–4283. [Google Scholar] [CrossRef] [Green Version]
  40. Rustgi, A.K.; El-Serag, H.B. Esophageal carcinoma. N. Engl. J. Med. 2014, 371, 2499–2509. [Google Scholar] [CrossRef]
  41. Mantziari, S.; Farinha, H.T.; Bouygues, V.; Vignal, J.-C.; Deswysen, Y.; Demartines, N.; Schäfer, M.; Piessen, G. Esophageal Cancer in Elderly Patients, Current Treatment Options and Outcomes; A Systematic Review and Pooled Analysis. Cancers 2021, 13, 2104. [Google Scholar] [CrossRef]
  42. Herskovic, A.; Martz, K.; Al-Sarraf, M.; Leichman, L.; Brindle, J.; Vaitkevicius, V.; Cooper, J.; Byhardt, R.; Davis, L.; Emami, B. Combined chemotherapy and radiotherapy compared with radiotherapy alone in patients with cancer of the esophagus. N. Engl. J. Med. 1992, 326, 1593–1598. [Google Scholar] [CrossRef]
  43. Ji, Y.; Du, X.; Zhu, W.; Yang, Y.; Ma, J.; Zhang, L. Efficacy of Concurrent Chemoradiotherapy With S-1 vs Radiotherapy Alone for Older Patients with Esophageal Cancer: A Multicenter Randomized Phase 3 Clinical Trial. JAMA Oncol. 2021, 7, 1459–1466. [Google Scholar] [CrossRef]
  44. Wakui, R.; Yamashita, H.; Okuma, K.; Kobayashi, S.; Shiraishi, K.; Terahara, A.; Sasano, N.; Ohtomo, K.; Nakagawa, K. Esophageal cancer: Definitive chemoradiotherapy for elderly patients. Dis. Esophagus 2010, 23, 572–579. [Google Scholar] [CrossRef]
  45. Vlacich, G.; Samson, P.P.; Perkins, S.M.; Roach, M.C.; Parikh, P.J.; Bradley, J.D.; Lockhart, A.C.; Puri, V.; Meyers, B.F.; Kozower, B.; et al. Treatment utilization and outcomes in elderly patients with locally advanced esophageal carcinoma: A review of the National Cancer Database. Cancer Med. 2017, 6, 2886–2896. [Google Scholar] [CrossRef] [PubMed]
  46. Chen, M.; Liu, X.; Han, C.; Wang, X.; Zhao, Y.; Pang, Q.; Sun, X.; Li, G.; Zhang, K.; Li, L.; et al. Does chemoradiotherapy benefit elderly patients with esophageal squamous cell cancer? A propensity-score matched analysis on multicenter data (3JECROG R-03A). BMC Cancer 2020, 20, 36. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Internullo, E.; Moons, J.; Nafteux, P.; Coosemans, W.; Decker, G.; De Leyn, P.; Van Raemdonck, D.; Lerut, T. Outcome after esophagectomy for cancer of the esophagus and GEJ in patients aged over 75 years. Eur. J. Cardio-Thorac. Surg. 2008, 33, 1096–1104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Morita, M.; Egashira, A.; Yoshida, R.; Ikeda, K.; Ohgaki, K.; Shibahara, K.; Oki, E.; Sadanaga, N.; Kakeji, Y.; Maehara, Y. Esophagectomy in patients 80 years of age and older with carcinoma of the thoracic esophagus. J. Gastroenterol. 2008, 43, 345–351. [Google Scholar] [CrossRef] [PubMed]
  49. Alexiou, C.; Beggs, D.; Salama, F.; Brackenbury, E.; Morgan, W. Surgery for esophageal cancer in elderly patients: The view from Nottingham. J. Thorac. Cardiovasc. Surg. 1998, 116, 545–553. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  50. Matsumoto, Y.; Kimura, K.; Zhou, Q.; Sasaki, K.; Saiki, T.; Moriyama, M.; Saijo, Y. Treatments and outcomes of older patients with esophageal cancer: Comparison with younger patients. Mol. Clin. Oncol. 2019, 11, 383–389. [Google Scholar] [CrossRef] [Green Version]
  51. Qu, X.M.; Biagi, J.J.; Hopman, W.M.; Mahmud, A. Shifting practice in definitive chemoradiation for localized esophageal cancer. Curr. Oncol. 2017, 24, e379–e387. [Google Scholar] [CrossRef] [Green Version]
  52. Honing, J.; Smit, J.K.; Muijs, C.T.; Burgerhof, J.G.M.; de Groot, J.W.; Paardekooper, G.; Muller, K.; Woutersen, D.; Legdeur, M.J.C.; Fiets, W.E.; et al. A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. Ann. Oncol. 2014, 25, 638–643. [Google Scholar] [CrossRef]
  53. Blom, R.L.G.M.; Sosef, M.N.; Nap, M.; Lammering, G.; Berkmortel, F.V.D.; Hulshof, M.C.; Meijer, S.; Wilmink, H.W.; Henegouwen, M.I.V.B. Comparison of two neoadjuvant chemoradiotherapy regimens in patients with potentially curable esophageal carcinoma. Dis. Esophagus 2013, 27, 380–387. [Google Scholar] [CrossRef]
  54. Münch, S.; Pigorsch, S.U.; Feith, M.; Slotta-Huspenina, J.; Weichert, W.; Friess, H.; Combs, S.E.; Habermehl, D. Comparison of neoadjuvant chemoradiation with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus. Radiat. Oncol. 2017, 12, 182. [Google Scholar] [CrossRef] [Green Version]
  55. Munch, S.; Pigorsch, S.U.; Devečka, M.; Dapper, H.; Weichert, W.; Friess, H. Comparison of definite chemoradiation therapy with carboplatin/paclitaxel or cisplatin/5-fluoruracil in patients with squamous cell carcinoma of the esophagus. Radiat. Oncol. 2018, 13, 139. [Google Scholar] [CrossRef] [PubMed]
  56. Steyerberg, E.W.; Neville, B.; Weeks, J.C.; Earle, C.C. Referral patterns, treatment choices, and outcomes in locoregional esophageal cancer: A population-based analysis of elderly patients. J. Clin. Oncol. 2007, 25, 2389–2396. [Google Scholar] [CrossRef] [PubMed]
  57. Bouchardy, C.; Rapiti, E.; Blagojevic, S.; Vlastos, A.-T.; Vlastos, G. Older female cancer patients: Importance, causes, and consequences of undertreatment. J. Clin. Oncol. 2007, 25, 1858–1869. [Google Scholar] [CrossRef] [PubMed]
  58. Dale, D.C. Poor prognosis in elderly patients with cancer: The role of bias and undertreatment. J. Support. Oncol. 2004, 1 (Suppl. 2), 11–17. [Google Scholar]
  59. Liu, C.-Y.; Chen, W.T.-L.; Kung, P.-T.; Chiu, C.-F.; Wang, Y.-H.; Shieh, S.-H.; Tsai, W.-C. Characteristics, survival, and related factors of newly diagnosed colorectal cancer patients refusing cancer treatments under a universal health insurance program. BMC Cancer 2014, 14, 446. [Google Scholar] [CrossRef]
  60. Kretschmer, E.-M.; Pavic, M.; Stark, L.S.; Hertler, C.; Guckenberger, M. Radiotherapy of the oldest old–feasibility and institutional analysis. Strahlenther. Onkol. 2020, 196, 683–690. [Google Scholar] [CrossRef]
  61. van Kooten, R.T.; Voeten, D.M.; Steyerberg, E.W.; Hartgrink, H.H.; van Berge Henegouwen, M.I.; van Hillegersberg, R. Patient-Related Prognostic Factors for Anastomotic Leakage, Major Complications, and Short-Term Mortality Following Esophagectomy for Cancer: A Systematic Review and Meta-Analyses. Ann. Surg. Oncol. 2022, 29, 1358–1373. [Google Scholar] [CrossRef]
  62. Hirpara, D.H.; Kidane, B.; Rogalla, P.; Cypel, M.; de Perrot, M.; Keshavjee, S.; Pierre, A.; Waddell, T.; Yasufuku, K.; Darling, G.E. Frailty assessment prior to thoracic surgery for lung or esophageal cancer: A feasibility study. Support. Care Cancer 2019, 27, 1535–1540. [Google Scholar] [CrossRef]
  63. Hamaker, M.E.; Jonker, J.M.; de Rooij, S.E.; Vos, A.G.; Smorenburg, C.H.; van Munster, B.C. Frailty screening methods for predicting outcome of a comprehensive geriatric assessment in elderly patients with cancer: A systematic review. Lancet Oncol. 2012, 13, e437–e444. [Google Scholar] [CrossRef]
  64. Prytherch, D.R.; Whiteley, M.S.; Higgins, B.; Weaver, P.C.; Prout, W.G.; Powell, S.J. POSSUM and Portsmouth POSSUM for predicting mortality. Physiological and Operative Severity Score for the enUmeration of Mortality and morbidity. Br. J. Surg. 1998, 85, 1217–1220. [Google Scholar] [CrossRef]
  65. Tekkis, P.P.; McCulloch, P.; Poloniecki, J.D.; Prytherch, D.R.; Kessaris, N.; Steger, A.C. Risk-adjusted prediction of operative mortality in oesophagogastric surgery with O-POSSUM. Br. J. Surg. 2004, 91, 288–295. [Google Scholar] [CrossRef] [PubMed]
  66. Steyerberg, E.W.; Neville, B.A.; Koppert, L.B.; Lemmens, V.E.; Tilanus, H.W.; Coebergh, J.W.W. Surgical mortality in patients with esophageal cancer: Development and validation of a simple risk score. J. Clin. Oncol. 2006, 24, 4277–4284. [Google Scholar] [CrossRef] [PubMed]
  67. D’Journo, X.B.; Boulate, D.; Fourdrain, A.; Loundou, A.; van Berge Henegouwen, M.I.; Gisbertz, S.S. Risk Prediction Model of 90-Day Mortality After Esophagectomy for Cancer. JAMA Surg. 2021, 156, 836–845. [Google Scholar] [CrossRef] [PubMed]
  68. Wang, J.; Wei, C.; Tucker, S.L.; Myles, B.; Palmer, M.; Hofstetter, W.L.; Swisher, S.G.; Ajani, J.A.; Cox, J.D.; Komaki, R.; et al. Predictors of postoperative complications after trimodality therapy for esophageal cancer. Int. J. Radiat. Oncol. Biol. Phys. 2013, 86, 885–891. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Rahimy, E.; Koong, A.; Toesca, D.; White, M.N.; Panjwani, N.; Fisher, G.; Chang, D.; Pollom, E. Outcomes and Tolerability of Definitive and Preoperative Chemoradiation in Elderly Patients with Esophageal Cancer: A Retrospective Institutional Review. Adv. Radiat. Oncol. 2020, 5, 1188–1196. [Google Scholar] [CrossRef]
  70. Ferreira, V.; Minnella, E.M.; Awasthi, R.; Gamsa, A.; Ferri, L.; Mulder, D.; Sirois, C.; Spicer, J.; Schmid, S.; Carli, F. Multimodal Prehabilitation for Lung Cancer Surgery: A Randomized Controlled Trial. Ann. Thorac. Surg. 2020, 112, 1600–1608. [Google Scholar] [CrossRef]
  71. Bausys, A.; Mazeikaite, M.; Bickaite, K.; Bausys, B.; Bausys, R.; Strupas, K. The Role of Prehabilitation in Modern Esophagogastric Cancer Surgery: A Comprehensive Review. Cancers 2022, 14, 2096. [Google Scholar] [CrossRef]
  72. Minnella, E.M.; Awasthi, R.; Loiselle, S.; Agnihotram, R.V.; Ferri, L.E.; Carli, F. Effect of Exercise and Nutrition Prehabilitation on Functional Capacity in Esophagogastric Cancer Surgery: A Randomized Clinical Trial. JAMA Surg. 2018, 153, 1081–1089. [Google Scholar] [CrossRef] [Green Version]
  73. Akiyama, Y.; Sasaki, A.; Fujii, Y.; Fujisawa, R.; Sasaki, N.; Nikai, H.; Endo, F.; Baba, S.; Hasegawa, Y.; Kimura, T.; et al. Efficacy of enhanced prehabilitation for patients with esophageal cancer undergoing esophagectomy. Esophagus 2021, 18, 56–64. [Google Scholar] [CrossRef]
  74. Deschamps, C.; Nichols, F.C., 3rd; Cassivi, S.D.; Allen, M.S.; Pairolero, P.C. Long-term function and quality of life after esophageal resection for cancer and Barrett’s. Surg. Clin. N. Am. 2005, 85, 649–656. [Google Scholar] [CrossRef]
  75. Ware, J.E.; Sherbourne, C.D. The MOS 36-Item Short-Form Health Survey (SF-36): I. Conceptual Framework and Item Selection. Med. Care 1992, 30, 473–483. [Google Scholar] [CrossRef] [PubMed]
  76. Xu, Y.; Wang, L.; He, B.; Li, W.; Wen, Q.; Wang, S.; Sun, X.; Meng, X.; Yu, J. Development and validation of a risk prediction model for radiotherapy-related esophageal fistula in esophageal cancer. Radiat. Oncol. 2019, 14, 181. [Google Scholar] [CrossRef] [PubMed]
  77. Muro, K.; Lordick, F.; Tsushima, T.; Pentheroudakis, G.; Baba, E.; Lu, Z.; Cho, B.C.; Nor, I.M.; Ng, M.; Chen, L.-T.; et al. Pan-Asian adapted ESMO Clinical Practice Guidelines for the management of patients with metastatic oesophageal cancer: A JSMO-ESMO initiative endorsed by CSCO, KSMO, MOS, SSO and TOS. Ann. Oncol. 2019, 30, 34–43. [Google Scholar] [CrossRef] [PubMed]
  78. Hulshof, M.C.C.M.; Geijsen, E.D.; Rozema, T.; Oppedijk, V.; Buijsen, J.; Neelis, K.J.; Nuyttens, J.J.M.E.; van der Sangen, M.J.C.; Jeene, P.M.; Reinders, J.G.; et al. Randomized Study on Dose Escalation in Definitive Chemoradiation for Patients With Locally Advanced Esophageal Cancer (ARTDECO Study). J. Clin. Oncol. 2021, 39, 2816–2824. [Google Scholar] [CrossRef] [PubMed]
  79. Bollschweiler, E.; Plum, P.S.; Mönig, S.P.; Hölscher, A.H. Current and future treatment options for esophageal cancer in the elderly. Expert Opin. Pharmacother. 2017, 18, 1001–1010. [Google Scholar] [CrossRef]
  80. Qiu, G.; Zhang, H.; Wang, F.; Zheng, Y.; Wang, Z.; Wang, Y. Metastasis Patterns and Prognosis of Elderly Patients With Esophageal Adenocarcinoma in Stage IVB: A Population-Based Study. Front. Oncol. 2021, 11, 625720. [Google Scholar] [CrossRef]
  81. Münch, S.; Aichmeier, S.; Hapfelmeier, A.; Duma, M.-N.; Oechsner, M.; Feith, M.; Combs, S.E.; Habermehl, D. Comparison of dosimetric parameters and toxicity in esophageal cancer patients undergoing 3D conformal radiotherapy or VMAT. Strahlenther. Onkol. 2016, 192, 722–729. [Google Scholar] [CrossRef]
  82. Cijs, T.M.; Verhoef, C.; Steyerberg, E.W.; Koppert, L.B.; Tran, T.K.; Wijnhoven, B.P.; Tilanus, H.W.; de Jonge, J. Outcome of esophagectomy for cancer in elderly patients. Ann. Thorac. Surg. 2010, 90, 900–907. [Google Scholar] [CrossRef]
  83. Adam, D.J.; Craig, S.R.; Sang, C.T.; Cameron, E.W.; Walker, W.S. Esophagectomy for carcinoma in the octogenarian. Ann. Thorac. Surg. 1996, 61, 190–194. [Google Scholar] [CrossRef]
  84. Rahamim, J.; Murphy, G.; Awan, Y.; Junemann-Ramirez, M. The effect of age on the outcome of surgical treatment for carcinoma of the oesophagus and gastric cardia. Eur. J. Cardio-Thorac. Surg. 2003, 23, 805–810. [Google Scholar] [CrossRef] [Green Version]
  85. Sabel, M.S.; Smith, J.L.; Nava, H.R.; Mollen, K.; Douglass, H.O.; Gibbs, J.F. Esophageal resection for carcinoma in patients older than 70 years. Ann. Surg. Oncol. 2002, 9, 210–214. [Google Scholar] [CrossRef] [PubMed]
  86. Paulus, E.; Ripat, C.; Koshenkov, V.; Prescott, A.T.; Sethi, K.; Stuart, H.; Tiesi, G.; Livingstone, A.S.; Yakoub, D. Esophagectomy for cancer in octogenarians: Should we do it? Langenbeck’s Arch. Surg. 2017, 402, 539–545. [Google Scholar] [CrossRef] [PubMed]
  87. Baranov, N.S.; Slootmans, C.; van Workum, F.; Klarenbeek, B.R.; Schoon, Y.; Rosman, C. Outcomes of curative esophageal cancer surgery in elderly: A meta-analysis. World. J. Gastrointest. Oncol. 2021, 13, 131–146. [Google Scholar] [CrossRef] [PubMed]
  88. Repetto, L. Greater risks of chemotherapy toxicity in elderly patients with cancer. J. Support. Oncol. 2004, 1 (Suppl. 2), 18–24. [Google Scholar]
  89. Wasil, T.; Lichtman, S.M. Clinical pharmacology issues relevant to the dosing and toxicity of chemotherapy drugs in the elderly. Oncologist 2005, 10, 602–612. [Google Scholar] [CrossRef]
  90. Kelly, R.J.; Ajani, J.A.; Kuzdzal, J.; Zander, T.; Van Cutsem, E.; Piessen, G.; Mendez, G.; Feliciano, J.; Motoyama, S.; Lièvre, A.; et al. Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer. N. Engl. J. Med. 2021, 384, 1191–1203. [Google Scholar] [CrossRef]
Cancers 15 00106 g001 550
Figure 1. Overall survival for the entire cohort. n = 34.
Figure 1. Overall survival for the entire cohort. n = 34.
Cancers 15 00106 g001
Cancers 15 00106 g002 550
Figure 2. Progression-free survival for the entire cohort. n = 34.
Figure 2. Progression-free survival for the entire cohort. n = 34.
Cancers 15 00106 g002
Cancers 15 00106 g003 550
Figure 3. Overall survival for nCRT and dCRT. n = 34. Log Rank (Mantel-Cox): p = 0.049.
Figure 3. Overall survival for nCRT and dCRT. n = 34. Log Rank (Mantel-Cox): p = 0.049.
Cancers 15 00106 g003
Cancers 15 00106 g004 550
Figure 4. Progression-free survival for nCRT and dCRT. n = 34. Log Rank (Mantel-Cox): p = 0.057.
Figure 4. Progression-free survival for nCRT and dCRT. n = 34. Log Rank (Mantel-Cox): p = 0.057.
Cancers 15 00106 g004
Table
Table 1. Patient and treatment characteristics (n).
Table 1. Patient and treatment characteristics (n).
Sex Grading
Female10 (29.4%)11 (2.9%)
Male24 (70.6%)216 (47.0%)
Age 311 (32.3%)
Median75 yGx/Unknown6 (17.6%)
Mean75.4 yT-stage
Range71–82 y27 (20.5%)
ECOG 325 (73.5%)
018 (52.9%)41 (2.9%)
112 (35.3%)Tx/Unknown1 (2.9%)
34 (11.8%)N-stage
Tumor site 01 (2.9%)
Cervical1 (2.9%)128 (82.3%)
Upper thoracic2 (5.9%)21 (2.9%)
Middle thoracic11 (32.4%)31 (2.9%)
Lower thoracic20 (58.8)Nx/Unknown3 (8.8%)
Histology M-stage
Adeno19 (55.9%)031 (91.1%)
SCC15 (44.1%)12 (5.8%)
Mx/Unknown1 (2.9%)
AJCC/UICC stage ISCCAdeno
II1 (2.9%)None
III12 (35.3%)13 (38.2%)
IVA2 (5.8%)None
IVBNone2 (5.8%)
UnknownNone4 (11.8%)
Chemotherapy RT technique
Neoadjuvant22 (64.7%)APPA (two-field)6 (17.6%)
Definite12 (35.2%)3D-CRT (multi-field)17 (50.0%)
Agents IMRT 10 (29.4%)
Carb/TAX29 (85.2%)Unknown1 (2.9%)
Others3 (8.8%)
None2 (5.8%)
Adeno adenocarcinoma, APPA anterior/posterior fields, Carb/TAX Carboplatin and paclitaxel, ECOG Eastern Cooperative Oncology Group, IMRT intensity modulated radiation therapy, RT radiation therapy, SCC squamous cell carcinoma, 3D-CRT three-dimensional conformal radiation therapy, Unknown Due to the retrospective character of the study, y years. I 8th edition, American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) staging of cancers of the esophagus and esophagogastric junction.
Table
Table 2. (Geriatric and categorical) Screening score characteristics (n).
Table 2. (Geriatric and categorical) Screening score characteristics (n).
Charlson Score ISCCAdeno
≤3 6 (17.6%)5 (14.7%)
≥3 9 (26.4%)14 (41.1%)
Age adjusted Charlson scoreActive smoking
≥534 (100%)Yes12 (35.2%), (5 SCC (14.7%))
Frail scale Mini Nutritional Assessment Short Form
Median1 ptMedian8.5 pt
Mean1.2 ptMean8.1 pt
Range0–3 ptRange3–12 pt
Fit and agile (0 pt)7 (20.6%)Normal nutritional state (12–14 pt)2 (5.9%)
Prefrail (1–2 pt)26 (76.5%)Risk for malnutrition (8–11 pt)17 (50%)
Frail (≥3 pt)1 (2.9%)Malnutrition (0–7 pt)15 (44.1%)
BMI (weight (kg)/[height(m)]2) Weight (kg)
Median24.6Median76
Mean24.5Mean75.1
Range15.2–37.2Range35–120
Obesity (30 pt or higher)4 (11.8%)C-reactive/albumin ratio
Overweight (25.0 to 29.9 pt)10 (29.4%)Median0.1
Healthy Weight (18.5 to 24.9 pt)15 (44.1%)Mean0.5
Underweight (below 18.5 pt)5 (14.7%)Range0.1–7.0
Adeno adenocarcinoma, BMI Body mass index, pt points, SCC squamous cell carcinoma, y years. I The final score was calculated for each patient by considering all comorbid conditions present with the inclusion of EC as a cancerous disease (+two points).
Table
Table 3. Acute treatment related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE, v5.0), absolute number of patients (n = 34).
Table 3. Acute treatment related toxicities according to Common Terminology Criteria for Adverse Events (CTCAE, v5.0), absolute number of patients (n = 34).
CTC Grade0%1%2%3%4%5%
Hematological720.61029.41338.225.912.912.9
Odynodysphagia1955.91029.425.938.80000
Nausea2882.4617.600000000
Skin toxicity2264.71132.40012.90000
Fatigue2470.6720.625.912.90000
Cardiopulmonary34100.00000000000
Inappetence/loss of weight3294.112.90012.90000
Other 13088.238.80012.90000
1 Other: diarrhea, thrush esophagitis, reflux esophagitis.
Table
Table 4. Late treatment related toxicities according to CTCAE v5.0, absolute number of patients.
Table 4. Late treatment related toxicities according to CTCAE v5.0, absolute number of patients.
All Grades Grade 1–2 Grade 3–5
n%n %n%
Odynodysphagia301000039.9
Nausea30100310.000
Skin toxicity30100413.300
Fatigue3010013.300
Cardiopulmonary3010013.300
Inappetence/loss of weight3010013.300
Other 130100310.000
1 Other: cardiac decompensation, renal failure, N-STEMI, progression of Parkinson’s disease.
Table
Table 5. Univariate Cox regression and subgroup analysis.
Table 5. Univariate Cox regression and subgroup analysis.
ParameterOS HR
[95% CI]		p-ValuePFS HR
[95% CI]		p-Value
Treatment regimen
(nCRT vs. dCRT)		0.381 [0.146; 0.998]0.0490.411 [0.164; 1.028]0.057
Age
70–74 y (nCRT vs. dCRT)0.067 [0.007; 0.674]0.0220.233 [0.050; 1.077]0.062
ECOG (2–3 vs. 0–1)17.808 [3.903; 81.258]<0.00111.391 [3.079; 42.138]<0.001
BMI
Healthy Weight (nCRT vs. dCRT)0.159 [0.029; 0.878]0.0350.500 [0.140; 1.789]0.286
T-stage
T3 (nCRT vs. dCRT)0.095 [0.022; 0.407]0.0020.205 [0.062; 0.678]0.009
Grading
G3 (nCRT vs. dCRT)0.309 [0.072; 1.326]0.1140.233 [0.053; 1.033]0.055
Histology
SCC (nCRT vs. dCRT)0.161 [0.018; 1.445]0.1030.142 [0.016; 1.290]0.083
AC (nCRT vs. dCRT)0.284 [0.073; 1.112]0.0710.469 [0.128; 1.713]0.252
dCRT definite chemoradiation therapy, HR Hazard ratio, CI Confidence interval, nCRT neoadjuvant chemoradiation therapy, OS Overall survival, PFS Progression-free survival, y years.
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Linde, P.; Mallmann, M.; Adams, A.; Wegen, S.; Fan, J.; Rosenbrock, J.; Trommer, M.; Marnitz, S.; Baues, C.; Celik, E. The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center. Cancers 2023, 15, 106. https://doi.org/10.3390/cancers15010106

AMA Style

Linde P, Mallmann M, Adams A, Wegen S, Fan J, Rosenbrock J, Trommer M, Marnitz S, Baues C, Celik E. The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center. Cancers. 2023; 15(1):106. https://doi.org/10.3390/cancers15010106

Chicago/Turabian Style

Linde, Philipp, Markus Mallmann, Anne Adams, Simone Wegen, Jiaqi Fan, Johannes Rosenbrock, Maike Trommer, Simone Marnitz, Christian Baues, and Eren Celik. 2023. "The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center" Cancers 15, no. 1: 106. https://doi.org/10.3390/cancers15010106

APA Style

Linde, P., Mallmann, M., Adams, A., Wegen, S., Fan, J., Rosenbrock, J., Trommer, M., Marnitz, S., Baues, C., & Celik, E. (2023). The Role of Age and Comorbidities in Esophagogastric Cancer Chemoradiation of the Frail Elderly (>70 Years): An Analysis from a Tertiary High Volume-Center. Cancers, 15(1), 106. https://doi.org/10.3390/cancers15010106

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