University of Groningen
Modern view on multimodality treatment of esophageal cancer
Faiz, Zohra
DOI:
10.33612/diss.98628913
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2019
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Faiz, Z. (2019). Modern view on multimodality treatment of esophageal cancer: thoughts on Patient Selection and Outcome. Rijksuniversiteit Groningen. https://doi.org/10.33612/diss.98628913
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
Increased Resection Rates and Survival Among
Patients Aged 75 Years and Older with Esophageal
Cancer: A Dutch Nationwide Population-Based
Study
Z. Faiz, V. E. P. P. Lemmens, P. D. Siersema, G. A. P. Nieuwenhuijzen, M. W. J. M. Wouters, T. Rozema, J. W. W. Coebergh and B. P. L. Wijnhoven
Background
The incidence of esophageal cancer has grown over the recent decades and 30 % of esophageal cancer patients are now 75 years or older at the time of diagnosis. The aim of this study was to evaluate trends in manage-ment and survival of patients aged 75 years or older with esophageal cancer.
Methods
In the Netherlands cancer registry, we identified all patients aged 75 years or older who were diagnosed with esophageal cancer between 1989 and 2008. Trends in manage-ment and survival were analyzed by time period (1989–2001 vs. 2002–2008), TNM stage, and age (75–79,80–84, and 85+ years). Chi2 testing was used to analyze time trends
in treatment, Kaplan–Meier analysis and log-rank testing to estimate survival, and Cox regression model to calculate hazard ratios for death.
Results
Some 7,253 patients were included in the study. The surgical resection rate increased over the 1989–2008 period from 8.9 to 12.6 % (p = 0.028), especially among patients aged 75–79 years (44.6 vs. 55.4 %, p < 0.001) and patients with TNM stage I disease (12.7 vs. 22.0 %,p < 0.001). The use of definitive chemoradiotherapy (CRT) also increased (0.19 vs. 2.20 %, p < 0.001). Whereas the use of chemotherapy as a single-modality treat-ment more than doubled (0.64 vs. 1.54 %, p = 0.004), that of radiotherapy alone decreased (38.1 vs. 31.6 %, p < 0.001). Although medi-an survival time was marginally higher in the 2002–2008 period than in 1989–2001, overall 5 year survival rates remained low at 6 and 5 %, respectively (p < 0.001).
Five-year survival rate after surgery increased from 16 to 30 % (p < 0.001).
Conclusions
In patients of 75 years or older, surgical treatment and use of definitive CRT have increased between 1989 and 2008. Also, an increase in the use of chemotherapy as a single modality was noted. Overall 5 year survival for all cancer patients was stable but remained poor, while survival of patients who underwent esophagectomy improved
significantly in the Netherlands since 1989.
Introduction
Due to the aging of the population in the Western world, the absolute incidence of esophageal cancer has grown over the recent decades. Some studies have also reported a shift in the age of peak incidence from 65–70 to 70–79 years [1]. At the time of diagnosis, 30 % of esophageal cancer patients are now 75 years or older [1]. Although esophagecto-my is still the treatment of choice for resect-able tumors without metastases, it is asso-ciated with an in-hospital mortality rate of around 3–5 %. Alternative treatment options are definitive CRT and endoscopic mucosal resection for T1 cancers. Palliative measures include chemotherapy, radiotherapy, and self-expandable stents to relieve dysphagia. Several studies have compared the out-come of elderly and younger patients after esophagectomy for cancer and aggre- ssive management in elderly patients remains controversial [2–5]. Most elderly patients are frail and have significant comorbidities that might negatively impact postoperative outcome [6–8]. However, the available evidence also shows that surgery is now acceptable in a well selected group between ages 70 and 75 [9–11]; there are limited data on patients aged 75 years and older [12]. The aim of this retrospective populationbased study was to evaluate time trends in the treatment of esophageal cancer and long-term survival among patients aged 75 years and older in the 1989–2008 period.
Patients and methods
We used the nationwide population-based Netherlands Cancer Registry to select all patients aged 75 years or older diagnosed with esophageal carcinoma between January 1989 and December 2008. In order not to miss any patients, this database is connec-ted to the Dutch Patho-logisch-Anatomisch Landelijk Geautomatiseerd Archief (PALGA) system which is the nationwide network and registry of all histo- and cytopathology in the Netherlands. The Netherlands Cancer Regis-try is compiled by trained registration clerks who obtained information from the medical records on diagnosis, staging, and treatment of all patients [13, 14]. From 1989 through 1998, registers used the 9th version of the international classification of disease oncol-ogy (ICD-9, codes 150.0–150.9); after 1999, they used the 10th version (ICD-10, codes C15.0–C15.9). Patients were categorized according to two time periods (1989–2001 and 2002–2008) and subdivided in three age groups (75–79, 80–84, and 85+ years). Only patients with primary esophageal can-cers were included in the study; the cancan-cers were subclassified as squamous cell carcino-ma, adenocarcinocarcino-ma, or unknown histology. With reference to tumor subsite assessment, we used data from endoscopic, radiological, surgical, and pathological examinations. For tumor staging the TNM stage of the Union Internationale Contre le Cancer (UICC) (6th edition) was used. TNM stage was based on pathological examination of the resect-ed specimen or, when missing, on clinical preoperative evaluation. Patients with TNM stage 0 (N = 10) following neoadjuvant treat-ment were excluded. Surgery encompassed esophagectomy with curative intent. Patients who underwent palliative surgical procedures such as placement of a feeding jejunostomy were excluded.
Chemotherapy and radiotherapy given as a single modality were generally used with palliative intent. Trends in management and
survival were analyzed by two time periods, defined as period I (1989–2001) and period II (2002–2008), TNM stage, and age (75–79, 80–84, and 85+ years). Chi2 testing was used to analyze the significance of differences in proportions. Multivariable logistic regres-sion analysis was performed to estimate the independent impact of gender, age, TNM classification, tumor grade, and period of diagnosis on the likelihood that the patient would undergo a radical resection or receive definitive chemoradiation, chemotherapy, or radiotherapy. Survival time was defined as the time from diagnosis until death or last follow-up. We used the Kaplan–Meier method and log-rank testing to estimate survival in relation to the two time periods, where survival was defined as survival 1, 3, and 5 years after surgery. We analyzed survival by the time of surgery (period I: 1989–2001 and period II: 2002–2008) for the whole group of esophageal cancer patients and for those who underwent esophagectomy. The Cox proportional-hazards regression model was used to identify changes in survi- val between these two periods and to calcu-late hazard ratios for death adjusted for age, sex, tumor stage, and treatment. Period I was used as the reference category. All statistical analyses were performed using the statistical package SPSS 16.0 (SPSS, Inc., Chicago, IL). A p < 0.05 within a 95% confidence interval was considered statistically significant.
Results
Patient and treatment characteristics
A total of 7,253 patients with esophageal cancer aged 75 years or older were identified in the Netherlands Cancer Registry between 1989 and 2008 (Table 1). Because of the low resection rates in elderly esophageal cancer patients, TNM stages were frequent-ly unknown. However, in accordance with improvements in staging techniques over
time, the percentage of tumors with unknown TNM stage declined from 61.8% in period I to 41.5% in the period II (p < 0.001) (data not shown).
Trends in management of esophageal cancer
The overall surgical resection rate was 10.7% and increased from 8.9% in period I to 12.6% in period II (Table 2; p = 0.024). Esophagectomy was performed more often in the 75–79 year age category (44.6% in period I vs. 55.4% in period II; OR = 1.3, 95% CI = 1.1–1.6, p<0.001) and mainly among patients with a TNM stage I disease (12.7% in period I vs. 22.0% period II, p<0.001). Use of chemotherapy or radiotherapy in combination with surgery was limited to 31 patients and 35 patients, respectively (Ta-ble 2). Almost all patients who underwent neoadjuvant chemoradiotherapy plus surgery were aged 75–79 years and treated during period II. Use of definitive CRT as an alter-native treatment with curative intent had also increased from 0.19 % in period I to 2.2 % in period II (p<0.001). This increase was more pronounced in the 75–79 year age category (0.7% in period I vs. 10.5% in period II, OR = 15.8, 95 % CI = 6.3–39.7, p<0.001) and the 80–84 year age category (0.2% in period I vs. 3.8% in period II, OR = 20.1, 95% CI = 2.6– 151.5, p<0.001) (data not shown). Adminis-tration of chemotherapy as a single-treatment modality increased significantly with time (p = 0.004). Multivariable analysis demonstrated that advanced age and TNM stage were inde-pendent factors for receiving chemotherapy as a single treatment. After adjustment for age, gender, TNM stage, histology, and grade of differentiation, the 2002–2008 period was associated with a lower likelihood of under-going radiation therapy as primary treatment (p<0.001).
Survival
Median survival was higher in period I than in period II (6.6 months, 95 % CI = 6.3–6.9 vs. 6.0 months, 95 % CI = 5.7–6.3; p = 0.001) (Fig. 1). One-, three-, and fiveyear survival rates are shown in Table 3. In the surgery group, median survival was significantly higher compared to that of patients trea-ted with definitive CRT (19 vs. 15 months, p<0.001) (Fig. 2). Any treatment was asso-ciated with improved survival as compared to patients who did not receive treatment. Median survival after surgery was significant-ly better in period II than in period I: 26.5 (95 % CI = 22.9–30.1) vs. 15.4 months (95 % CI = 12.4–18.5) (p<0.001) (Fig. 3; Table 4). Age, tumor stage, and period were independent predictors of survival after esophagectomy.
Discussion
This study showed that in patients 75 years or older, surgical treatment of esophageal cancer increased between 1989 and 2008. Overall 5 year survival for all cancer patients was poor, whereas survival of patients who underwent esophagectomy with curative intent improved significantly in the Netherlands since 1989. These changes over time suggest that a shift toward more aggressive treatment of elderly patients with esophageal cancer has taken place in the last two decades.
Our analysis also demonstrated increasing use of both definitive CRT and neoadjuvant CRT followed by surgery. The increased use of neoadjuvant CRT followed by surgery could be explained by the initiation of a Dutch randomized controlled trial on neoadjuvant CRT in 2004 [15]. Although patients aged 76 years or older were not eligible to participate, it can be hypothesized that some older but fit patients underwent neoadjuvant CRT outside the ‘‘official’’ study protocol. Also, increased awareness of the benefits of (neoadjuvant) CRT might have played a role [16, 17]. This may also have stimulated use of definitive chemoradiation in patients deemed unfit for surgery because of age and severe comorbidity. At the same time, we showed that survival of elderly patients following definitive chemoradiotherapy is worse than of patients who undergo surgery.
There are limited data on tolerance and outcome of CRT in patients aged 75 years and older. At least two studies concluded that full-dose CRT is tolerable in some elderly patients over 75 but with significant morbidity [18, 19].
More studies are needed to identify predictive factors of treatment-related complications, especially among elderly patients.
The observed improved survival after esophagectomy in the more recent years of the study period is striking.
Earlier diagnosis, improved tumor staging, and better management of the less advanced stage may explain this change. However,
even after adjustment for tumor stage, survival of patients after esophagectomy in the second study period was still better. Improvements in surgical techniques and perioperative risk evaluation are therefore more likely explanations for this increased survival rate and have also likely reduced op-erative morbidity and mortality [20]. Several studies have shown improvements in short-term survival among elderly patients after esophagectomy [12,21, 22].
A limitation of these studies is that these patients were likely to be selected from a larger cohort hence representing the fittest population. This underlines a limitation of our study, i.e., the lack of data on the presence and severity of frailty and comor-bidities in the patients who were deemed unfit for surgery. It remains challenging in this regard to determine which patients are fit or unfit for surgery. However, it might be that the ongoing evolution of minimally invasive surgery for esophageal cancer especially leads to a further minimization of surgical morbidity and mortality, which could be of special benefit for the elderly patients [23]. A 3 year survival rate of 32 % after
esophagectomy among patients aged 85 years and older seems acceptable, although it is important to note that almost all patients had died 5 years after surgery. While information on cancerspecific survival was not available, it may well be that noncancer-related causes of death, such as cardiovascular diseases, were responsible for this decline in survival. Because of this, it seems reasonable to withhold surgery in this age group, especially when taking into
consideration the major impact of surgery on patients’ quality of life. In this regard, alternative treatment options such as definitive CRT, chemotherapy, radiotherapy, or even less invasive palliative measures to relief dysphagia may be valuable alternatives in this age group. An interesting finding of our study was the declining use of palliative
radiotherapy over time. One explanation could be the increased use of definitive CRT. However, at the same time we have also shown that the use of chemotherapy as a sin-gle modality treatment increased in the same period, which makes this explanation less likely. Inrecent years also, the use of self-ex-pandable stents has increased to relief dys-phagia in patients with a predicted short-term survival. Stents achieve rapid restoration of swallowing and relief of dysphagia in the ma-jority of patients and this treatment was prob-ably favored in elderly patients. Our study is the first nationwide population-based retro-spective study that has shown an improved survival after esophagectomy among patients with esophageal cancer who are 75 years or older. One of the advantages of our analysis is that the results are applicable to the general population. Another strength of this study is the absence of selection bias that can be found in data from observational studies and randomized trials. Other advantages include the length of observation, the identical stag-ing system, the complete follow-up period, and access to diagnostic data and to data for pre- and postoperative management. Despite these advantages, a limitation of this study is the high proportion of unknown tumor stages. Nevertheless, improved staging over the years resulted in a decreasing proportion over time of patients with unknown tumor stage. Moreover, after multivariable analysis, advanced and unknown tumor stages were associated with a poor survival rate. Other limitations include the lack of information on the exact surgical (open vs. minimally inva-sive techniques) and nonsurgical management and the absence of cancerspecific survival rates. However, this study shows a clear trend toward more invasive and multimodal therapy in the management of esophageal cancer in the elderly.
Acknowledgments
This research was performed within the framework of the project ‘‘Progress against cancer in the Netherlands since the 1970s?’’ (Dutch Cancer Society grant 715401).
References
1.van Blankenstein M, Looman CW, Siersema PD et al (2007) Trends in the incidence of adenocarcinoma of the oesophagus and cardia in the Netherlands 1989–2003. Br J Cancer 96:1767–1771
2.Thomas P, Doddoli C, Neville P et al (1996) Esopha-geal cancer resection in the elderly. Eur J Cardiothorac Surg 10:941–946
3.Alexiou C, Beggs D, Salama FD et al (1998) Surgery for esophageal cancer in elderly patients: the view from Nottingham. J Thorac Cardiovasc Surg 116:545–553 4.Cijs TM, Verhoef C, Steyerberg EW et al (2010) Out-come of esophagectomy for cancer in elderly patients. Ann Thorac Surg 90:900–907
5.Pultrum BB, Bosch DJ, Nijsten MW et al (2010) Extended esophagectomy in elderly patients with eso- phageal cancer: minor effect of age alone in determining the postoperative course and survival. Ann Surg Oncol 17:1572–1580
6.Ma JY, Wu Z, Wang Y et al (2006) Clinicopatho-logic characteristics of esophagectomy for esophageal carcinoma in elderly patients. World J Gastroenterol 12:1296–1299
7.Moskovitz AH, Rizk NP, Venkatraman E et al (2006) Mortality increases for octogenarians undergoing eso- phagogastrectomy for esophageal cancer. Ann Thorac Surg 82:2031–2036
8.Janssen-Heijnen ML, Houterman S, Lemmens VE et al (2005) Prognostic impact of increasing age and co-mor-bidity in cancer patients: a population-based approach. Crit Rev Oncol Hematol 55:231–240
9.Ellis FH Jr, Williamson WA, Heatley GJ (1998) Cancer of the esophagus and cardia: does age influence treat-ment selection and surgical outcomes? J Am Coll Surg 187(4):345–351
10.Poon RT, Law SY, Chu KM et al (1998) Esophagec-tomy for carcinoma of the esophagus in the elder-ly—results of current surgical management. Ann Surg 227:357–364
11.Sabel MS, Smith JL, Nava HR et al (2002) Esoph-ageal resection for carcinoma in patients older than 70 years. Ann Surg Oncol 9:210–214
12.Adam DJ, Craig SR, Sang CT et al (1996) Esophagec-tomy for carcinoma in the octogenarian. Ann Thorac Surg 61:190–194
13.Schouten LJ, Straatman H, Kiemeney LA et al (1994) The capture–recapture method for estimation of cancer registry completeness: a useful tool? Int J Epidemiol 23:1111–1116
14.Schouten LJ, Jager JJ, van den Brandt PA et al (1993) Quality of cancer registry data: a comparison of data pro-vided by clinicians with those of registration personnel. Br J Cancer 68:974–977
15.van Heijl M, van Lanschot JJ, Koppert LB et al (2008) Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS). BMC Surg 8:21
16.Walsh TN, Noonan N, Hollywood D et al (1996) A comparison of multimodal therapy and surgery for esophageal adenocarcinoma. N Engl J Med 335:462–467 17.Stahl M, Stuschke M, Lehmann N et al (2005) Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus. J Clin Oncol 23:2310–2317
18.Mak RH, Mamon HJ, Ryan DP et al (2010) Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older. Dis Esophagus 23:316–323 19.Kosugi S, Sasamoto R, Kanda T et al (2009) Retro-spective review of surgery and definitive chemoradio-therapy in patients with squamous cell carcinoma of the thoracic esophagus aged 75 years or older. Jpn J Clin Oncol 39:360–366
20.al-Sarraf M, Martz K, Herskovic A et al (1997) Progress report of combined chemoradiotherapy versus radiotherapy alone in patients with esophageal cancer. J Clin Oncol 15:277–284
21.van de Poll-Franse LV, Lemmens VE, Roukema JA et al (2011) Impact of concentration of oesophageal and gastric cardia cancer surgery on long-term popula-tion-based survival. Br J Surg 98(7):956–963 22.Ferguson MK, Martin TR, Reeder LB et al (1997) Mortality after esophagectomy: risk factor analysis. World J Surg 21:599–603. doi:10.1007/s002689900279 23.Ferguson MK, Durkin AE (2002) Preoperative prediction of the risk of pulmonary complications after esophagectomy for cancer. J Thorac Cardiovasc Surg 123:661–669
24.Hoppo T, Jobe BA, Hunter JG et al (2011) Minimally invasive esophagectomy: the evolution and technique of minimally invasive surgery for esophageal cancer. World J Surg 35:1454–1463.
