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.
Download date: 28-06-2021
Modern view on multimodality treatment of esophageal cancer
Thoughts on Patient Selection and Outcome
proefschrift
ter verkrijging van de graad van doctor aan de Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. C. Wijmenga en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op maandag 14 oktober 2019 om 12.45 uur.
Zohra Faiz
geboren op 11 september 1984 te Kabul, Afghanistan.
door
Promotores
Prof. dr. J.T.M. Plukker Prof. dr. V. Lemmens Copromotores Dr. B.P.L. Wijnhoven Dr. C.T. Muijs
Beoordelingscommissie
Prof. dr. J.A. Langendijk
Prof. dr. H. Grabsch
Prof. dr. H.J. Hoekstra
Design Henry de Beer Numana Chaudhry Printing
STIP Stencilwerk
The studies in this thesis were financially supported by Departments of Radiotherapy, Clinical Genetics and Pathology of the University Medical Centre Groningen.
Printing of this thesis was financially supported by: De Rijksuniversiteit Groningen, Integraal Kankercentrum Nederland
ISBN: 978-94-034-1862-9 ISBN Eboek 978-94-034-1861-2
Copyright of the published articles is with the corresponding journal or otherwise the author. No part of this book may be reproduced, stored, or transmitted in any form or by any means without prior premission from the author or corresponding journal.
While writing my thesis I was inspirited by the spirit animal dragonfly and the color turquoise.
The dragonfly is an elegant and powerful insect.
She achieves her purpose simply and effectively with her two pairs of wings, a long slim abdomen, and large eyes.
The flight of the dragonfly stands for progress and flexibility, but also the endlessness of possibilities in life.
In various cultures the dragonfly is seen as the bringer of new insights and she represents playfulness, change, and harmony. The dragonfly stands for spiritual growth and positive thoughts. As a totem animal, the dragonfly demands strength in the balance between emotions, thoughts, and change. Coherent, turquoise is a color of creativity and vision with the ancient symbol reformer and key phrase future-oriented innovation. This capacity is achieved by searching for new forms of living together through humanization and technocratic society reform.
Through collaboration with different departments, agencies, and people both nationally and internationally, we have tried to bring together the power of various insights into innovative approaches. As a result, the stud- ies described in this thesis aim to provide novel insights into the management and treatment outcome in patients with esophageal cancer.
Preface
7
General introduction and outline of the thesis 9 PART I Impact of age and co-morbidity: population-based studies 17 Chapter 1 Increased resection rates and survival among patients aged 75 year 19
and older with esophageal cancer: a Dutch nationwide population-based study.
Chapter 2 Impact of co-morbidity on treatment choices in patients with potentially 35 curable esophageal cancer: a population-based study.
Chapter 3 Implementation of age and co-morbidity in the treatment guideline of 55 patients with esophageal squamous cell carcinoma
PART II Impact of different clinico-pathological factors on prognosis 59 Chapter 4 Prognostic value of the circumferential resection margin in esophageal 61
cancer patients after neoadjuvant chemoradiotherapy.
Chapter 5 Prevalence and prognostic significance of extramural venous invasion in 79 patients with locally advanced esophageal cancer.
Chapter 6 Reflections in diagnostic significance of extramural venous invasion 101 in patients with locally advanced esophageal cancer.
PART III Frequent treatment failures and intended curative treatment of 105 locoregional recurrent and persistent disease.
Chapter 7 A comprehensive motion analysis - consequences for high precision image 107 guided radiotherapy in esophageal cancer patients.
Chapter 8 Site of residual locoregional esophageal cancer after neo-adjuvant 135 chemoradiotherapy regarding anatomical layers and radiation target fields:
a histopathologic evaluation.
Chapter 9 A meta-analysis on salvage surgery as a potentially curative procedure in 157 patients with isolated local recurrent or persistent esophageal cancer after
chemoradiotherapy.
Summary, general discussion and future perspectives 181
Summery 181
Samenvatting 193
Dankwoord 197
Table of contents
8
9
General introduction and outline of the thesis
Curative treatment strategies in esophageal cancer
While the incidence of esophageal cancer (EC) in Europe is rising, survival remains poor despite improved and more sophistica- ted treatments in recent years. EC is a hetero- geneous disease, therefore it is necessary to identify clinicopathological factors in order to stratify patients better for adequate treatment aiming to prevent unnecessary side effects, to limit postoperative morbidity and to improve outcome.
Due to the aging of the population in the Western world with a shift in the peak inci- dence from 65–70 to 70–79 years, the abso- lute incidence of EC has grown over the past decades. At the time of diagnosis, 30% of the patients with EC are currently ≥75 years [1].
Approximately 50% of patients with EC have incurable disease due to invasion of sur- rounding organs (T4b-stage) or syste- mic metastases (M-stage). Of patients with a potentially curable esophageal tumor, more than 40% has locally advanced disease with regional nodal involvement [2].
During the last two decades, both staging and curative treatment regimens have evolved.
Although curative treatment options com- monly depend on the extension of the primary tumor and presence of locoregional lymph node metastases, patient- and other tumor-re- lated factors including co-morbidity, age, histologic type, and tumor location play a role in the treatment decision. For early EC, (Tis- T1a), endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are well-established techniques with a rela- tively low morbidity. For years, esophagec- tomy performed via an open transthoracic approach with regional lymph node dissection
was the treatment of choice. During the late 1990 and early 2000, tri-modality treatment, including neoadjuvant chemoradiotherapy (nCRT) plus surgery was introduced and this has led to improved outcomes. Nowadays, nCRT or (perioperative) chemotherapy (CT) followed by esophagectomy is the treatment of choice for locally advanced EC (T3-T4a) or documented lymph node (LN) involvement according to the 8th edition of the AJCC (Ta- ble 1). Definitive chemo-radiotherapy (dCRT) has shown to be an alternative in patients who are medically unfit for surgery or deny curative intended resection and for locally irresectabele (cT4b) tumors.
Neoadjuvant CRT may induce down staging/
sizing of the primary tumor and sterilization of nodal metastases in up to 60% of patients.
Moreover, by targeting locoregional and distant micro-metastases, nCRT seems to de- crease the potential risk of developing distant metastases. Two commonly used preoperative CRT regimes, cisplatin and 5-fluorouracil in combination with 50.4 Gy, and carboplatin with paclitaxel and 41.4 to 50.4 Gy, are now considered as standard care in the Western world [5-7]. Following nCRT and surgery, the resection specimen may show different pathologic tumor response grades including a pathologic complete, partial or no response.
Pathologic complete response to chemora- diotherapy is associated with improved long term survival. This may be explained by an increased rate of a resection with micro- scopic tumor-negative resection margins (so-called radical or R0-resection) and, as a consequence, decreased rate of locoregional recurrences [5].
10
About 15-36% of the resection specimens after nCRT show a pathologic complete response (pCR), including absence of micro- scopic vital tumor cells both at the primary tumor site and nodal regions (ypT0N0) [8].
Theoretically, esophagectomy is not of addi- tional value in these patients [5].
However, identification of patients with a complete response, even with state of art imaging modalities prior to surgery is difficult, whereas esophagectomy may cure patients with partial response (PR) and persistent disease after nCRT. Moreover, pa- tients with little or no response (NR) to nCRT are also advised to undergo an esophagec- tomy although it is known that these pa- tients generally have a poor outcome [9]. At present, all patients are exposed to the risks of morbidity and mortality of neoadjuvant treatment and surgery given the fact that it is still impossible to accurately predict response to treatment and prognosis in individual patients.
A German study showed equal overall survival (OS) in patients with squamous cell carcinoma (SCC) following nCRT (41.4 Gy) with surgery compared to patients after dCRT (65 Gy or more) [10]. Likewise, a French trial reported no survival benefit of surgical resection after nCRT compared to dCRT [11]. These studies underline the use of dCRT as an alternative in patients with a potentially curative EC. Definitive CRT in patients with locally advanced EC can be applied for several reasons. Patients may be medically unfit to undergo high risk surgery or have a technically difficult localisation of the tumor and/or locoregional disease, while some patients do not opt for surgery [12-16].
To improve the outcome for dCRT, Minsky et al. investigated the benefit of high radia- tion dose (64.8 Gy) compared to a standard dose, but found no benefit and even a trend towards reduced survival in the experimental arm [17]. In response to these results and the observed side effects, the standard radiation dose for dCRT is 50–50.4 Gy in the United States and Europe.
Although the clinical CR (cCR) rates are high and short-term survival is favorable following dCRT, persistent or recurrent locoregional (LR) cancer is common [9]. In some Japanese studies the observed cCR rate is between 63- 89% among patients with stage I to stage II/
III SCC disease [18,19]. However, in patients with T4 tumors and/or extraregional lymph node metastases (previously called M1a), the reported cCR after dCRT is around 33% [20].
Depending on the histological type about 40-60% of the patients who achieved cCR eventually will develop local recurrences (LR)[21, 22]. Usually additional CRT will not control the LR potential because most patients already have received the maximal radiation doses, whereas the chance for dis- tant metastasis is relatively high precluding the possibility to perform curative surgery.
On the other hand, a selected group of patients with an isolated LR may be suitable for curative intended “ salvage surgery” after adequate staging [9].
The increased experience with dCRT and a more intensive follow up of patients after- wards may increase the number of patients who benefit from salvage surgery in case of isolated recurrent or persistent EC. The reported rate of salvage surgery ranges be- tween 4% and 29% and most procedures are performed 4 to18 months after completion of dCRT, reflecting the lack of criteria in the management of LR in EC [9]. However, sal- vage esophagectomy is associated with high rates of morbidity and in-hospital mortality of around 50-79% and 6-22%, respectively. The reported 5year survival rates vary between 0 and 33 % [13, 23, 24]. Postoperative com- plications, including pneumonia and sepsis, occur frequently and impact on patient’s pulmonary, cardiac, and renal functioning, di- minishing the long-term health-related quality of life and survival. Another problem is that patients’ immune system seems to be sup- pressed after dCRT, and that the irradiation of the proximal stomach, particularly in distal EC, may affect the viability of the gastric conduit and anastomosis [11].
11
Given the high rate of complications after salvage esophagectomy, this procedure should be limited to a carefully selected group of patients and in hospitals with ample experience in upper GI surgery. Crucial in the selection of patients with isolated recurrent or persistent disease is the adequacy of
follow-up of potential candidates [9].
However, there are still no guidelines to select patients properly for follow up and eventually surgery. According to recent publications it is relevant to take into account the accuracy of restaging methods following dCRT, patient’s performance status / fitness, the potential to obtain a complete R0 resec- tion, and the detection of suspected systemic metastases [25-27].
A better understanding of biological behavior in combination with improved technology like molecular targeted therapy, new radio- therapy techniques such as proton therapy will provide us the opportunity to improve individual therapies, diagnosis and prevention strategies in EC.
12
Outline of the thesis
This thesis is divided in three parts. PART I includes the impact of co-morbidity on treatment offered to patients in two pop- ulation based studies. PART II focuses on clinico-pathological factors and outcome after treatment. PART III addresses the different treatment options with respect to persistent and recurrent disease.
PART I - Impact of co-morbidity: popula- tion-based studies
Chapter 1
In the Netherlands, the incidence of esopha- geal cancer (EC) has increased over the last three decades, particularly in patients over the age of 50 years. Nowadays 30% of the patients are 75 years or older at the time of diagnosis. In this chapter we evaluated trends in management and survival of patients aged 75 years or older with EC.
Chapter 2-3
Surgery still is the cornerstone in the treat- ment of EC patients. However, some patients with locally advanced EC (T1/N1-3 and T2-4a/any N/M0) are not fit for surgery due to severe co-morbidity or have denied surgery for other reasons. Definitive chemoradiothe- rapy (dCRT) is a good alternative for these patients. In this chapter, we assessed the impact of co-morbidity and age >75 years on the choices of treatment made by the multi- disciplinary board.
PART II - Impact of different clinico-patho- logical factors on prognosis
Chapter 4
Besides the presence and number of nodal metastases, lymph vascular involvement, intramural metastases and circumferential resection margin (CRM) predict poor progno- sis. Earlier studies showed that involvement of the CRM is an independent prognostic factor for recurrent disease and survival after surgery alone. In this chapter, we evalua- ted the usefulness and impact on prognosis of both definitions of CRM as tumor-free (R0) based on a surgery-alone approach as described by the College of American Patho- logists (CAP;>0 mm) or the Royal College of Pathologists (RCP;>1 mm), in current practice with nCRT.
Chapter 5 and 6
Extramural venous invasion (EMVI) is a known potent adverse prognostic factor in patients with colorectal carcinoma. In contrast to colorectal cancer, the incidence and prognostic significance of EMVI in EC have not been studied. As nCRT is a common standard treatment for EC, nCRT may have a potential effect on the degree of EMVI and survival as seen in colorectal cancer patients.
In this chapter, we described the prevalence, prognostic and diagnostic value of EMVI in patients with locally advanced stage T3/
T4 EC and the potential impact for patients treated with nCRT.
13
PART III – Frequent treatment failures and intended curative treatment on locoregional recurrent and persistent disease
Chapter 7
In the curative treatment of patients with esophageal cancer (EC), external beam radiotherapy is commonly used either in a neo-adjuvant or definitive approach. Brea- thing motion of surrounding vital organs are of influence on planned dose distributions in thoracic radiotherapy. In this prospective study we have evaluated the magnitude of the breathing motion on repeat 4D computed tomography scans, by using the diaphragm as an anatomical landmark for EC.
Chapter 8
Improvements in the treatment of patients with esophageal cancer with neoadjuvant chemoradiotherapy (nCRT) have significantly increased the rates of pathologic complete response. Recently, a watchful waiting strategy and surgery only as needed has been proposed for patients with a clinical complete response in a study context. In this study, we investigated the site of residual tumor after nCRT in relation to target volumes and its impact on prognosis.
Chapter 9
Definitive CRT is a curative treatment option for a selected group of patients with local ly advanced EC. The presence of isolated persistent or recurrent local/regional disease after dCRT could be an indication for salvage surgery. In this chapter, we reported a syste- matic review that investigated the safety and efficacy of salvage surgery in persistent or recurrent EC after dCRT and in patients after nCRT who underwent delayed surgery.
14
References
1.van Blankenstein M, Looman CW, Siersema PD, Kuipers EJ, Coebergh JW. Trends in the incidence of adenocarcinoma of the oesophagus and cardia in the Netherlands 1989–2003. Br J Cancer. 2007 Jun 4;96(11):1767-71.
2.D’Journo XB, Thomas PA. Current ma- nagement of esophageal cancer. J Thorac Dis. 2014 May;6 Suppl 2:S253-64.
3.van Heijl M1, van Lanschot JJ, Koppert LB, van Berge Henegouwen MI et al. Neoadjuvant chemoradiation fol- lowed by surgery versus surgery alone for patients with adenocarcinoma. BMC Surg. 2008 Nov 26;8:21.
4.Rice TW, Patil DT, Blackstone EH. 8th edition AJCC/
UICC staging of cancers of the esophagus and eso- phagogastric junction: application to clinical practice.
Ann Cardiothorac Surg. 2017 Mar;6(2):119-130.
5.Stahl M, Wilke H, Fink U, Stuschke M, Walz MK, Siewert JR, et al. Combined preoperative chemotherapy and radiotherapy in patients with locally advanced eso- phageal cancer: interim analysis of a Phase II trial. J Clin Oncol 1996;14: 829–37.
6.Tepper J, Krasna MJ, Niedzwiecki D, Hollis D, Reed CE et al. Phase III trial of trimodality therapy with cis- platin, fluorouracil, radiotherapy, and surgery compared with surgery alone for esophageal cancer: CALGB 9781.
J Clin Oncol. 2008 Mar 1;26(7):1086-92.
7.van Hagen P, Hulshof M, van Lanschot J, et al. Preop- erative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med 2012 May 31;366(22):2074e84.
8.de Gouw DJJM, Klarenbeek BR, Driessen M, Bou- wense SAW, van Workum F et al. Detecting Patholog- ical Complete Response in Esophageal Cancer after Neoadjuvant Therapy Based on Imaging Techniques: A Diagnostic Systematic Review and Meta-Analysis.
J Thorac Oncol. 2019 Jul;14(7):1156-1171.
9.Tachimori Y. Role of salvage esophagectomy after definitive chemoradiotherapy. Gen Thorac Cardiovasc Surg. 2009;57:71–8.
10.Stahl M, Stuschke M, Lehmann N, Meyer HJ, Walz MK, Seeber S, et al. Chemoradiation with and without surgery in patients with locally advanced squamous cell carcinoma of the esophagus,
J Clin Oncol 2005;23:2310–7.
11. Bedenne L, Michel P, Bouché O, Milan C, Mariette C, Conroy T, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102, J Clin Oncol 2007;25:1160–8.
12.Hofstetter WL. Salvage esophagectomy. J Thorac Dis.
2014;6: S341–9.
13.Kato H, Nakajima M. Treatments for esophageal cancer: a review Gen Thorac Cardiovasc Surg. 2013 Jun;61(6):330-5.
14.Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radi- ation Therapy Oncology Group. JAMA. 1999 May 5;281(17):1623-7.
15.Daly JM, Fry WA, Little AG, Winchester DP, McKee RF, Stewart AK, et al. Esophageal cancer: results of an American College of Surgeons Patient Care Evaluation Study. J Am Coll Surg 2000;190:562–73.
16.Ishida K, Ando N, Yamamoto S, Ide H, Shinoda M. Phase II study of cisplatin and 5-fl uorouracil with concurrent radiotherapy in advanced squamous cell car- cinoma of the esophagus: a Japan Esophageal Oncology Group (JEOG)/Japan Clinical Oncology Group trial (JCOG9516). Jpn J Clin Oncol 2004;34:615–9.
17.Minsky BD, Pajak TF, Ginsberg RJ, Pisansky TM, Martenson J, Komaki R, et al. INT 0123 (Radiation Therapy Oncology Group 94–05) phase III trial of com- bined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol.
2002;20:1167–74.
18.Kato H, Sato A, Fukuda H, et al. A phase II trial of chemoradiotherapy for stage I esophageal squamous cell carcinoma: Japan Clinical Oncology Group study (JCOG9708). Jpn J Clin Oncol. 2009;39:638–43.
19.Kato K, Muro K, Manashi K, et al. Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II-III esophageal squamous cell carcinoma:
JCOG trial (JCOG 9906). Int J Radiat Oncol Biol Phys.
2011;81:684–90.
20.Ohtsu A, Baku N, Muro K, et al. Definitive chemo- radiotherapy for T4 and/or M1 lymph node squa- mous cell carcinoma of the esophagus. J Clin Oncol.
1999;17:2915–21.
21.Yamamoto S, Ishihara R, Motoori M, et al. Com- parison between definitive chemoradiotherapy and esophagectomy in patients with clinical stage I eso- phageal squamous cell carcinoma. Am J Gastroenterol.
2011;106:1048–54.
22.Kumagai K, Mariosa D, Tsai JA, Nilsson M, Ye W, Lundell L, Rouvelas I. Systematic review and meta-ana- lysis on the significance of salvage esophagectomy for persistent or recurrent esophageal squamous cell carcino-
15
ma after definitive chemoradiotherapy. Dis Esophagus.
2016 Oct;29(7):734-739.
23.Watanabe M, Mine S, Nishida K, Yamada K, Shigaki H, Matsumoto A, Sano T. Salvage Esophagectomy After Definitive Chemoradiotherapy for Patients with Esophageal Squamous Cell Carcinoma: Who Really Benefits from this High-Risk Surgery? Ann Surg Oncol.
2015 Apr 11.
24.Tachimori Y, Kanamori N, Uemura N, Hokamura N, Igaki H, Kato H. Salvage esophagectomy after high-dose chemoradiotherapy for esophageal squamous cell carci- noma. J Thorac Cardiovasc Surg. 2009;137:49–54.
25.Swisher SG, Wynn P, Putnam JB, Mosheim MB, Cor- rea AM, Komaki RR, et al. Salvage esophagectomy for recurrent tumors after definitive chemotherapy and radio- therapy. J Thorac Cardiovasc Surg 2002;123:175–83.
26.Nakamura T, Hayashi K, Ota M, Eguchi R, Ide H, Takasaki K, et al. Salvage esophagectomy after definitive chemotherapy and radiotherapy for advanced esophageal cancer. Am J Surg 2004;188:261–6.
27.Tomimaru Y, Yano M, Takachi K, Miyashiro I, Ishiha- ra R, Nishiyama K et al. Factors affecting the prognosis of patients with esophageal cancer undergoing salvage surgery after definitive chemoradiotherapy. J Surg Oncol 2006; 93: 422–428.
27.Schieman C, Wigle DA, Deschamps C, Nichols FC 3rd, Cassivi SD, Shen KR, Allen MS. Salvage resections for recurrent or persistent cancer of the proximal esoph- agus after chemoradiotherapy. Ann Thorac Surg. 2013 Feb;95(2):459-63.
16
‘The specialist must know everything of something, something of everything.’’
- C.V. Wedgwood
17
PART I
‘The specialist must know everything of something, something of everything.’’
- C.V. Wedgwood
Impact of co-morbidity: population-based studies
18
19
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
20
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.
Abstract
21
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 cancers were subclassified as squamous cell carcino- ma, adenocarcinoma, 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
22
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).
23
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.
24
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
25
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).
26
27
Tables & figures
28
29
30
31
31
32
32
33
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.
34
35 35
Impact of Age and Comorbidity on Choice and Outcome of Two Different Treatment Options for Patients with Potentially Curable Esophageal Cancer
Z. Faiz, M. van Putten, R. H. A. Verhoeven, J. W. van Sandick, G. A. P. Nieuwenhui- jzen, M. J. C. van der Sangen, V. E. P. P. Lemmens, B. P. L. Wijnhoven, and J. T. M.
Plukker.
36
Purpose
This study was designed to assess the im- pact of age and comorbidity on choice and outcome of definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy plus surgery.
Methods
In this population-based study, all patients with potentially curable EC (cT1N+/cT2-3, TX, any cN, cM0) diagnosed in the South East of the Netherlands between 2004 and 2014 were included. Kaplan–Meier method with log-rank tests and multivariable Cox regression analysis were used to compare overall survival (OS).
Results
A total of 702 patients was included. Age ≥ 75 years and multiple comorbidities were associated with a higher probability for dCRT (odds ratio [OR] 8.58; 95% confidence inter- val [CI] 4.72–15.58; and OR 3.09; 95% CI 1.93–4.93). The strongest associations were found for the combination of hypertension plus diabetes (OR 3.80; 95% CI 1.97–7.32) and the combination of cardiovascular with pulmonary comorbidity (OR 3.18; 95% CI 1.57–6.46). Patients with EC who underwent dCRT had a poorer prognosis than those who underwent nCRT plus surgery, irrespective of age, number, and type ofcomorbidities.
In contrast, for patients with squamous cell carcinoma with ≥ 2 comorbidities or age ≥ 75 years, OS was comparable between both groups (hazard ratio [HR] 1.52; 95% CI 0.78–2.97; and HR 0.73; 95% CI 0.13–4.14).
Conclusions
Histological tumor type should be acknow- ledged in treatment choices for patients with esophageal cancer. Neoadjuvant chemora- diotherapy plus surgery should basically be advised as treatment of choice for operable esophageal adenocarcinoma patients. For pa- tients with esophageal squamous cell carcino- ma with ≥ 2 comorbidities or age ≥ 75 years, dCRT may be the preferred strategy.
Abstract
37
Introduction
For potentially curable esophageal cancer (EC), radical surgery after neoadjuvant chemoradiotherapy (nCRT) has been the standard of care in the Netherlands since 2008 [1]. However, surgery is associated with post operative morbidity in up to 60%
of patients with a 90 day mortality rate of 7–13%[2–6]. In general, comorbidity and older age are related to early postoperative mortality after gastrointestinal cancer surgery.
[7]. A less aggressive treatment approach may be considered in these patients [8]. Definitive chemoradiotherapy (dCRT) is an alternative curative intended treatment option in elderly patients and in patients with severe comorbid- ities [3,9–11]. Similar survivalrates have been reported after chemoradiotherapy with or without surgery for patients with esophageal squamous cell carcinoma (ESCC)[11,12].
In patients with esophageal adenocarcinoma (EAC), surgery is recommended unless there is a high risk for threatening postoperative complications and/or mortality [13–16].
Long-term outcome data following dCRT for potentially curable EC are scarce and guide- lines for selecting the appropriate treatment in patients with severe comorbidity and older age are not available [13,17]. The purpose of this population based, retrospective study was to assess the impact of age and comorbidity on the choice of curative intended treatment and long-term overall survival among patients with potentially curable esophageal cancer.
Patients and methods
Data from all patients with a primary esopha- geal cancer (CI 5.1–5.9), diagnosed between 2004 and 2014 in the South East of the Netherlands, were obtained from the population-based nationwide Netherlands Cancer Registry (NCR). Data from this region was used, because data on comorbidi- ties was not routinely registered by the NCR in other parts of the Netherlands during the study period. Trained data managers of the NCR routinely extract information on diagno- sis, tumor stage, comorbidity, and treatment from the medical hospital records, using a strict registration and coding manual. Tumors were clinically staged according to the UICC/
AJCC TNM classification that was valid at the time of diagnosis. Patients with potential- ly curable EC (cT1N+/cT2-3, TX, any cN, cM0) and treated with dCRT or nCRT plus surgery were eligible for this study (Fig. 1).
Patients were classified as cTX when the tu- mor could not be sufficiently subcategorized, for example due to an obstructing tumor that could not be passed during endoscopic ultra- sonography. Patients were considered poten- tially curable if they had clinically no distant metastasis (cM0 according to TNM-7 and cM1a, i.e., positive coeliac nodes, according to TNM-6), and no tumor invasion into sur- rounding organs (no cT4 according to TNM-6 and no cT4a or cT4b according to TNM-7).
Although patients with a cT4a tumor could theoretically be treated with curative intent, all cT4 tumors were excluded, because they were only distinguished after 2010 by TNM- 7. For the analysis, patients with a cM1a tumor according to TNM-6 were categorized as having cN+ according to TNM-7. As of 2010, coding regulations to register a cM0 or cM1 status into the NCR were less strict than before 2010. As a consequence, since 2010, relatively more patients were registered with no (cM0) rather than unknown clinical distant metastases into the NCR.
38
To account for this, we decided to include all patients with cMX. Patients with cervical esophageal cancer (CI 5.0) and those with a cT1N0 tumor were excluded, because surgery was not standard care in these patients.
Patients who underwent palliative or other treatment were excluded from the analysis (Fig. 1). In this study, neoadjuvant CRT with curative intent consisted of 5 cycles of car- boplatin (area under the curve 2 mg/ml/min)/
paclitaxel 50 mg/m2 and 41.4 Gy/1.8 Gy or occasionally 50.4 Gy/1.8 Gy radiotherapy fol- lowed by potentially curative surgery, based on the CROSS regimen [1,18]. Definitive or primary CRT usually included concurrent chemotherapy (cisplatin/5-FU or carboplatin/
paclitaxel) and radiotherapy[50.4 Gy/1.8–2 Gy as first treatment in patients who were unable to undergo surgical resection [19, 20].
In the analysis, patients with primary intend- ed nCRT of 41.4–50.4 Gy/1.8 Gy in whom additional surgical resection was denied because of deteriorated medical condition and potentially high risk for severe morbidity and mortality. In the NCR, comorbidities were registered according to a slightly modified version of the Charlson comorbidity index [21]. The Charlson comorbidity index is most widely used for recording comorbidity and was validated in various studies. Comorbidity was defined as life-shortening diseases that were present at the time of cancer diagnosis [22–24]. The following groups of comorbid- ities were included in our analyses: pulmo- nary disease (COPD, emphysema, chronic bronchitis), cardiovascular disease (angina pectoris, myocardial infarction, cardiomy- opathy, myocarditis, vascular disease, TIA, CVA), hypertension, diabetes mellitus, and previous invasive malignancies. Patients with no serious comorbidity in the medical file were registered as having no comorbidity.
Patients were excluded if comorbidity status was not registered.
Statistics
Netherlands developed an indicator of Socio- Economic Status Score (SES), using indivi- dual fiscal data based on the economic value of the home and household income. This SES indicator is provided at an aggregated level for each postal code (covering an average of 17 households). SES was categorized as low (deciles 1–3), medium (deciles 4–7), or high (deciles 8–10). A separate category was made for postal codes of care-providing institu- tions, because assigning SES for those living in nursing home or other care providing institutions is difficult. Differences between patient groups were analysed by using Chi square tests. Multivariable logistic regression analyses were performed to examine the impact of clinicopathological factors on the choice of curative-intended treatment (dCRT vs. nCRT followed by surgery). Survival time was defined as time from 6 months after di- agnosis until death or until February 2017 for patients who were still alive. Thus, patients who died within 6 months after diagnosis were excluded from survival analysis. This was done to deal with immortal time bias, i.e., the waiting period of 6–8 weeks between end of CRT and surgery in patients undergo- ing nCRT, because total treatment duration for those who underwent dCRT is shorter [25]. Overall survival (OS) was calculated with the Kaplan–Meier analysis, and log-rank tests were performed to test for differenc- es between groups. Multivariable survival analyses were performed using the Cox proportional hazards model (HR and 95%
confidence intervals) to investigate the prog- nosis after dCRT versus nCRT plus surgery after adjustment for confounders. According to histological tumor type, separate models were performed for age categories, number of comorbidities, and for each type of comor- bidity. All analyses were performed in SAS version 9.4, and two-sided p values <0.05 were considered statistically significant
39
Results
Clinicopathological Characteristics A total of 702 patients was included in the study (Fig. 1). Neoadjuvant CRT with surgery was performed in 386 patients (55%) and dCRT in 316 patients (45%). Frequently re- ported comorbidities were cardiovascular dis- ease (33%), hypertension (33%), pulmonary disease (15%), and diabetes (15%; Table 1).
Most tumors were adenocarcinomas (65%) and in a locally advanced stage with cT3 (65%) and cN1-3 (60%). Approximately 81%
of the patients were treated after 2008.
Association Between Age and Treatment Of the patients treated with nCRT and surgery, less than 8% (29/386 patients) were 75 years or older (Table 2), whereas 19%
(60/316) of the patients treated with dCRT were younger than 60 years. Approximate- ly 78% (102/131 patients) of the elderly (≥
75 years) patients were treated with dCRT, whereas only 33% (60/184 patients) of the patients younger than 60 years underwent dCRT.
Association Between Comorbidity and Treatment
Patients with multiple comorbidities under- went more often dCRT (160/273 patients;
59%), whereas patients without comorbidities more often underwent nCRT plus surgery (142/211 patients; 67%; Table 2). Multivari- able logistic regression analysis confirmed the associations of age and comorbidities with type of treatment. Patients ≥ 75 years of age (odds ratio [OR] 8.58; 95% confidence interval [CI] 4.72–15.58) and patients with multiple comorbidities (OR 3.09; 95% CI 1.93–4.93) had a higher probability to receive dCRT than nCRT plus surgery. Regarding type of comorbidity and the likelihood to receive dCRT, the association was higher for the combination hypertension and diabetes (OR 3.80; 95% CI 1.97–7.32) and for cardio- vascular with pulmonary comorbidity (OR 3.18; 95% CI 1.57–6.46; Table 2).
Long-Term Overall Survival
Two-year overall survival (OS) of all patients was significantly better following nCRT plus surgery compared with dCRT (61% vs. 38%;
p<0.01). Even after stratification for histo- logical tumor type, the survival differences remained statistically significant (EAC: 60%
vs. 33% respectively, p<0.01; ESSC: 68% vs.
42% respectively, p<0.01; Fig. 2a).
Long-Term Overall Survival
Two-year overall survival (OS) of all patients was significantly better following nCRT plus surgery compared with dCRT (61% vs. 38%;
p<0.01). Even after stratification for histo- logical tumor type, the survival differences remained statistically significant (EAC: 60%
vs. 33% respectively, p<0.01; ESSC: 68% vs.
42% respectively, p<0.01; Fig. 2a).
Impact of Age and Comorbidity on Long- Term Overall Survival
Kaplan–Meier survival analysis showed that the 2-year OS was worse among patients with EAC who underwent dCRT compared with those who underwent nCRT plus surgery, regardless of the number of comorbidities (Fig. 2b). In contrast, the 2-year OS for ESCC patients with multiple comorbidities after dCRT (46%) was comparable to the 2-year OS (51%) following nCRT plus surgery (Fig.
2c). Multivariable Cox regression analyses showed that EAC patients had a poorer prog- nosis following dCRT compared with nCRT plus surgery, irrespective of age and number of comorbidities (Table 3). Especially, among patients with cardiovascular diseases, hyper- tension or diabetes survival was poorer after dCRT. In contrast, among ESCC patients with
≥ 2 comorbidities or age ≥ 75 years, OS after dCRT was comparable to OS after nCRT plus surgery. This was especially the case among ESCC patients with cardiovascular diseases or previous malignancies. However, ESCC patients with hypertension as the only comor- bidity had a poorer OS after dCRT compared with nCRT plus surgery. The impact of pulmonary diseases or diabetes could not be assessed accurately due to the small number of patients (Table 3).
40 40
Discussion
The results of this population-based study support the use of nCRT plus surgery in ope- rable patients with EAC, which was associ- ated with a better overall survival regardless of age, number and type of pretreatment co- morbidities. The administration of dCRT was preferable in patients with ESCC with at least two comorbidities or age ≥ 75 years, because there were no differences in overall survival than with nCRT plus surgery in these patients.
This was seen particularly among those with cardiovascular diseases or previous malignan- cies as their overall survival after dCRT was comparable to the overall survival for patients after nCRT plus surgery. In the Netherlands, nCRT in combination with surgery is the standard potentially curative treatment for lo- cally advanced esophageal cancer. This treat- ment potentially downstages the tumor and increases the radical resectability (R0) rate, which in turn reduces locoregional recur- rences with improved long-term survival [1].
Moreover, the regimen of the CROSS trial also showed control of distant disease beyond the first 24 months after nCRT, supporting a direct systemic effect [25].
Of great importance for a prolonged survival is a pathological complete response following nCRT, which occurred in 49% of the patients with ESSC included in the CROSS trial and in 23% of those with EAC [1]. In our study, 78% of the elderly patients were treated with dCRT and survival in elderly patients with ESCC was equal for both treatment modali- ties. Elderly patients are generally regarded as less suitable for surgery because of advanced age (≥ 75 years), comorbidity severity or decreased performance status. Moreover, dCRT seems a well-tolerated alternative for patients with EC who are not fit enough to undergo surgery [1, 7, 11, 12, 17, 22, 23, 26, 27]. Nevertheless, selecting the appropriate treatment for elderly patients requires the presence a consulted geriatric physician in the multidisciplinary board [28].
A relatively good outcome was reported after dCRT in selected groups of patients [12, 29–32]. Two studies have found a comparable OS after dCRT compared with surgery alone for patients with resectable ESCC [11, 12].
However, in these studies, survival differ- ences were not investigated according to number and type of comorbidities. We found no significant difference in OS following dCRT or nCRT plus surgery in patients with ESCC having at least two comorbidities. This suggests that patients derive the same benefits from both treatment methods, although the type of comorbidity may have an impact on the outcome. In patients with EAC, the stan- dard approach of nCRT followed by surgery indeed resulted in a better survival, which also was found in the group with diabetes mellitus, hypertension, or cardiovascular disease. Tougeron et al. reported a more fre- quent use of dCRT in advanced staged EAC, in elderly patients and those with comor- bidities of Charlson score ≥ 2 [13]. Despite selection bias may be present, survival after surgery was better compared with survival after dCRT (median overall survival 36.2 vs.
16.5 months; P = 0.02). Another study has found a significant improvement in median survival for patients with locally advanced EAC treated with nCRT followed by surgery compared with dCRT [14]. These differences in treatment response between patients with EAC and ESCC may be associated with tumor aggressiveness and different carcino- genesis [13]. Moreover, tumor site (distal vs.
proximal) and pulmonary based differences with larger fields of radiotherapy in lower esophageal tumors also may play a role in outcome differences between EAC and ESCC following dCRT [33]. With current radiation techniques, including intensitymodulated radiotherapy (IMRT), direct simulation based on 3D or 4D planning CT, respiratory gated radiotherapy, and intensity-modulated proton therapy the radiation dose can be accurately delivered with less damage to normal tissues [15, 33–36]. Moreover, in diminishing tox-
41 41
icity of chemotherapy regimens, the combi- nation of carboplatin/paclitaxel has shown to be a good alternative or even the standard approach in dCRT, especially in patients with cardiovascular and pulmonary comorbidities [37]. Our study has some limitations. First, the intent of curative treatment with chemo- radiotherapy (primary dCRT or nCRT) was uncertain in this retrospective study. As pa- tients with M1 disease were excluded, it was assumed that chemoradiotherapy was given with curative intent in all included patients.
However, a small subset of patients were not fit enough or unable to undergo the planned surgery after nCRT and were treated with CRT alone or allocated to the dCRT group.
This may lead to a less homogeneous group of patients treated with dCRT. Moreover, of the excluded EC patients who had surgery alone (Fig. 1), surgery could had been still a treatment options for some patients not suitable for chemoradiotherapy. As reported, a considerable number of these patients were not eligible for surgery due high age ( >75 years) and serious multiple comorbidities, the OS was worse after surgery alone in a previous analysis of potentially curable EC patients (n = 1,184) during 1995–2013 [2, 3, 19]. The 3-year OS in patients with EAC after surgery alone was worse but comparable among those with > 2 comorbidities after dCRT (HR 1.07; 95% CI 0.72–1.60). The 3-year OS among ESCC patients after dCRT was comparable with those after surgery alone, despite the number of comorbidities, and even more favourable in those with pul- monary disease (HR 0.81; 95% CI 0.32–0.71) [38]. Second, limited information was given about the radiotherapy techniques and schedules of the given chemoradiotherapy.
Since 2004, however, there was an increased preference for carboplatin/paclitaxel with less severe toxicity (6%) compared with
cisplatin/5-FU (15%) as standard regimen in dCRT, especially in patients with cardio- vascular comorbidity[37]. Third, the impact of type of some comorbidities could not be assessed accurately due to a small number
of patients. Moreover, information about the performance status was not registered for the study period. Furthermore, the accuracy of the diagnostic and staging methods used is unknown, while endoscopic ultrasonogra- phy was not always possible in patients with EC leading to unknown reported clinical T-stage in 15% of patients. Although out of the scope of this study, salvage surgery in solitary localized recurrences or persistent disease after CRT could be a curative option in selective cases. However, these procedures were not registered accurately at that time, because intensive follow-up was not com- monly performed, and these procedures were then only performed occasionally in special centers [19].
The strength of this population-based study is that the results are based on patients dia- gnosed in ten hospitals providing an overview of everyday clinical practice, rather than single-institution results in which patients are possibly more carefully selected. In conclusion, neoadjuvant chemoradiotherapy plus surgery should basically be advised in operable patients with potentially curable esophageal adenocarcinoma regardless of age, number, and the type of comorbidities.
Definitive CRT may be preferred in patients with esophageal squamous cell carcinoma having at least two comorbidities or being older than 75 years. For a better selection of patients, who may benefit from dCRT, pro- spective studies are needed.
