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Clinical Factors and Outcomes of Octogenarians Receiving Curative Surgery for Esophageal Cancer
j o u r n a l o f s u r g i c a l r e s e a r c h j u l y 2 0 2 0 ( 2 5 1 ) 1 0 0 e1 0 6
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Clinical Factors and Outcomes of Octogenarians Receiving Curative Surgery for Esophageal Cancer Ethan Y. Song, BA,a Jessica M. Frakes, MD,b Martine Extermann, MD,c Farina Klocksieben, MPH,a Rutika Mehta, MD, MPH,c Sabrina Saeed, BA,c Sarah E. Hoffe, MD,b and Jose M. Pimiento, MDc,* a
University of South Florida Morsani College of Medicine, Tampa, Florida Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida c Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida b
article info
abstract
Article history:
Background: The incidence of esophageal cancer is increasing in the United States. Although
Received 23 June 2019
neoadjuvant therapy (NAT) for locally advanced cancers followed by surgical resection is
Received in revised form
the standard of care, there are no clearly defined guidelines for patients aged 79 y.
20 September 2019
Methods: Query of an institutional review boardeapproved database of 1031 esophagec-
Accepted 8 January 2020
tomies at our institution revealed 35 patients aged 79 y from 1999 to 2017 who underwent
Available online xxx
esophagectomy. Age, gender, tumor location, histology, clinical stage, Charlson Comorbidity Index (CCI), NAT administration, pathologic response rate to NAT, surgery type,
Keywords:
negative margin resection status, postoperative complications, postoperative death, length
Octogenarian
of stay, 30- and 90-d mortality, and disease status parameters were analyzed in association
Clinical outcomes
with clinical outcome.
Esophageal cancer
Results: The median age of the octogenarian cohort was 82.1 y with a male preponderance
Surgery
(91.4%). American Joint Committee on Cancer clinical staging was stage I for 20% of pa-
Neoadjuvant therapy
tients, stage II for 27% of patients, and stage III for 50% of patients, which was not statistically significant compared with the younger cohort (P ¼ 0.576). Within the octogenarian group, 54% received NAT compared with 67% in the younger group (P ¼ 0.098). There was no difference in postoperative complications (P ¼ 0.424), postoperative death (P ¼ 0.312), and recurrence rate (P ¼ 0.434) between the groups. However, CCI was significantly different between the octogenarian and nonoctogenarian cohort (P ¼ 0.008), and octogenarians had shorter overall survival (18 versus 62 mo, P<0.001). None of the other parameters assessed were associated with clinical outcomes. Conclusions: Curative surgery is viable and safe for octogenarians with esophageal cancer. Long-term survival was significantly shorter in the octogenarian group, suggesting the need for better clinical selection criteria for esophagectomy after chemoradiation and that identification of complete responders for nonoperative management is warranted. ª 2020 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Senior Adult Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Tel.: þ1 813 745 6898; fax: 8137457729. E-mail address: [email protected] (J.M. Pimiento). 0022-4804/$ e see front matter ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2020.01.002
song et al octogenarian outcomes after esophagectomy
Introduction With an aging baby boomer population and continued improvements in longevity, individuals aged 65 y in the United States are projected to comprise approximately 20% of the total population by 2030.1 The growing aging population has also been tied to an increase in gastrointestinal malignancies, one of which is esophageal cancer. Esophageal cancers, which are generally considered to predominantly affect older patients, often present in the sixth and seventh decades.2,3 Octogenarians, or those who are in their eighth decade of life, will soon represent a large proportion of the older patient population with esophageal cancer.4 This group of patients is also very heterogenous with regards to comorbidity and physical reserve which presents additional complexity to approaching cancer therapy. Currently, the most appropriate treatment modality for older patients with esophageal cancer is controversial. For locally advanced esophageal cancers, neoadjuvant chemoradiotherapy followed by surgical resection is superior to surgery alone and is the standard treatment option.5 However, two concerns arise when evaluating older patients for esophagectomy: whether age by itself is an independent risk factor for complications and death and whether there is a survival benefit from esophagectomy in older patients.6 Curative esophagectomy has been associated with a 5%-10% rate of postoperative mortality and increased postoperative morbidity in the United States,7 with older age predicting for worse surgical outcomes after esophagectomy. Complication rates, mortality, length of hospital stay, and intensive care unit admissions also increase with patient age, which can offset oncologic advantages.8-11 Despite the high incidence of esophageal cancer in older patients, there are limited data to direct optimal treatment guidelines, especially within the octogenarian population. Regardless of the advances in surgical technique and chemoradiotherapy delivery, the prognosis of esophageal cancer remains poor. Given the increased rates of postoperative complications in older patients, it remains unclear whether individual octogenarian patients can, and under what clinical circumstances should, be considered as candidates for esophagectomy. In this study, we aim to identify clinical factors associated with the outcomes of the octogenarian population who underwent curative esophagectomy.
101
therapy (CRT) consisting of 5-fluorouracilebased chemotherapy along with either cisplatin or oxaliplatin or carboplatin/Taxol and radiation with either 2D or 3D radiation therapy or intensity-modulated radiation therapy, followed by esophagectomy. The following are the mode of approaches for esophagectomy: open or laparoscopic-assisted Ivor Lewis, transhiatal, or three-field. Minimally invasive abdominal surgery has been used at our institution since 2007 and transthoracic robotic surgery since 2011. Contraindications for a transthoracic approach are intolerance to single-lung ventilation or a “hostile” thorax. Our institutional preference is for the transthoracic approach owing to the possibility for a more extensive lymphadenectomy.
Statistical analysis Patient characteristics were evaluated using Pearson Chisquare analysis. Significant dependent variables were then further analyzed using binomial logistic regression. Age, gender, tumor location, histology, Charlson Comorbidity Index (CCI), neoadjuvant therapy administration, pathologic response rate to neoadjuvant therapy, stage, surgery type (Ivor Lewis versus transhiatal versus three field esophagectomy both open and minimally invasive), robotic surgery utilization, negative margin resection status, postoperative complication rate, postoperative death, length of stay, 30-d and 90d mortality, and disease status parameters were analyzed in association with clinical outcome, with statistical significance determined at P < 0.05. Values significant with univariate analysis were then run on a linear regression multivariate analysis. Life expectancy by age and noncancer comorbidities at time of diagnosis was calculated using an actuarial life calculator.12 Survival, defined as time from date of surgery to death or last follow-up, was studied using the Kaplan-Meier method and compared by logrank analysis. Cox regression analysis was performed for significant findings. Statistical analysis was completed using SPSS 24 (Windows Version 24.0; IBM Corp., Armonk, NY).
Statement of ethics The study was approved by the Institutional Review Board (Moffitt Cancer Center).
Results Methods
Patient demographics and disease characteristics
Patients and treatment
Demographics and clinical characteristics of the 1031 patients are displayed in Table 1. Of the 1031 patients included in this analysis, 35 patients were 79 y of age. The median age was 82.1 y (range: 79-86) among the octogenarian cohort with a male preponderance (n ¼ 32, 91.4%). Of the octogenarian patients, 85.7% had esophageal adenocarcinoma originating mainly in either the lower esophagus (60%) or gastroesophageal junction (40%). Between the octogenarian and nonoctogenarian groups, there were no differences in gender (P ¼ 0.418), clinical stage (P ¼ 0.576), histology (P ¼ 0.834), and
Query of an institutional review boradeapproved database of 1031 esophagectomies at Moffitt Cancer Center, Tampa, FL revealed 35 patients 79 y of age with esophageal cancer from 1999 to 2017 who underwent esophagectomy after neoadjuvant treatment. An age cutoff of 79 y was set because multiple patients were near their 80th birthday during initiation of neoadjuvant therapy leading to surgery. Patients who met eligibility criteria were treated with chemoradiation
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Table 1 e Patient demographics and disease characteristics. Age 79
Demographics/Characteristics n
Age <79 %
n
Total patients
35
996
Age, median (range, y)
82.1 (79-86)
64.7 (17-78)
P value %
Gender Male Female
0.418 32
91.4%
832
93.5%
3
8.6%
164
16.5% 0.008
CCI 0
e
e
68
6.8%
1
e
e
149
15.0%
2
35
100.0%
779
78.2%
Stage 0
e
e
18
2.2%
Stage I
6
20.0%
113
13.6%
Stage IIA
6
20.0%
178
21.4%
Stage IIB
2
6.7%
120
14.5%
Stage III
15
50.0%
365
44.0%
Stage IV
e
e
25
3.0%
2
10.5%
11
1.3%
30
85.7%
827
84.6%
4
11.4%
128
13.1%
Clinical stage
Cannot be assessed
0.576
Histology Adenocarcinoma Squamous cell Adenosquamous carcinoma Other
0.834
e 1
e
9
0.9%
2.9%
14
1.4%
Tumor location
0.562
Upper 1/3
e
e
15
1.5%
Middle 1/3
e
e
69
7.0%
Lower 1/3
21
60.0%
551
55.5%
GEJ
14
40.0%
342
34.5%
Proximal gastric
e
e
13
1.3%
Unknown
e
e
2
0.2%
Neoadjuvant therapy administration
0.098
Yes
19
54.3%
669
67.6%
No
16
45.7%
320
32.40%
1
2.9%
25
2.5%
Ivor-Lewis
21
60.0%
636
64.4%
Transhiatal
4
11.4%
65
6.6%
Three-field
e
e
18
1.8%
Thoraco-abdominal
e
Surgery type Aborted procedure
0.103
e
1
0.1%
2
5.7%
169
17.1%
MIS transhiatal
6
17.1%
64
6.5%
MIS three-field
e
e
5
0.5%
1
2.9%
5
0.5%
4
11.4%
245
24.2%
MIS Ivor Lewis
Other Surgery technique Robotic esophagectomy
0.081
Bold means statistically significant P < 0.005. CCI ¼ Charlson Comorbidity Index; GEJ ¼ gastroesophageal junction; MIS ¼ minimally invasive.
tumor location (P ¼ 0.562). Neoadjuvant therapy administration trended more toward patients aged <79 y, but this was not statistically significant (P ¼ 0.098). Ivor Lewis (65.7%) was
the most frequent approach to esophagectomy in our octogenarian study population, followed by transhiatal (28.5%), but surgery type was not statistically different between the
103
song et al octogenarian outcomes after esophagectomy
was not significantly different (P ¼ 0.434), median overall survival was significantly shorter in the octogenarian cohort (18 versus 62 mo, respectively; P < 0.001). Survival distribution for different levels of the CCI 0, 1, or 2þ were statistically significantly different (P ¼ 0.002). Patients with a CCI 2þ had lower overall survival than those with a CCI of 0 or 1, as shown in Figure 1. Survival distribution for age 79 y and < 79 y were statistically significantly different (P < 0.001) as shown in Figure 2. Patients who were 79 y of age had lower overall survival than those who were <79 y of age. Upon regression analysis for relationship with comorbidities, the risk of death increases by 1.852 times for those older than 79 y as compared with those younger than 79 y, holding Charlson score constant (P ¼ 0.002). Expected survival was calculated by age and noncancer comorbidities at the time of diagnosis for octogenarians. The median life expectancy for the cohort was found to be 86.5 y (SD: 2.5 y), whereas the actual age of patients at last follow-up was 84.6 y (SD: 3.6 y), corresponding to a loss of expected life of 1.9 y (SD: 3.6 y). In addition, at a median follow-up of 34 mo, 75% of patients had lower life expectancy based on actuarial calculations and 25% outlasted their life expectancy, with 38% of the patients still alive at the time of analysis with a median follow-up of 36 mo.
two groups (P ¼ 0.103). Robotic assisted surgery usage trended toward significance between the octogenarian and nonoctogenarian groups (11.4% versus 24.2%, respectively; P ¼ 0.081). However, the CCI was revealed to be statistically significantly different between the octogenarian and nonoctogenarian cohort (P ¼ 0.008).
Patient response rates and clinical outcomes Patient response rates and clinical outcomes are displayed in Table 2. Between the octogenarian and nonoctogenarian groups, there were no differences in pathologic complete response (P ¼ 0.517), negative margin resection (P ¼ 0.668), postoperative complications Clavien-Dindo II or more (P ¼ 0.424), postoperative death (P ¼ 0.312), length of stay (12.4 versus 10 d, respectively; P ¼ 0.340), or disease recurrence (P ¼ 0.434). The 30-d mortality was not significantly different between octogenarian and nonoctogenarian cohorts (2.8% versus 2.5%, respectively; P ¼ 0.597), and 90-d mortality was also similar (5.7 % versus 5.8%, respectively; P ¼ 1.000). However, the calculated median overall survival was revealed to be statistically significantly different between the octogenarian and nonoctogenarian cohort (18 versus 62 mo, respectively; P < 0.001).
Survival analysis
Discussion At the time of analysis, the mean duration of follow-up was 48.7 mo for the entire cohort. Although disease recurrence between the octogenarian and nonoctogenarian population
As worldwide life expectancy increases, the number of candidates for surgical treatment of esophageal cancer in the
Table 2 e Patient response rates and clinical outcomes. Age 79
Clinical outcomes
Age <79
P value
n
%
n
%
Yes
6
35.3%
250
40.4%
No
11
65.7%
368
59.6%
Yes
31
91.2%
910
94.6%
No
3
8.8%
52
5.4%
Yes
25
71.4%
641
64.9%
No
10
28.6%
347
35.1%
Yes
2
5.9%
28
2.9%
No
32
94.1%
944
97.1%
Pathologic complete response
0.517
Negative margin resection
0.668
Postoperative complications
0.424
Postoperative death
Length of stay (SD, d)
0.312
12.4 (15)
10 (10)
0.340
Disease recurrence
0.434
Yes
7
20.6%
257
26.6%
No
27
79.4%
709
73.4%
30-d mortality
2.8%
2.5%
90-d mortality
5.7%
5.8%
Median survival (range, mo) Bold means statistically significant P < 0.005. SD ¼ standard deviation.
18 (9-26)
62 (48-77)
0.597 1.000 <0.001
104
j o u r n a l o f s u r g i c a l r e s e a r c h j u l y 2 0 2 0 ( 2 5 1 ) 1 0 0 e1 0 6
Fig. 1 e Kaplan-Meier estimates of overall survival by Charlson’s Comorbidity Index. Patients with a Charlson score of ‡2 had overall lower survival than those with a score of <2. (Color version of figure is available online.)
older population will progressively increase. In an outcomes analysis by the Society of Thoracic Surgeons General Thoracic Database of 2315 patients who underwent esophagectomy,
30% of patients were 70 y and 5% were >80 y.13 Age has often served as a surrogate to evaluate patients when considering candidates for surgical resection, screening for those who
Fig. 2 e Kaplan-Meier estimates of overall survival by age. Patients ‡79 y receiving esophagectomy had lower overall survival than those <79. (Color version of figure is available online.)
song et al octogenarian outcomes after esophagectomy
may experience more difficulty in tolerating treatment and its related side effects. Indeed, medical management of the older patient remains challenging, given the frequent presence of comorbid conditions. In our study, the octogenarian population receiving esophagectomy had higher rates of comorbidities than the younger population, which is consistent with several other studies.6,14,15 However, other disease characteristics such as clinical stage, histology, and tumor location were comparable between the two groups. Although octogenarians in our study had higher rates of comorbidities, we did not observe a significant increase in rates of postoperative complications in patients 79 y and <79 y (71.4% versus 64.9%, respectively; P ¼ 0.424). Although this finding has been similarly detailed in previous studies,16,17 it is contrasted in an analysis by Tapias et al.,6 which reported that octogenarians had a significant increase in postoperative complications compared with those from 70 to 79 y (62.5% versus 47.6%, respectively). Surgery in our patient cohort was well tolerated with low, comparable rates of postoperative death in patients 79 y and <79 y (5.9% versus 2.9%, respectively; P ¼ 0.312), and high negative margin resection (91.2% versus 94.6%, respectively; P ¼ 0.668). Our findings suggest that esophagectomy can be performed in octogenarians even with multiple comorbidities when carefully selected. Despite the comparable short-term clinical outcomes in octogenarians with the younger cohort, we found that octogenarians were associated to have a significantly lower median survival than nonoctogenarians (18 versus 62 mo, respectively; P < 0.001), which has been corroborated by other institutional experiences.14,18 One challenge that arises within the study of patients diagnosed with complex gastrointestinal malignancies is the difficulty to accurately assess diseasespecific survival. Assessing disease-specific survival is particularly challenging for older patients as many may develop failure to thrive or other symptoms affecting performance status that could arise secondary to postoperative anatomic changes that are not related to cancer recurrence. Meanwhile, other symptoms that are attributed to age-related functional decline could actually be caused by undiagnosed cancer recurrence. Therefore, our group decided to use overall survival for our analysis as it may help patients in the decision-making process when considering surgical resection. Regarding comorbidities, survival distributions were also statistically significantly different between CCI of 0, 1, 2þ, with lower survival seen in patients with a CCI of 2þ. After adjusting for CCI, survival remained lower in the octogenarian population than in the younger population. Decreased survival may be attributed to comorbidities and reduced physiologic reserve. As survival for octogenarians can vary based on comorbid conditions, we used an actuarial life expectancy calculator to identify expected survival as a reference point. Our analysis of the octogenarian cohort shows that a cancer diagnosis and subsequent surgery was associated with a loss of 1.9 expected years of life. Despite this, 38% of our cohort was still alive at the time of analysis and at least 25% had outlived comorbidity-adjusted expected survival, bolstering the concept that surgery is a viable option for octogenarians. Currently, data are lacking on whether or not there is an overall survival benefit for octogenarian patients who
105
received esophagectomy after neoadjuvant therapy and those who did not. There is ongoing debate between the selection of neoadjuvant chemoradiation followed by esophagectomy and definitive chemoradiation for the treatment of esophageal cancer in the elderly. One study analyzing definitive CRT for elderly patients with esophageal cancer observed that median survival from initiation of therapy for a cohort of 56 octogenarian patients was 15.5 mo.19 Our analysis found survival among octogenarians to be longer, although the difference (2.5 mo) was minimal. In addition, our analysis defined survival starting from after completion of all therapies and usually from time of surgery, a factor that would add approximately 4 mo for neoadjuvant-treated patients (54% of our cohort). Moreover, the limited available literature for octogenarians emphasizes the point that further research is required to identify the most appropriate treatment modality for this group of patients. Although there is an association of older age with poorer prognosis, chronologic age does not necessarily translate directly to physiologic organ impairment or poor performance status, both of which can vary substantially between individuals.20 Therefore, management of optimal cancer treatment should focus on the assessment of the extent of comorbidity and functional status. Utilization of a comprehensive geriatric assessment can help address individual problems that may compromise safety and effectiveness of treatment.21 Furthermore, octogenarian patients considered fit for curative surgery may benefit from a risk/benefit assessment within a comprehensive geriatric assessment, given the context of a projected shorter overall survival. There are several limitations to our study because of its retrospective nature, patient referral and selection bias, and heterogeneity in preoperative treatment. There is an inherent referral and selection bias in choosing patients for esophagectomy, particularly those aged 79 y. Geriatric patients may be less likely to be referred to surgery based on a perception that they are generally frail and unfit for highly invasive procedures. In addition, although some objective criteria such as performance status were used to exclude patients from esophagectomy, the surgeons’ judgment was difficult to measure but did reflect the work of 6 academic surgeons in the same tertiary group practice over the duration of the study. Patients undergoing surgery were assessed for high functional status and the ability to tolerate a highly invasive procedure. Therefore, the outcomes reported were of patients that our institution viewed as healthier than the entire population of octogenarians with esophageal cancer treated at our institution. Although the total number of octogenarians in this study is small (n ¼ 35), our cohort size is comparable with other previous studies on octogenarian cohorts undergoing esophagectomy.18,22 Overall, our results suggest that there is no significant difference between initial disease presentation between octogenarian and nonoctogenarian patients aside from preexisting comorbidities. Surgery should not be denied to octogenarian patients as they have comparable response rates and clinical outcomes with younger patients, but decreased overall survival should be an important consideration. However, when survival was adjusted for comorbidities using an actuarial life expectancy calculator, a sizable proportion of
106
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patients outlived their life expectancy after esophagectomy. Future strategies are needed to focus on better patient selection for upfront identification of those octogenarians most likely to respond completely versus incompletely so that surgeries can be offered to those most likely to benefit.
Conclusions Esophagectomy should be carefully considered in patients aged 79 y and can be justified with low mortality. However, the shorter overall survival of octogenarians suggests that further tools are needed to tailor the outcome predictions for individual patients, warranting further study of the role of definitive CRT and nonoperative management in patients identified as potential complete responders. Advanced age, however, should not be a contraindication to esophageal resection for those with residual disease after CRT.
Acknowledgment Funding: None. Author contributions: The manuscript was prepared by Ethan Y. Song, Sarah E. Hoffe, and Jose M. Pimiento. Study concepts and study design were organized by Jose M. Pimiento. Statistical analysis was completed by Farina Klocksieben and Jose M. Pimiento. Data acquisition, manuscript review, and final approval were completed by all authors.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
1. Yancik R, Ries LA. Cancer in older persons: an international issue in an aging world. Semin Oncol. 2004;31:128e136. 2. Coleman HG, Xie SH, Lagergren J. The epidemiology of esophageal adenocarcinoma. Gastroenterology. 2018;154:390e405. 3. Napier KJ, Scheerer M, Misra S. Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol. 2014;6:112e120. 4. Finlayson E, Fan Z, Birkmeyer JD. Outcomes in octogenarians undergoing high-risk cancer operation: a national study. J Am Coll Surg. 2007;205:729e734. 5. van Hagen P, Hulshof MC, van Lanschot JJ, et al. Preoperative chemoradiotherapy for esophageal or junctional cancer. N Engl J Med. 2012;366:2074e2084.
6. Tapias LF, Muniappan A, Wright CD, et al. Short and longterm outcomes after esophagectomy for cancer in elderly patients. Ann Thorac Surg. 2013;95:1741e1748. 7. Steyerberg EW, Neville BA, Koppert LB, et al. Surgical mortality in patients with esophageal cancer: development and validation of a simple risk score. J Clin Oncol. 2006;24:4277e4284. 8. Al-Refaie WB, Parsons HM, Habermann EB, et al. Operative outcomes beyond 30-day mortality: colorectal cancer surgery in oldest old. Ann Surg. 2011;253:947e952. 9. Audisio RA, Bozzetti F, Gennari R, et al. The surgical management of elderly cancer patients; recommendations of the SIOG surgical task force. Eur J Cancer. 2004;40:926e938. 10. Marcantonio ER, Flacker JM, Michaels M, Resnick NM. Delirium is independently associated with poor functional recovery after hip fracture. J Am Geriatr Soc. 2000;48:618e624. 11. Hurria A, Leung D, Trainor K, Borgen P, Norton L, Hudis C. Factors influencing treatment patterns of breast cancer patients age 75 and older. Crit Rev Oncol Hematol. 2003;46:121e126. 12. Life expectancy calculator: Bankrate. 2019. Available at: https://www.bankrate.com/calculators/retirement/life-ageexpectancy-calculator.aspx. Accessed October 9, 2019. 13. Wright CD, Kucharczuk JC, O’Brien SM, Grab JD, Allen MS. Society of thoracic surgeons general thoracic surgery D. Predictors of major morbidity and mortality after esophagectomy for esophageal cancer: a society of thoracic surgeons general thoracic surgery database risk adjustment model. J Thorac Cardiovasc Surg. 2009;137:587e595. discussion 96. 14. Poon RT, Law SY, Chu KM, Branicki FJ, Wong J. Esophagectomy for carcinoma of the esophagus in the elderly: results of current surgical management. Ann Surg. 1998;227:357e364. 15. Ruol A, Portale G, Zaninotto G, et al. Results of esophagectomy for esophageal cancer in elderly patients: age has little influence on outcome and survival. J Thorac Cardiovasc Surg. 2007;133:1186e1192. 16. Pultrum BB, Bosch DJ, Nijsten MW, et al. Extended esophagectomy in elderly patients with esophageal cancer: minor effect of age alone in determining the postoperative course and survival. Ann Surg Oncol. 2010;17:1572e1580. 17. Ellis Jr FH, Williamson WA, Heatley GJ. Cancer of the esophagus and cardia: does age influence treatment selection and surgical outcomes? J Am Coll Surg. 1998;187:345e351. 18. Moskovitz AH, Rizk NP, Venkatraman E, et al. Mortality increases for octogenarians undergoing esophagogastrectomy for esophageal cancer. Ann Thorac Surg. 2006;82:2031e2036. discussion 6. 19. Xu C, Xi M, Moreno A, et al. Definitive chemoradiation therapy for esophageal cancer in the elderly: clinical outcomes for patients exceeding 80 years old. Int J Radiat Oncol Biol Phys. 2017;98:811e819. 20. Wo JY, Hong TS, Kachnic LA. Impact of age and comorbidities on the treatment of gastrointestinal malignancies. Semin Radiat Oncol. 2012;22:311e320. 21. Balducci L, Extermann M. Management of cancer in the older person: a practical approach. Oncologist. 2000;5:224e237. 22. Zehetner J, Lipham JC, Ayazi S, et al. Esophagectomy for cancer in octogenarians. Dis Esophagus. 2010;23:666e669.
Available online at www.sciencedirect.com
ScienceDirect journal homepage: www.JournalofSurgicalResearch.com
Clinical Factors and Outcomes of Octogenarians Receiving Curative Surgery for Esophageal Cancer Ethan Y. Song, BA,a Jessica M. Frakes, MD,b Martine Extermann, MD,c Farina Klocksieben, MPH,a Rutika Mehta, MD, MPH,c Sabrina Saeed, BA,c Sarah E. Hoffe, MD,b and Jose M. Pimiento, MDc,* a
University of South Florida Morsani College of Medicine, Tampa, Florida Department of Radiation Oncology, Moffitt Cancer Center, Tampa, Florida c Department of Gastrointestinal Oncology, Moffitt Cancer Center, Tampa, Florida b
article info
abstract
Article history:
Background: The incidence of esophageal cancer is increasing in the United States. Although
Received 23 June 2019
neoadjuvant therapy (NAT) for locally advanced cancers followed by surgical resection is
Received in revised form
the standard of care, there are no clearly defined guidelines for patients aged 79 y.
20 September 2019
Methods: Query of an institutional review boardeapproved database of 1031 esophagec-
Accepted 8 January 2020
tomies at our institution revealed 35 patients aged 79 y from 1999 to 2017 who underwent
Available online xxx
esophagectomy. Age, gender, tumor location, histology, clinical stage, Charlson Comorbidity Index (CCI), NAT administration, pathologic response rate to NAT, surgery type,
Keywords:
negative margin resection status, postoperative complications, postoperative death, length
Octogenarian
of stay, 30- and 90-d mortality, and disease status parameters were analyzed in association
Clinical outcomes
with clinical outcome.
Esophageal cancer
Results: The median age of the octogenarian cohort was 82.1 y with a male preponderance
Surgery
(91.4%). American Joint Committee on Cancer clinical staging was stage I for 20% of pa-
Neoadjuvant therapy
tients, stage II for 27% of patients, and stage III for 50% of patients, which was not statistically significant compared with the younger cohort (P ¼ 0.576). Within the octogenarian group, 54% received NAT compared with 67% in the younger group (P ¼ 0.098). There was no difference in postoperative complications (P ¼ 0.424), postoperative death (P ¼ 0.312), and recurrence rate (P ¼ 0.434) between the groups. However, CCI was significantly different between the octogenarian and nonoctogenarian cohort (P ¼ 0.008), and octogenarians had shorter overall survival (18 versus 62 mo, P<0.001). None of the other parameters assessed were associated with clinical outcomes. Conclusions: Curative surgery is viable and safe for octogenarians with esophageal cancer. Long-term survival was significantly shorter in the octogenarian group, suggesting the need for better clinical selection criteria for esophagectomy after chemoradiation and that identification of complete responders for nonoperative management is warranted. ª 2020 Elsevier Inc. All rights reserved.
* Corresponding author. Department of Senior Adult Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, Tampa, FL 33612. Tel.: þ1 813 745 6898; fax: 8137457729. E-mail address: [email protected] (J.M. Pimiento). 0022-4804/$ e see front matter ª 2020 Elsevier Inc. All rights reserved. https://doi.org/10.1016/j.jss.2020.01.002
song et al octogenarian outcomes after esophagectomy
Introduction With an aging baby boomer population and continued improvements in longevity, individuals aged 65 y in the United States are projected to comprise approximately 20% of the total population by 2030.1 The growing aging population has also been tied to an increase in gastrointestinal malignancies, one of which is esophageal cancer. Esophageal cancers, which are generally considered to predominantly affect older patients, often present in the sixth and seventh decades.2,3 Octogenarians, or those who are in their eighth decade of life, will soon represent a large proportion of the older patient population with esophageal cancer.4 This group of patients is also very heterogenous with regards to comorbidity and physical reserve which presents additional complexity to approaching cancer therapy. Currently, the most appropriate treatment modality for older patients with esophageal cancer is controversial. For locally advanced esophageal cancers, neoadjuvant chemoradiotherapy followed by surgical resection is superior to surgery alone and is the standard treatment option.5 However, two concerns arise when evaluating older patients for esophagectomy: whether age by itself is an independent risk factor for complications and death and whether there is a survival benefit from esophagectomy in older patients.6 Curative esophagectomy has been associated with a 5%-10% rate of postoperative mortality and increased postoperative morbidity in the United States,7 with older age predicting for worse surgical outcomes after esophagectomy. Complication rates, mortality, length of hospital stay, and intensive care unit admissions also increase with patient age, which can offset oncologic advantages.8-11 Despite the high incidence of esophageal cancer in older patients, there are limited data to direct optimal treatment guidelines, especially within the octogenarian population. Regardless of the advances in surgical technique and chemoradiotherapy delivery, the prognosis of esophageal cancer remains poor. Given the increased rates of postoperative complications in older patients, it remains unclear whether individual octogenarian patients can, and under what clinical circumstances should, be considered as candidates for esophagectomy. In this study, we aim to identify clinical factors associated with the outcomes of the octogenarian population who underwent curative esophagectomy.
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therapy (CRT) consisting of 5-fluorouracilebased chemotherapy along with either cisplatin or oxaliplatin or carboplatin/Taxol and radiation with either 2D or 3D radiation therapy or intensity-modulated radiation therapy, followed by esophagectomy. The following are the mode of approaches for esophagectomy: open or laparoscopic-assisted Ivor Lewis, transhiatal, or three-field. Minimally invasive abdominal surgery has been used at our institution since 2007 and transthoracic robotic surgery since 2011. Contraindications for a transthoracic approach are intolerance to single-lung ventilation or a “hostile” thorax. Our institutional preference is for the transthoracic approach owing to the possibility for a more extensive lymphadenectomy.
Statistical analysis Patient characteristics were evaluated using Pearson Chisquare analysis. Significant dependent variables were then further analyzed using binomial logistic regression. Age, gender, tumor location, histology, Charlson Comorbidity Index (CCI), neoadjuvant therapy administration, pathologic response rate to neoadjuvant therapy, stage, surgery type (Ivor Lewis versus transhiatal versus three field esophagectomy both open and minimally invasive), robotic surgery utilization, negative margin resection status, postoperative complication rate, postoperative death, length of stay, 30-d and 90d mortality, and disease status parameters were analyzed in association with clinical outcome, with statistical significance determined at P < 0.05. Values significant with univariate analysis were then run on a linear regression multivariate analysis. Life expectancy by age and noncancer comorbidities at time of diagnosis was calculated using an actuarial life calculator.12 Survival, defined as time from date of surgery to death or last follow-up, was studied using the Kaplan-Meier method and compared by logrank analysis. Cox regression analysis was performed for significant findings. Statistical analysis was completed using SPSS 24 (Windows Version 24.0; IBM Corp., Armonk, NY).
Statement of ethics The study was approved by the Institutional Review Board (Moffitt Cancer Center).
Results Methods
Patient demographics and disease characteristics
Patients and treatment
Demographics and clinical characteristics of the 1031 patients are displayed in Table 1. Of the 1031 patients included in this analysis, 35 patients were 79 y of age. The median age was 82.1 y (range: 79-86) among the octogenarian cohort with a male preponderance (n ¼ 32, 91.4%). Of the octogenarian patients, 85.7% had esophageal adenocarcinoma originating mainly in either the lower esophagus (60%) or gastroesophageal junction (40%). Between the octogenarian and nonoctogenarian groups, there were no differences in gender (P ¼ 0.418), clinical stage (P ¼ 0.576), histology (P ¼ 0.834), and
Query of an institutional review boradeapproved database of 1031 esophagectomies at Moffitt Cancer Center, Tampa, FL revealed 35 patients 79 y of age with esophageal cancer from 1999 to 2017 who underwent esophagectomy after neoadjuvant treatment. An age cutoff of 79 y was set because multiple patients were near their 80th birthday during initiation of neoadjuvant therapy leading to surgery. Patients who met eligibility criteria were treated with chemoradiation
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Table 1 e Patient demographics and disease characteristics. Age 79
Demographics/Characteristics n
Age <79 %
n
Total patients
35
996
Age, median (range, y)
82.1 (79-86)
64.7 (17-78)
P value %
Gender Male Female
0.418 32
91.4%
832
93.5%
3
8.6%
164
16.5% 0.008
CCI 0
e
e
68
6.8%
1
e
e
149
15.0%
2
35
100.0%
779
78.2%
Stage 0
e
e
18
2.2%
Stage I
6
20.0%
113
13.6%
Stage IIA
6
20.0%
178
21.4%
Stage IIB
2
6.7%
120
14.5%
Stage III
15
50.0%
365
44.0%
Stage IV
e
e
25
3.0%
2
10.5%
11
1.3%
30
85.7%
827
84.6%
4
11.4%
128
13.1%
Clinical stage
Cannot be assessed
0.576
Histology Adenocarcinoma Squamous cell Adenosquamous carcinoma Other
0.834
e 1
e
9
0.9%
2.9%
14
1.4%
Tumor location
0.562
Upper 1/3
e
e
15
1.5%
Middle 1/3
e
e
69
7.0%
Lower 1/3
21
60.0%
551
55.5%
GEJ
14
40.0%
342
34.5%
Proximal gastric
e
e
13
1.3%
Unknown
e
e
2
0.2%
Neoadjuvant therapy administration
0.098
Yes
19
54.3%
669
67.6%
No
16
45.7%
320
32.40%
1
2.9%
25
2.5%
Ivor-Lewis
21
60.0%
636
64.4%
Transhiatal
4
11.4%
65
6.6%
Three-field
e
e
18
1.8%
Thoraco-abdominal
e
Surgery type Aborted procedure
0.103
e
1
0.1%
2
5.7%
169
17.1%
MIS transhiatal
6
17.1%
64
6.5%
MIS three-field
e
e
5
0.5%
1
2.9%
5
0.5%
4
11.4%
245
24.2%
MIS Ivor Lewis
Other Surgery technique Robotic esophagectomy
0.081
Bold means statistically significant P < 0.005. CCI ¼ Charlson Comorbidity Index; GEJ ¼ gastroesophageal junction; MIS ¼ minimally invasive.
tumor location (P ¼ 0.562). Neoadjuvant therapy administration trended more toward patients aged <79 y, but this was not statistically significant (P ¼ 0.098). Ivor Lewis (65.7%) was
the most frequent approach to esophagectomy in our octogenarian study population, followed by transhiatal (28.5%), but surgery type was not statistically different between the
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song et al octogenarian outcomes after esophagectomy
was not significantly different (P ¼ 0.434), median overall survival was significantly shorter in the octogenarian cohort (18 versus 62 mo, respectively; P < 0.001). Survival distribution for different levels of the CCI 0, 1, or 2þ were statistically significantly different (P ¼ 0.002). Patients with a CCI 2þ had lower overall survival than those with a CCI of 0 or 1, as shown in Figure 1. Survival distribution for age 79 y and < 79 y were statistically significantly different (P < 0.001) as shown in Figure 2. Patients who were 79 y of age had lower overall survival than those who were <79 y of age. Upon regression analysis for relationship with comorbidities, the risk of death increases by 1.852 times for those older than 79 y as compared with those younger than 79 y, holding Charlson score constant (P ¼ 0.002). Expected survival was calculated by age and noncancer comorbidities at the time of diagnosis for octogenarians. The median life expectancy for the cohort was found to be 86.5 y (SD: 2.5 y), whereas the actual age of patients at last follow-up was 84.6 y (SD: 3.6 y), corresponding to a loss of expected life of 1.9 y (SD: 3.6 y). In addition, at a median follow-up of 34 mo, 75% of patients had lower life expectancy based on actuarial calculations and 25% outlasted their life expectancy, with 38% of the patients still alive at the time of analysis with a median follow-up of 36 mo.
two groups (P ¼ 0.103). Robotic assisted surgery usage trended toward significance between the octogenarian and nonoctogenarian groups (11.4% versus 24.2%, respectively; P ¼ 0.081). However, the CCI was revealed to be statistically significantly different between the octogenarian and nonoctogenarian cohort (P ¼ 0.008).
Patient response rates and clinical outcomes Patient response rates and clinical outcomes are displayed in Table 2. Between the octogenarian and nonoctogenarian groups, there were no differences in pathologic complete response (P ¼ 0.517), negative margin resection (P ¼ 0.668), postoperative complications Clavien-Dindo II or more (P ¼ 0.424), postoperative death (P ¼ 0.312), length of stay (12.4 versus 10 d, respectively; P ¼ 0.340), or disease recurrence (P ¼ 0.434). The 30-d mortality was not significantly different between octogenarian and nonoctogenarian cohorts (2.8% versus 2.5%, respectively; P ¼ 0.597), and 90-d mortality was also similar (5.7 % versus 5.8%, respectively; P ¼ 1.000). However, the calculated median overall survival was revealed to be statistically significantly different between the octogenarian and nonoctogenarian cohort (18 versus 62 mo, respectively; P < 0.001).
Survival analysis
Discussion At the time of analysis, the mean duration of follow-up was 48.7 mo for the entire cohort. Although disease recurrence between the octogenarian and nonoctogenarian population
As worldwide life expectancy increases, the number of candidates for surgical treatment of esophageal cancer in the
Table 2 e Patient response rates and clinical outcomes. Age 79
Clinical outcomes
Age <79
P value
n
%
n
%
Yes
6
35.3%
250
40.4%
No
11
65.7%
368
59.6%
Yes
31
91.2%
910
94.6%
No
3
8.8%
52
5.4%
Yes
25
71.4%
641
64.9%
No
10
28.6%
347
35.1%
Yes
2
5.9%
28
2.9%
No
32
94.1%
944
97.1%
Pathologic complete response
0.517
Negative margin resection
0.668
Postoperative complications
0.424
Postoperative death
Length of stay (SD, d)
0.312
12.4 (15)
10 (10)
0.340
Disease recurrence
0.434
Yes
7
20.6%
257
26.6%
No
27
79.4%
709
73.4%
30-d mortality
2.8%
2.5%
90-d mortality
5.7%
5.8%
Median survival (range, mo) Bold means statistically significant P < 0.005. SD ¼ standard deviation.
18 (9-26)
62 (48-77)
0.597 1.000 <0.001
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Fig. 1 e Kaplan-Meier estimates of overall survival by Charlson’s Comorbidity Index. Patients with a Charlson score of ‡2 had overall lower survival than those with a score of <2. (Color version of figure is available online.)
older population will progressively increase. In an outcomes analysis by the Society of Thoracic Surgeons General Thoracic Database of 2315 patients who underwent esophagectomy,
30% of patients were 70 y and 5% were >80 y.13 Age has often served as a surrogate to evaluate patients when considering candidates for surgical resection, screening for those who
Fig. 2 e Kaplan-Meier estimates of overall survival by age. Patients ‡79 y receiving esophagectomy had lower overall survival than those <79. (Color version of figure is available online.)
song et al octogenarian outcomes after esophagectomy
may experience more difficulty in tolerating treatment and its related side effects. Indeed, medical management of the older patient remains challenging, given the frequent presence of comorbid conditions. In our study, the octogenarian population receiving esophagectomy had higher rates of comorbidities than the younger population, which is consistent with several other studies.6,14,15 However, other disease characteristics such as clinical stage, histology, and tumor location were comparable between the two groups. Although octogenarians in our study had higher rates of comorbidities, we did not observe a significant increase in rates of postoperative complications in patients 79 y and <79 y (71.4% versus 64.9%, respectively; P ¼ 0.424). Although this finding has been similarly detailed in previous studies,16,17 it is contrasted in an analysis by Tapias et al.,6 which reported that octogenarians had a significant increase in postoperative complications compared with those from 70 to 79 y (62.5% versus 47.6%, respectively). Surgery in our patient cohort was well tolerated with low, comparable rates of postoperative death in patients 79 y and <79 y (5.9% versus 2.9%, respectively; P ¼ 0.312), and high negative margin resection (91.2% versus 94.6%, respectively; P ¼ 0.668). Our findings suggest that esophagectomy can be performed in octogenarians even with multiple comorbidities when carefully selected. Despite the comparable short-term clinical outcomes in octogenarians with the younger cohort, we found that octogenarians were associated to have a significantly lower median survival than nonoctogenarians (18 versus 62 mo, respectively; P < 0.001), which has been corroborated by other institutional experiences.14,18 One challenge that arises within the study of patients diagnosed with complex gastrointestinal malignancies is the difficulty to accurately assess diseasespecific survival. Assessing disease-specific survival is particularly challenging for older patients as many may develop failure to thrive or other symptoms affecting performance status that could arise secondary to postoperative anatomic changes that are not related to cancer recurrence. Meanwhile, other symptoms that are attributed to age-related functional decline could actually be caused by undiagnosed cancer recurrence. Therefore, our group decided to use overall survival for our analysis as it may help patients in the decision-making process when considering surgical resection. Regarding comorbidities, survival distributions were also statistically significantly different between CCI of 0, 1, 2þ, with lower survival seen in patients with a CCI of 2þ. After adjusting for CCI, survival remained lower in the octogenarian population than in the younger population. Decreased survival may be attributed to comorbidities and reduced physiologic reserve. As survival for octogenarians can vary based on comorbid conditions, we used an actuarial life expectancy calculator to identify expected survival as a reference point. Our analysis of the octogenarian cohort shows that a cancer diagnosis and subsequent surgery was associated with a loss of 1.9 expected years of life. Despite this, 38% of our cohort was still alive at the time of analysis and at least 25% had outlived comorbidity-adjusted expected survival, bolstering the concept that surgery is a viable option for octogenarians. Currently, data are lacking on whether or not there is an overall survival benefit for octogenarian patients who
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received esophagectomy after neoadjuvant therapy and those who did not. There is ongoing debate between the selection of neoadjuvant chemoradiation followed by esophagectomy and definitive chemoradiation for the treatment of esophageal cancer in the elderly. One study analyzing definitive CRT for elderly patients with esophageal cancer observed that median survival from initiation of therapy for a cohort of 56 octogenarian patients was 15.5 mo.19 Our analysis found survival among octogenarians to be longer, although the difference (2.5 mo) was minimal. In addition, our analysis defined survival starting from after completion of all therapies and usually from time of surgery, a factor that would add approximately 4 mo for neoadjuvant-treated patients (54% of our cohort). Moreover, the limited available literature for octogenarians emphasizes the point that further research is required to identify the most appropriate treatment modality for this group of patients. Although there is an association of older age with poorer prognosis, chronologic age does not necessarily translate directly to physiologic organ impairment or poor performance status, both of which can vary substantially between individuals.20 Therefore, management of optimal cancer treatment should focus on the assessment of the extent of comorbidity and functional status. Utilization of a comprehensive geriatric assessment can help address individual problems that may compromise safety and effectiveness of treatment.21 Furthermore, octogenarian patients considered fit for curative surgery may benefit from a risk/benefit assessment within a comprehensive geriatric assessment, given the context of a projected shorter overall survival. There are several limitations to our study because of its retrospective nature, patient referral and selection bias, and heterogeneity in preoperative treatment. There is an inherent referral and selection bias in choosing patients for esophagectomy, particularly those aged 79 y. Geriatric patients may be less likely to be referred to surgery based on a perception that they are generally frail and unfit for highly invasive procedures. In addition, although some objective criteria such as performance status were used to exclude patients from esophagectomy, the surgeons’ judgment was difficult to measure but did reflect the work of 6 academic surgeons in the same tertiary group practice over the duration of the study. Patients undergoing surgery were assessed for high functional status and the ability to tolerate a highly invasive procedure. Therefore, the outcomes reported were of patients that our institution viewed as healthier than the entire population of octogenarians with esophageal cancer treated at our institution. Although the total number of octogenarians in this study is small (n ¼ 35), our cohort size is comparable with other previous studies on octogenarian cohorts undergoing esophagectomy.18,22 Overall, our results suggest that there is no significant difference between initial disease presentation between octogenarian and nonoctogenarian patients aside from preexisting comorbidities. Surgery should not be denied to octogenarian patients as they have comparable response rates and clinical outcomes with younger patients, but decreased overall survival should be an important consideration. However, when survival was adjusted for comorbidities using an actuarial life expectancy calculator, a sizable proportion of
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patients outlived their life expectancy after esophagectomy. Future strategies are needed to focus on better patient selection for upfront identification of those octogenarians most likely to respond completely versus incompletely so that surgeries can be offered to those most likely to benefit.
Conclusions Esophagectomy should be carefully considered in patients aged 79 y and can be justified with low mortality. However, the shorter overall survival of octogenarians suggests that further tools are needed to tailor the outcome predictions for individual patients, warranting further study of the role of definitive CRT and nonoperative management in patients identified as potential complete responders. Advanced age, however, should not be a contraindication to esophageal resection for those with residual disease after CRT.
Acknowledgment Funding: None. Author contributions: The manuscript was prepared by Ethan Y. Song, Sarah E. Hoffe, and Jose M. Pimiento. Study concepts and study design were organized by Jose M. Pimiento. Statistical analysis was completed by Farina Klocksieben and Jose M. Pimiento. Data acquisition, manuscript review, and final approval were completed by all authors.
Disclosure The authors reported no proprietary or commercial interest in any product mentioned or concept discussed in this article.
references
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