Rectal cancer treatment and outcomes in elderly patients treated with curative intent
- Authors:
- Published online on: October 14, 2021 https://doi.org/10.3892/mco.2021.2418
- Article Number: 256
-
Copyright: © Kang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Colorectal cancer is the third and second most common cancer in males and females respectively (1). Rectal cancers comprise a third of colorectal cancer cases and more commonly affects the elderly with a peak incidence at 80-84 years (2).
Management of non-metastatic, locally advanced rectal cancer is challenging and requires multidisciplinary care. Elderly patients are at risk of aged-based disparities in cancer treatment, which may include being under-treated due to their chronological age, or over-treated for their degree of frailty (3). It is often challenging for the treating physician to find the optimal balance between attaining good disease control and limiting the toxicities of treatment for the elderly patient who may also have competing comorbidities. Data to guide treatment of elderly patients with rectal cancer is limited as the elderly patients are often under-represented in prospective clinical trials (4). The optimal treatment approach in this group will likely become even more nuanced with the gradual paradigm shift toward non-operative approaches in locally advanced rectal cancer (5).
The current standard surgical management of rectal cancer involves performing a total mesorectal excision (TME) for improved local control of disease and survival (6,7). Other operative approaches for selected patients with low risk early rectal cancers include transanal endoscopic microsurgery (TEM) and local excision (8,9). For locally advanced rectal cancer (clinical ≥T3 or node positive), trimodality therapy consisting of neoadjuvant chemoradiotherapy followed with surgery, with adjuvant post-operative chemotherapy, is the current standard of care (10). Trimodality therapy has been shown to have a survival benefit in elderly patients. Cancer specific survival was shown to be 70% in patients aged >75 who received neoadjuvant therapy, compared to 52% with surgery alone and 60% with adjuvant therapy (11). Multiple studies have found that older patients are less likely to receive neoadjuvant therapy, and that this is associated with poorer cancer-specific survival (12-14). One study found that each 5 years over the age of 70 was associated with a 37% increase in cancer-related mortality (13).
The reasons for a lower uptake of trimodality therapy in the older patients is multifactorial, including an increased incidence of treatment-related complications. The literature is divided on this, with some studies demonstrating an increase in complication rates (15-17), and some reporting a good tolerance of treatment (18-20).
Taking the evidence into account, the literature suggests that selected elderly patients should be treated in the same way, if comorbidity allows (21-23). The likelihood of initiation of therapy was found to be 22% lower in elderly patients, even after adjusting for comorbidities and other variables (24).
There is also data to suggest that elderly patients may have a different biology to younger patients. Patients over the age of 75 were found to have a lower likelihood of having distant metastases (12) and less advanced stage at presentation (13).
Given the lack of clarity in the literature, we aimed to examine the treatment patterns and outcomes of the elderly population with non-metastatic rectal cancer.
Materials and methods
Study population
The study received approval from the South Western Sydney Local Health District and the Illawarra Shoalhaven Local Health District ethics committees. The study was performed in accordance with the Declaration of Helsinki. The need for informed consent was waived due to the low and negligible risk, and retrospective nature, of the work.
We utilised data from prospectively collated electronic records to identify patients with a histological diagnosis of rectal adenocarcinoma from 2006-2015, treated in the South Western Sydney and Illawarra Shoalhaven Local Health Districts, Australia. Patients with metastatic disease at diagnosis were excluded. Stage of disease was based on the 8th edition of the American Joint Committee on Cancer and College of American Joint Pathologists (AJCC) (25). Staging was based on clinical stage in patients undergoing neoadjuvant therapy, or pathological stage for patients who had surgery upfront. Clinicopathological variables, treatment modalities, recurrence and survival data were analysed.
Relapse-free survival was defined as the date of diagnosis to recurrence locally or distantly. Cancer specific survival was defined as date of diagnosis to death from rectal cancer. Overall survival was defined as the date of diagnosis to death from any cause. Patients who had not recurred and are still alive were censored at the date of last follow up.
Statistical analysis
Clinicopathological factors and treatment utilisation rates between patients <70 and ≥70 years were compared using Chi-Square. Median values for survival and corresponding 95% confidence intervals (CI) were calculated using Kaplan-Meier methods, and the log rank test was used to calculate P-values. Unadjusted and multivariable Cox proportional hazards regression analyses were used to estimate the association of age with survival outcomes, and to calculate corresponding hazard ratios (HRs) and 95% confidence intervals. The following variables were included in the multivariate model: Age, grade, lymphovascular invasion, perineural invasion, TNM stage, and receipt of adjuvant treatment. All statistical analyses were performed using SAS 9.2 software (SAS Institute, Inc.).
Results
Clinicopathological variables
We identified 736 patients with localized (stage I-III) rectal cancer, with median follow-up of 3.4 years. Of these, 326 (44.2%) were ≥70 years (median age at diagnosis 67 years, range 21-94). Elderly patients were more likely to present with earlier stage disease (stage III 47.6 vs. 57.1%, P=0.03), but there were no differences in other histopathological variables with age (Table I).
Treatment modalities
Elderly patients were more likely to be treated with a non-operative approach across all stages (7.4 vs. 2.0%, P=0.0014). In the management of stage I rectal cancer, a small percentage of elderly patients were treated non-operatively whilst all patients <70 years had curative intent surgery (8.8 vs. 0%, P=0.0079). In patients with stage III disease, elderly patients were more likely to be treated with surgery alone (25.2 vs. 4.3%, P<0.001), less likely to receive neoadjuvant (36.8 vs. 54.3%, P=0.007) or adjuvant therapy (47.1 vs. 79.1%, P<0.001). These results are shown in Table II. Two hundred and eight patients received neoadjuvant chemoradiotherapy and only 4 (2%) patients did not complete the entire radiotherapy course. Of these, 3 patients were <70 years and 1 patient was ≥70 years.
Surgical modality also differed with age, with the elderly patients less likely to undergo anterior resection and more likely to have a Hartmann's procedure (P<0.0001). The elderly cohort were also more likely to die within 30 days of surgery (P=0.0014) and less likely to be discussed at a multidisciplinary meeting (P=0.01), as depicted in Table I. The majority of post-operative deaths were from emergency surgeries for acute presentations such as bowel perforation.
Relapse and survival data
Overall survival was poorer in the elderly cohort (5 year overall survival 52 vs. 82%, P<0.0001), Fig. 1A. Univariate analyses for overall survival showed age, grade, presence of lymphovascular or perineural invasion, stage and adjuvant therapy to be significant predictors (Table III). Age, tumour grade, perineural invasion and adjuvant treatment remained significant in multivariate analyses.
Cancer specific survival was also poorer in the elderly cohort (5 year cancer specific survival 75 vs. 85%, P=0.008), Fig. 1B. For cancer-specific survival, age and histopathological variables were significant, but treatment modality did not impact outcomes in multivariate analysis (Table III).
Relapse-free survival was affected significantly by grade, lymphovascular and perineural invasion, as well as stage (Table IV). Use of neoadjuvant and adjuvant therapy predicted for worse survival in univariate analyses but were not significant in multivariate analyses.
Cancer-specific survival stratified by age
Elderly patients with stage III disease have worse outcomes compared to younger patients (Table V). However, elderly patients who received neoadjuvant +/- adjuvant therapy did not have significantly different outcomes compared to younger patients.
Summary of salient findings
Elderly patients composed almost half of the cohort, and presented with earlier stage disease. They were less likely to undergo trimodality therapy or discussed in a multidisciplinary meeting. Surgery in the elderly patients was more commonly a Hartmann's procedure, and surgery was associated with increased immediate post-operative mortality. Elderly patients had worse overall survival and cancer-specific survival, particularly evident in stage III disease. Elderly patients in this subgroup treated with trimodality therapy had similar survival outcomes to younger patients.
Discussion
Our study found that almost half of patients with non-metastatic rectal cancer undergoing treatment were over the age of 70. Although the majority (>90%) of elderly rectal cancer patients were treated with curative intent, this was significantly less than in younger patients. Elderly patients were less likely to receive trimodality therapy or be discussed in a multidisciplinary meeting. The more conservative approach toward treatment in the elderly may be largely due to the uncertainty around clinical decision making in this group, as they are largely excluded from clinical trials. In addition, the elderly have competing comorbidities which may complicate treatment. The elderly group was also less likely to undergo an anterior resection, and more likely to undergo a Hartmann's procedure or abdominoperineal resection. Surgery was associated with a higher death rate within 30 days post-operatively, albeit rates are still low (2.5%) with most of these being emergency surgeries for acute presentations such as bowel perforation.
In this study, the overall survival and cancer specific survival for elderly patients with non-metastatic rectal cancer was significantly worse compared to younger patients. In stage III patients, we found that cancer-specific outcomes were more than two times poorer compared to younger patients. However, in the subgroup treated with trimodality therapy, outcomes were not inferior to the younger patients. These findings are consistent with previous studies in the literature which have reported lower utilisation of trimodality therapy in the elderly patients (12-14). The literature also reports inferior cancer specific outcomes in the older population (11,13). However we did not find significant differences in recurrence rates in the elderly patients, suggesting that cancer specific survival may potentially be impacted by variable treatment modalities at the time of recurrence, or alternatively differences in surveillance post curative intent therapy.
The elderly population in our study presented with earlier stage disease which may reflect a difference in tumour biology or be attributed to incidental findings whilst screening for other conditions. This is consistent with some studies in the literature (12,13). A study exploring the genomic makeup of colorectal tumours found that older patients, defined as ≥70, had a greater index of genetic mutations, and a higher incidence of KRAS and BRAF mutations but less PTEN/PIK3CA mutations (26).
Limitations of this study include its retrospective nature, and the inability to assess the benefits of treatment due to selection bias. Fitter patients are expected to be selected to undergo adjuvant therapy thereby affecting overall survival, and patients with poor biology or very locally advanced disease are expected to undergo trimodality therapy hence translating to worse cancer specific outcomes. We recognise that we did not collect data on comorbidities and performance status which may impact on treatment pattern selection. Future research focused on the geriatric population will require information on comorbidities, nutritional status, cognitive status, and can employ the use of geriatric screening tools.
The toxicities and morbidity associated with trimodality therapy for locally advanced rectal cancer impact deliverability, especially in the elderly population. These patients are often excluded in clinical trial populations and hence the best management strategies and outcomes of treatment are unclear. There is also a shift towards a non-operative approach in the treatment of locally advanced rectal cancer (5), making treatment decision making in the older patients even more nuanced. Our study adds valuable insight into the treatment practices and outcomes in these patients, which comprise a large proportion of the patient population. Consideration should be given into deciding whether an ‘elderly’ patient should receive trimodality therapy, depending on their biological age and comorbidities, and not purely on chronological age alone. Elderly patients would benefit from being discussed in a multidisciplinary meeting. This is especially the case as life expectancy continues to rise, chronic illnesses are better managed, and definitions of the older patient are likely to shift upwards with time.
Acknowledgements
The authors would like to acknowledge Dr Sharlyn Kang (Illawarra Cancer Care Centre, University of Wollongong, Wollongong, New South Wales, Australia) for her contribution to the research in this manuscript before her passing and would like to dedicate this work to her memory. The abstract was presented in poster form at the American Society of Clinical Oncology (ASCO) Gastrointestinal Cancers Symposium January 2019 in San Francisco, CA and published as abstract no. 4 in Journal of Clinical Oncology Volume 37 (Suppl) (February 01, 2019) 678-678.
Funding
No funding was received.
Availability of data and materials
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Authors' contributions
SK, KJW, DB and SHSL designed and conceived the present study. SK, KJW, DB, WC, WN, JC, EN, ML, KW, LB, RW, SP, CSL and SHSL were all responsible for the provision of patient materials and data collection. SK, KJW, DB and SHSL performed data analysis and interpretation. SK, KJW and DB confirm the authenticity of all the raw data. All authors wrote the manuscript. All authors have read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by the South Western Sydney Local Health District (approval no. HREC/12/LPOOL/102) and the ethics committee of the Illawarra Shoalhaven Local Health District (approval no. LNR/15/WGONG/61). This study was performed in accordance with the Declaration of Helsinki. The need for informed consent was waived due to the low and negligible risk, and retrospective nature of the work.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
References
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015.PubMed/NCBI View Article : Google Scholar | |
Australian Institute of Health and Welfare 2015. Australia's Welfare 2015. Australia's welfare series no. 12. Cat. no. AUS 189. Canberra, 2015. | |
Lawler M, Selby P, Aapro MS and Duffy S: Ageism in cancer care. BMJ. 348(g1614)2014.PubMed/NCBI View Article : Google Scholar | |
Hurria A, Dale W, Mooney M, Rowland JH, Ballman KV, Cohen HJ, Muss HB, Schilsky RL, Ferrell B, Extermann M, et al: Designing therapeutic clinical trials for older and frail adults with cancer: U13 conference recommendations. J Clin Oncol. 32:2587–2594. 2014.PubMed/NCBI View Article : Google Scholar | |
Greer JB and Hawkins AT: Non-operative management of rectal cancer. Semin Colon Rectal Surg. 30:79–84. 2019.PubMed/NCBI View Article : Google Scholar | |
Heald RJ and Ryall RD: Recurrence and survival after total mesorectal excision for rectal cancer. Lancet. 1:1479–1482. 1986.PubMed/NCBI View Article : Google Scholar | |
Kapiteijn E, Putter H and van de Velde CJ: Cooperative investigators of the Dutch ColoRectal Cancer Group. Impact of the introduction and training of total mesorectal excision on recurrence and survival in rectal cancer in The Netherlands. Br J Surg. 89:1142–1149. 2002.PubMed/NCBI View Article : Google Scholar | |
Ahn T: What should be considered for local excision in early rectal cancer? Ann Coloproctol. 35:155–157. 2019.PubMed/NCBI View Article : Google Scholar | |
Althumairi AA and Gearhart SL: Local excision for early rectal cancer: Transanal endoscopic microsurgery and beyond. J Gastrointest Oncol. 6:296–306. 2015.PubMed/NCBI View Article : Google Scholar | |
Sauer R, Liersch T, Merkel S, Fietkau R, Hohenberger W, Hess C, Becker H, Raab HR, Villanueva MT, Witzigmann H, et al: Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: Results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years. J Clin Oncol. 30:1926–1933. 2012.PubMed/NCBI View Article : Google Scholar | |
Wan JF, Zhu J, Li GC, Sun WJ and Zhang Z: Implications for determining the optimal treatment for locally advanced rectal cancer in elderly patients aged 75 years and older. Oncotarget. 6:30377–30383. 2015.PubMed/NCBI View Article : Google Scholar | |
Jung B, Pahlman L, Johansson R and Nilsson E: Rectal cancer treatment and outcome in the elderly: An audit based on the Swedish Rectal Cancer Registry 1995-2004. BMC Cancer. 9(68)2009.PubMed/NCBI View Article : Google Scholar | |
Chang GJ, Skibber JM, Feig BW and Rodriguez-Bigas M: Are we undertreating rectal cancer in the elderly? An epidemiologic study. Ann Surg. 246:215–221. 2007.PubMed/NCBI View Article : Google Scholar | |
Thiels CA, Bergquist JR, Meyers AJ, Johnson CL, Behm KT, Hayman AV, Habermann EB, Larson DW and Mathis KL: Outcomes with multimodal therapy for elderly patients with rectal cancer. Br J Surg. 103:e106–e114. 2016.PubMed/NCBI View Article : Google Scholar | |
Shahir MA, Lemmens VE, van de Poll-Franse LV, Voogd AC, Martijn H and Janssen-Heijnen ML: Elderly patients with rectal cancer have a higher risk of treatment-related complications and a poorer prognosis than younger patients: A population-based study. Eur J Cancer. 42:3015–3021. 2006.PubMed/NCBI View Article : Google Scholar | |
Margalit DN, Mamon HJ, Ancukiewicz M, Kobayashi W, Ryan DP, Blaszkowsky LS, Clark J, Willett CG and Hong TS: Tolerability of combined modality therapy for rectal cancer in elderly patients aged 75 years and older. Int J Radiat Oncol Biol Phys. 81:e735–e741. 2011.PubMed/NCBI View Article : Google Scholar | |
Francois E, Azria D, Gourgou-Bourgade S, Jarlier M, Martel-Laffay I, Hennequin C, Etienne PL, Vendrely V, Seitz JF, Conroy T, et al: Results in the elderly with locally advanced rectal cancer from the ACCOR12/PRODIGE 2 phase III trial: Tolerance and efficacy. Radiother Oncol. 110:144–149. 2014.PubMed/NCBI View Article : Google Scholar | |
Choi Y, Kim JH, Kim JW, Kim JW, Lee KW, Oh HK, Kim DW, Kang SB, Song C and Kim JS: Preoperative chemoradiotherapy for elderly patients with locally advanced rectal cancer-a real-world outcome study. Jpn J Clin Oncol. 46:1108–1117. 2016.PubMed/NCBI View Article : Google Scholar | |
Guimas V, Boustani J, Schipman B, Lescut N, Puyraveau M, Bosset JF and Servagi-Vernat S: Preoperative chemoradiotherapy for rectal cancer in patients aged 75 Years and older: Acute toxicity, compliance with treatment, and early results. Drugs Aging. 33:419–425. 2016.PubMed/NCBI View Article : Google Scholar | |
Pasetto LM, Friso ML, Pucciarelli S, Basso U, Falci C, Bortolami A, Toppan P, Agostini M, Rugge M, Serpentini S, et al: Rectal cancer neoadjuvant treatment in elderly patients. Anticancer Res. 26 (5B):3913–3923. 2006.PubMed/NCBI | |
Jiang DM, Raissouni S, Mercer J, Kumar A, Goodwin R, Heng DY, Tang PA, Doll C, MacLean A, Powell E, et al: Clinical outcomes of elderly patients receiving neoadjuvant chemoradiation for locally advanced rectal cancer. Ann Oncol. 26:2102–2106. 2015.PubMed/NCBI View Article : Google Scholar | |
Tougeron D, Roullet B, Paillot B, Hamidou H, Tourani JM, Bensadoun RJ, Michel P and Silvain C: Safety and outcome of chemoradiotherapy in elderly patients with rectal cancer: Results from two French tertiary centres. Dig Liver Dis. 44:350–354. 2012.PubMed/NCBI View Article : Google Scholar | |
Dobie SA, Warren JL, Matthews B, Schwartz D, Baldwin LM and Billingsley K: Survival benefits and trends in use of adjuvant therapy among elderly stage II and III rectal cancer patients in the general population. Cancer. 112:789–799. 2008.PubMed/NCBI View Article : Google Scholar | |
Bohac GC, Guaqueta D, Cheng DM, Aschengrau A and Hartshorn KL: Disparity in the use of combined modality therapy for rectal cancer in the older adult. J Geriatr Oncol. 4:90–97. 2013.PubMed/NCBI View Article : Google Scholar | |
Amin MB, Greene FL, Edge SB, Compton CC, Gershenwald JE, Brookland RK, Meyer L, Gress DM, Byrd DR and Winchester DP: The Eighth Edition AJCC cancer staging manual: Continuing to build a bridge from a population-based to a more ‘personalized’ approach to cancer staging. CA Cancer J Clin. 67:93–99. 2017.PubMed/NCBI View Article : Google Scholar | |
Berg M, Danielsen SA, Ahlquist T, Merok MA, Agesen TH, Vatn MH, Mala T, Sjo OH, Bakka A, Moberg I, et al: DNA sequence profiles of the colorectal cancer critical gene set KRAS-BRAF-PIK3CA-PTEN-TP53 related to age at disease onset. PLoS One. 5(e13978)2010.PubMed/NCBI View Article : Google Scholar |