Annals of Oncology Advance Access published July 11, 2014 1
Treatment of colorectal cancer in older patients. International Society of Geriatric Oncology (SIOG) consensus recommendations 2013
D. Papamichael1, R. A. Audisio2, B. Glimelius3, A. de Gramont4, R. Glynne-Jones5, D. Haller6, C-H. Köhne7, S. Rostoft8, V. Lemmens9, E. Mitry10, H. Rutten11, D. Sargent12, J. Sastre13, M. Seymour14, N. Starling15, E. Van Cutsem16, and M. Aapro17 1
Department of Medical Oncology, B.O.Cyprus Oncology Centre, Nicosia, Cyprus
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St Helens Teaching Hospital, St Helens, UK
Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala, Sweden 4
Hôpital Saint Antoine, Paris, France
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Mount Vernon Hospital, Northwood, UK
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Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 7
Klinikum Oldenburg, Oldenburg, Germany
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Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
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Erasmus MC University Medical Centre, Rotterdam, The Netherlands and Eindhoven Cancer Registry, Comprehensive Cancer Centre South (IKZ), Eindhoven, The Netherlands 10
Department of Medical Oncology, Institut Curie, Paris, France and Université Versailles Saint-Quentin, Guyancourt, France
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Catharina Hospital Eindhoven, Eindhoven, The Netherlands and Maastricht University Medical Center, Maastricht, The Netherlands 12
Mayo Clinic, Rochester, Minnesota, USA
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Department of Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain
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Cancer Medicine and Pathology, University of Leeds, Leeds, UK
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Gastrointestinal Unit, Royal Marsden Hospital, London, UK
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Digestive Oncology, Leuven Cancer Insitute, Leuven, Belgium
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SIOG Office, Clinique de Genolier, Genolier, Switzerland
Corresponding author: Dr D. Papamichael, Consultant Medical Oncologist, Director, Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Ave., Strovolos 2006, Nicosia, CYPRUS, Tel: +357 22 841306, Fax: +357 22 511870, Email: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers both in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members.
Key words: colorectal cancer; guidelines; geriatric assessment; older, SIOG; International Society of Geriatric Oncology
Key message Oncologists and surgeons managing patients with colorectal cancer need to appreciate that approximately 60% of their patients are >70 years of age, more than 40% are >75 years and that these proportions may increase further in the future. Many of these patients will have co-morbidity and frailty issues. In an era of increased availability of anti-tumoral agents and expanding treatment strategies, elderly patients present a challenging therapeutic scenario. What may be considered “standard” management for the general population does not necessarily apply to this group where evidence-based data are lacking. It is against this backdrop that SIOG convened a task force meeting to review and update their existing recommendations for the treatment of elderly patients with colorectal cancer.
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data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of
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introduction Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide [1]. There are marked differences in incidence trends between countries, with the total number of cases affected both by changes in individual risk at a given age (the age-standardized rate, ASR) and by the changing age demographic of the population. In the US the ASR fell by over 30% between 1975 and 2010, perhaps reflecting lifestyle changes and the uptake of opportunistic screening [2], while rates in Canada, New Zealand and elsewhere were broadly stable [3]. However, over the same period the ASR rate in the UK, although remaining unchanged in women, rose by 30% in men [4]. Changes in age-standardized rates do not, however, mortailty from heart disease and other non-cancer causes reduces, this leaves an elderly population at high risk of developing bowel cancer. This has major implications for the organization of cancer services: for example, in the UK the number of new cases of bowel cancer diagnosed in patients >75 years rose by 30%, from 13,400 elderly patients in 1993 to 17,300 in 2010 [5]. And even countries with a stable ASR may see a rising number of cases of CRC in the elderly. Oncologists and surgeons managing patients with CRC must recognize that approximately 60% of their patients are >70 years of age and 43% >75 years [5], that these proportions may increase further, and that many of these older patients will have problems of frailty and co-morbidity which demand careful patient assessment and, if necessary, individualized treatment approaches [6, 7]. Currently, the majority of patients with stage I or II CRC are treated and cured by surgery [8, 9]. For patients with stage III colon cancer the standard treatment is surgery followed by adjuvant chemotherapy, whilst for those patients with metastatic CRC (mCRC) systemic chemotherapy alone or in combination with targeted biologics is usually the treatment of choice. Also, increasingly, patients with mCRC are managed within multidisciplinary teams (MDTs) and being considered for surgical resection of their metastatic disease wherever possible [10]. For patients with rectal cancer, treatment may involve surgery alone, preoperative short-course radiation therapy (SCPRT) or chemoradiotherapy (CRT) with surgical resection followed by postoperative adjuvant chemotherapy in selected patients. Co-morbidity, functional dependency and older age are associated with early post-operative mortality in patients with gastrointestinal malignancies, with 30-day post-operative mortality rates underestimating post-operative mortality in older patients [11]. The International Society of Geriatric Oncology (SIOG) previously recommended that CRC patients >65 years of age requiring surgery should undergo a preoperative whole patient evaluation of the most common physiological side effects of aging, physical and mental ability and social support [12]. Furthermore, for those patients assessed as having physical or psychological co-morbidities it was recommended that ‘a geriatrician was involved in patient management’ [12]. One of the major challenges is the physiological heterogeneity of the older patient population with frequent discrepancies between physiological and chronological age coupled with the additional complications of co-existing medical conditions and the potential psychological and social care issues alluded to above. Defining old or elderly patients is challenging. The patient’s biological age should
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represent the overall burden of disease. The age-specific risk rises markedly with age, and as
4 ideally be established through a comprehensive geriatric assessment in order to aid therapeutic decisions. There is a paucity of clinical trial data for these patients in terms of their poor functional reserves, major co-morbidities and frailty. Indeed, there is a huge debate in the literature about how to define frail patients and how to differentiate frailty from co-morbidity and disability [13-16]. Experts anticipate that by distinguishing the fit from the more vulnerable older patients, treatment can be adjusted to maximize its effectiveness, avoid complications and better meet the individual requirements of the older patient. It is against this backdrop that SIOG convened a task force meeting to review and update their existing recommendations for the treatment of older patients with CRC [12], based on recent publications and personal experience.
The task force comprised two surgeons, one epidemiologist, ten medical oncologists, two radiation oncologists, one geriatrician and one statistician. The key areas for discussion were structured under five headings: 1. Patient assessment 2. Surgery in older patients 3. Adjuvant chemotherapy 4. Palliative chemotherapy 5. Rectal cancer
patient assessment A geriatric assessment (GA) evaluates a patient’s functional status (activities of daily living [ADL], physical performance and Eastern Cooperative Oncology Group/World Health Organization performance status), co-morbidities, polypharmacy, nutritional status, cognitive function, emotional function (anxiety and depression), and social support. However, other key issues related to older patients are limited life expectancy, reduced treatment tolerance, and in frail patients, different treatment goals. Regardless of objective measures of treatment toxicity, older patients, either frail or non-frail, may have different views about the acceptability of certain of the medical interventions proposed, and may arrive at different personal trade-offs in terms of the positive and negative impacts of such interventions. The question is how to address these issues in everyday clinical practice, with only limited evidence to aid decision making. The use of a GA is feasible in the oncology setting, with some domains associated with adverse outcomes [17]. Of four studies that examined the impact of such an assessment on treatment decisions [18-21], two [20, 21] judged the assessment to impact on 40–50% of treatment decisions, mostly involving changes in the chemotherapy regimen. Components of the GA, such as age and functional status, are also associated with certain treatment modalities such as surgery alone [17]. However, a systematic review of seven frailty screening methods in older patients receiving surgery, radiotherapy or chemotherapy concluded that they had insufficient discriminatory power to refine patient selection [22]. The recommendation was that it might be beneficial for all older patients with
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methods
5 cancer to receive a general GA [22], but that further research was required to elucidate the role of the GA in oncology [23]. Physical frailty increases the risk of major complications following surgery (odds ratio (OR): 4.1 (1.4–11.6) in patients ≥75 (range 75–93) years [24], and is predictive for both complications and survival in patients ≥70 years following surgery [25, 26]. Older patients are also vulnerable to chemotherapy toxicity, and whilst frail patients are considered to be unfit to receive chemotherapy, non-frail patients with co-morbidities may be considered for less intensive therapy. A prospective multicenter study showed at least 53% of older patients (mean age 73 years) receiving chemotherapy to experience at least one grade 3–5 toxicity, and that a risk stratification schema could be used to changes in brain activation after chemotherapy have recently been linked to an increase in cognitive complaints in patients with breast cancer [28]. [However, other issues that need to be addressed include remaining life expectancy and the impact of pre-treatment optimization based on a GA. A Norwegian study which analyzed survival in all patients curatively resected for CRC over a 10-year period showed survival to increase significantly after the implementation of national management strategies. The improvements, however, were least for those patients with colon cancer and those >75 years of age with lymph node-positive disease; both possibly being a reflection of the age cut-off of 75 years for adjuvant chemotherapy in the previous Norwegian guidelines [29]. Current evidence supports evaluating elements of the GA, especially co-morbidity, functional status, cognitive dysfunction and frailty, which are consistently associated with adverse treatment outcomes in relation to both toxicity and mortality, in both the clinical trial and routine clinical practice settings. An assessment of cognitive function is essential in order to establish whether a patient is able to consent to and comply with, their treatment and follow-up. The outcomes that need to be considered in relation to surgery and chemotherapy for older patients are presented in Table 1.
surgery in older patients with CRC Surgery remains the cornerstone of treatment for patients with CRC. The improvement in survival for patients with CRC over time has in large part been due to a decrease in post-operative mortality and, to a lesser degree, the resection of hepatic metastases in selected patients [30-35]. However, despite these improvements the survival gain is smaller in older patients than in younger patients and the gap is widening [36-39]. Survival also varies substantially between countries [40, 41]. Not only do comorbidity and emergency surgery have a negative impact on survival but age itself has been identified in several population-based studies as a negative prognostic factor [11, 42]. Malnourishment also impacts on outcome [43-45]. Decreased survival in older (≥75 years) patients post surgery has mainly been attributed to differences in early mortality [46]. Older patients with CRC who survive the first year may have the same overall cancer-related survival as younger patients [47, 48]. Thus, the treatment of older patients with CRC should focus on perioperative care and the first post-operative year [48]. Indeed, if the data are corrected for the competitive risk of dying, older CRC patients respond well to different
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establish the risk of severe chemotherapy-induced toxicity in these patients [27]. Furthermore,
6 cancer treatments [48-50]. Manceau et al. concluded that older patients with rectal cancer undergoing surgery should receive the same treatment as their younger counterparts but with an adjustment of treatment strategy in the case of co-morbidity, limited physiologic reserves, and emergency situations [50]. Currently, older patients undergoing surgery risk being under-treated, resulting in a worse oncological outcome [51], or over-treated, with the possibility of subsequent excess morbidity and mortality. Thus, it is important to optimize and individualize CRC surgery [52-54]. For example a lower morbidity rate is seen if surgery is delayed following short-course radiotherapy [55, 56]. One of the specific requirements for achieving safe and effective surgical treatment is an explicit risk assessment with CRC should be discussed by a MDT prior to the commencement of any therapy. Geriatricians are not typically members of MDTs [26, 54, 57]. However, there is clear evidence that the majority of older CRC patients can be safely treated in specialized centers where the expertise is available to provide the most favorable surgical treatment and care [57-61]. Also, where a GA is not feasible, quick screening tools for frailty can predict surgical outcomes in older patients [62]. Thus the updated recommendations for CRC patients undergoing surgery are that: A protocol should be devised to identify those patients for whom a geriatrician needs to be involved and for whom co-morbidity and frailty are a hazard. A formal GA should be considered and if this is not feasible, rapid screening tools for frailty should be used. A prehabilitation program should be considered, where necessary, which should include correction of malnutrition, and optimization of cardiovascular and pulmonary co-morbidities as well as medication use. For patients requiring prehabilitation, major resection should be postponed and emergency surgery avoided. Emergency surgery should be kept to a minimum, and, in the case of obstructive disease alternative procedures such as the construction of a diverting stoma or stenting, if cure is not the aim, must be considered [63-65]. Careful consideration should also be given to the consequences of the construction and siting of the stoma [66]. The combination of an emergency procedure with a major resection or multimodality treatment within too short a time frame should be avoided [63, 65]. Patients (especially high-risk patients) and their families need to be informed about the risks, possible functional impairment and oncological outcome before consenting to a treatment plan. High-risk patients should be offered alternative options, ranging from no tumor-controlling treatment at all, to palliative treatment, through to full treatment. Ideally, the preferences of patients if serious complications occur should be discussed.
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as stated in the previous guidelines [12], with the specific recommendation that every older patient
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adjuvant chemotherapy The benefits of 5-fluorouracil (5-FU)-based adjuvant chemotherapy for patients with stage III colon cancer are well established for both younger and older patients [67-71], although its use in the management of patients with stage II disease remains controversial [72, 73]. An important question is: can these benefits be extended beyond 5-FU/leucovorin (LV) in older patients with high-risk stage II or stage III colon cancer? Also, does the convenience of administration achieved by replacing intravenous 5-FU with the oral fluoropyrimidine capecitabine outweigh the problems seen in elderly patients with poor renal function and the issues of under or over compliance? It is anticipated that prospective pooled analysis in >10,500 patients with stage III colon cancer, from six trials (SCOT, PRODIGE, CALGB/SWOG C80702, TOSCA, HORG and ACHIEVE), will help address some of the issues surrounding the use of oxaliplatin-based adjuvant therapy in older colon cancer patients. However, these results are not expected to be available until 2015/2016.[74] Today, based on the results of three adjuvant studies (MOSAIC, NSABP-C-07, and XELOXA), oxaliplatin-based combination chemotherapy is considered to be a standard of care in patients with stage III colon cancer [8, 67, 72, 75-77]. In the MOSAIC trial, which compared FOLFOX4 with 5FU/LV in 2,246 patients with resected stage II (40%, 25% high-risk) and III colon cancer [8], the 6year overall survival (OS) rates were 78.5% and 76.0% (HR 0.84, 95% CI: 0.71–1.00, P=0.046) respectively in favor of FOLFOX4 [67], with the benefit, attributable almost entirely to patients with stage III disease (5-FU/LV 68.7%, FOLFOX4 72.9%, HR 0.80, 95%CI: 0.65–0.97, P=0.023). Subgroup analyses showed there to be no statistically significant benefit conferred by the addition of oxaliplatin in terms of DFS or OS for either stage II or older patients (70–75 years), although female patients 70–75 years had the same oxaliplatin benefit as younger patients [72]. Interestingly, the DFS and OS benefits in patients 70-75 years were similar to those of younger patients for the first 3 years of follow up, but were lost later on due to deaths from other causes. In the NSABP-C-07 trial the addition of oxaliplatin to bolus 5-FU/LV (FLOX) improved DFS in patients with stage II/III colon cancer with the benefit still apparent after 8 years of follow-up (HR 0.82, 95% CI: 0.72–0.93, P=0.002). OS was also significantly improved for patients 12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database. J Clin Oncol 2009; 27(15S): Abstract 4010.
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10-year results of the Lyon R 96-02 randomized trial. Int J Radiat Oncol Biol Phys 2012; 83: e165-171. 139. Saltz LB, Cox JV, Blanke C et al. Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. N Engl J Med 2000; 343: 905-914. 140. Douillard JY. Irinotecan and high-dose fluorouracil/leucovorin for metastatic colorectal cancer. Oncology 2000; 14: 51-55. 141. Kohne CH, van Cutsem E, Wils J et al. Phase III study of weekly high-dose infusional fluorouracil plus folinic acid with or without irinotecan in patients with metastatic colorectal cancer: European Organisation for Research and Treatment of Cancer Gastrointestinal Group Study 40986. J Clin Oncol 2005; 23: 4856-4865. 142. Seymour MT, Maughan TS, Ledermann JA et al. Different strategies of sequential and combination chemotherapy for patients with poor prognosis advanced colorectal cancer (MRC FOCUS): a randomised controlled trial. Lancet 2007; 370: 143-152. 143. de Gramont A, Figer A, Seymour M et al. Leucovorin and fluorouracil with or without oxaliplatin as first-line treatment in advanced colorectal cancer. J Clin Oncol 2000; 18: 29382947. 144. Rothenberg ML, Oza AM, Bigelow RH et al. Superiority of oxaliplatin and fluorouracilleucovorin compared with either therapy alone in patients with progressive colorectal cancer after irinotecan and fluorouracil-leucovorin: interim results of a phase III trial. J Clin Oncol 2003; 21: 2059-2069. 145. Goldberg RM, Sargent DJ, Morton RF et al. A randomized controlled trial of fluorouracil plus leucovorin, irinotecan, and oxaliplatin combinations in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 2004; 22: 23-30. 146. Jonker DJ, O'Callaghan CJ, Karapetis CS et al. Cetuximab for the treatment of colorectal cancer. N Engl J Med 2007; 357: 2040-2048.
Table 1. Treatment considerations for older patients with CRC
Outcomes that need to be considered in Outcomes that need to be considered in relation to surgery relation to chemotherapy
1. 2.
7. 8.
QoL, quality of life.
1. Toxicity (which can be divided into numerous subcategories) 2. Completion of therapy 3. QoL 4. Functional status 5. Progression 6. Survival 7. Composite endpoints (overall treatment utility)
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3. 4. 5. 6.
Immediate post-operative morbidity 30-day post-operative morbidity and mortality Length of stay Discharge to nursing home 1-year mortality Short-term and long-term functional outcomes QoL (short- and long-term) Survival
Table 2. Outcomes of experimental (combination or oral FU) versus control arm (IV 5-FU) by treatment and age [81] Disease-free survival
*
Overall survival
*
Time to recurrence
*
Deaths within 6 months, experimental vs control
Treatment arm
HR
95% CI
HR
95% CI
HR
95% CI
%
P value
All trials Age
Treatment of colorectal cancer in older patients. International Society of Geriatric Oncology (SIOG) consensus recommendations 2013
D. Papamichael1, R. A. Audisio2, B. Glimelius3, A. de Gramont4, R. Glynne-Jones5, D. Haller6, C-H. Köhne7, S. Rostoft8, V. Lemmens9, E. Mitry10, H. Rutten11, D. Sargent12, J. Sastre13, M. Seymour14, N. Starling15, E. Van Cutsem16, and M. Aapro17 1
Department of Medical Oncology, B.O.Cyprus Oncology Centre, Nicosia, Cyprus
2
St Helens Teaching Hospital, St Helens, UK
Department of Radiology, Oncology and Radiation Science, University of Uppsala, Uppsala, Sweden 4
Hôpital Saint Antoine, Paris, France
5
Mount Vernon Hospital, Northwood, UK
6
Abramson Cancer Center at the University of Pennsylvania, Philadelphia, Pennsylvania, USA 7
Klinikum Oldenburg, Oldenburg, Germany
8
Department of Geriatric Medicine, Oslo University Hospital, Oslo, Norway
9
Erasmus MC University Medical Centre, Rotterdam, The Netherlands and Eindhoven Cancer Registry, Comprehensive Cancer Centre South (IKZ), Eindhoven, The Netherlands 10
Department of Medical Oncology, Institut Curie, Paris, France and Université Versailles Saint-Quentin, Guyancourt, France
11
Catharina Hospital Eindhoven, Eindhoven, The Netherlands and Maastricht University Medical Center, Maastricht, The Netherlands 12
Mayo Clinic, Rochester, Minnesota, USA
13
Department of Medical Oncology, Hospital Clinico San Carlos, Madrid, Spain
14
Cancer Medicine and Pathology, University of Leeds, Leeds, UK
15
Gastrointestinal Unit, Royal Marsden Hospital, London, UK
16
Digestive Oncology, Leuven Cancer Insitute, Leuven, Belgium
17
SIOG Office, Clinique de Genolier, Genolier, Switzerland
Corresponding author: Dr D. Papamichael, Consultant Medical Oncologist, Director, Department of Medical Oncology, Bank of Cyprus Oncology Centre, 32 Acropoleos Ave., Strovolos 2006, Nicosia, CYPRUS, Tel: +357 22 841306, Fax: +357 22 511870, Email: [email protected]
© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected].
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3
2
Abstract Colorectal cancer (CRC) is one of the most commonly diagnosed cancers both in Europe and worldwide, with the peak incidence in patients >70 years of age. However, as the treatment algorithms for the treatment of patients with CRC become ever more complex, it is clear that a significant percentage of older CRC patients (>70 years) are being less than optimally treated. This document provides a summary of an International Society of Geriatric Oncology (SIOG) task force meeting convened in Paris in 2013 to update the existing expert recommendations for the treatment of older (geriatric) CRC patients published in 2009 and includes overviews of the recent older CRC patients to tolerate surgery, adjuvant chemotherapy, treatment of their metastatic disease including palliative chemotherapy with and without the use of the biologics, and finally the use of adjuvant and palliative radiotherapy in the treatment of older rectal cancer patients. An overview of each area was presented by one of the task force experts and comments invited from other task force members.
Key words: colorectal cancer; guidelines; geriatric assessment; older, SIOG; International Society of Geriatric Oncology
Key message Oncologists and surgeons managing patients with colorectal cancer need to appreciate that approximately 60% of their patients are >70 years of age, more than 40% are >75 years and that these proportions may increase further in the future. Many of these patients will have co-morbidity and frailty issues. In an era of increased availability of anti-tumoral agents and expanding treatment strategies, elderly patients present a challenging therapeutic scenario. What may be considered “standard” management for the general population does not necessarily apply to this group where evidence-based data are lacking. It is against this backdrop that SIOG convened a task force meeting to review and update their existing recommendations for the treatment of elderly patients with colorectal cancer.
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data on epidemiology, geriatric assessment as it relates to surgery and oncology, and the ability of
3
introduction Colorectal cancer (CRC) is one of the most commonly diagnosed cancers worldwide [1]. There are marked differences in incidence trends between countries, with the total number of cases affected both by changes in individual risk at a given age (the age-standardized rate, ASR) and by the changing age demographic of the population. In the US the ASR fell by over 30% between 1975 and 2010, perhaps reflecting lifestyle changes and the uptake of opportunistic screening [2], while rates in Canada, New Zealand and elsewhere were broadly stable [3]. However, over the same period the ASR rate in the UK, although remaining unchanged in women, rose by 30% in men [4]. Changes in age-standardized rates do not, however, mortailty from heart disease and other non-cancer causes reduces, this leaves an elderly population at high risk of developing bowel cancer. This has major implications for the organization of cancer services: for example, in the UK the number of new cases of bowel cancer diagnosed in patients >75 years rose by 30%, from 13,400 elderly patients in 1993 to 17,300 in 2010 [5]. And even countries with a stable ASR may see a rising number of cases of CRC in the elderly. Oncologists and surgeons managing patients with CRC must recognize that approximately 60% of their patients are >70 years of age and 43% >75 years [5], that these proportions may increase further, and that many of these older patients will have problems of frailty and co-morbidity which demand careful patient assessment and, if necessary, individualized treatment approaches [6, 7]. Currently, the majority of patients with stage I or II CRC are treated and cured by surgery [8, 9]. For patients with stage III colon cancer the standard treatment is surgery followed by adjuvant chemotherapy, whilst for those patients with metastatic CRC (mCRC) systemic chemotherapy alone or in combination with targeted biologics is usually the treatment of choice. Also, increasingly, patients with mCRC are managed within multidisciplinary teams (MDTs) and being considered for surgical resection of their metastatic disease wherever possible [10]. For patients with rectal cancer, treatment may involve surgery alone, preoperative short-course radiation therapy (SCPRT) or chemoradiotherapy (CRT) with surgical resection followed by postoperative adjuvant chemotherapy in selected patients. Co-morbidity, functional dependency and older age are associated with early post-operative mortality in patients with gastrointestinal malignancies, with 30-day post-operative mortality rates underestimating post-operative mortality in older patients [11]. The International Society of Geriatric Oncology (SIOG) previously recommended that CRC patients >65 years of age requiring surgery should undergo a preoperative whole patient evaluation of the most common physiological side effects of aging, physical and mental ability and social support [12]. Furthermore, for those patients assessed as having physical or psychological co-morbidities it was recommended that ‘a geriatrician was involved in patient management’ [12]. One of the major challenges is the physiological heterogeneity of the older patient population with frequent discrepancies between physiological and chronological age coupled with the additional complications of co-existing medical conditions and the potential psychological and social care issues alluded to above. Defining old or elderly patients is challenging. The patient’s biological age should
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represent the overall burden of disease. The age-specific risk rises markedly with age, and as
4 ideally be established through a comprehensive geriatric assessment in order to aid therapeutic decisions. There is a paucity of clinical trial data for these patients in terms of their poor functional reserves, major co-morbidities and frailty. Indeed, there is a huge debate in the literature about how to define frail patients and how to differentiate frailty from co-morbidity and disability [13-16]. Experts anticipate that by distinguishing the fit from the more vulnerable older patients, treatment can be adjusted to maximize its effectiveness, avoid complications and better meet the individual requirements of the older patient. It is against this backdrop that SIOG convened a task force meeting to review and update their existing recommendations for the treatment of older patients with CRC [12], based on recent publications and personal experience.
The task force comprised two surgeons, one epidemiologist, ten medical oncologists, two radiation oncologists, one geriatrician and one statistician. The key areas for discussion were structured under five headings: 1. Patient assessment 2. Surgery in older patients 3. Adjuvant chemotherapy 4. Palliative chemotherapy 5. Rectal cancer
patient assessment A geriatric assessment (GA) evaluates a patient’s functional status (activities of daily living [ADL], physical performance and Eastern Cooperative Oncology Group/World Health Organization performance status), co-morbidities, polypharmacy, nutritional status, cognitive function, emotional function (anxiety and depression), and social support. However, other key issues related to older patients are limited life expectancy, reduced treatment tolerance, and in frail patients, different treatment goals. Regardless of objective measures of treatment toxicity, older patients, either frail or non-frail, may have different views about the acceptability of certain of the medical interventions proposed, and may arrive at different personal trade-offs in terms of the positive and negative impacts of such interventions. The question is how to address these issues in everyday clinical practice, with only limited evidence to aid decision making. The use of a GA is feasible in the oncology setting, with some domains associated with adverse outcomes [17]. Of four studies that examined the impact of such an assessment on treatment decisions [18-21], two [20, 21] judged the assessment to impact on 40–50% of treatment decisions, mostly involving changes in the chemotherapy regimen. Components of the GA, such as age and functional status, are also associated with certain treatment modalities such as surgery alone [17]. However, a systematic review of seven frailty screening methods in older patients receiving surgery, radiotherapy or chemotherapy concluded that they had insufficient discriminatory power to refine patient selection [22]. The recommendation was that it might be beneficial for all older patients with
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methods
5 cancer to receive a general GA [22], but that further research was required to elucidate the role of the GA in oncology [23]. Physical frailty increases the risk of major complications following surgery (odds ratio (OR): 4.1 (1.4–11.6) in patients ≥75 (range 75–93) years [24], and is predictive for both complications and survival in patients ≥70 years following surgery [25, 26]. Older patients are also vulnerable to chemotherapy toxicity, and whilst frail patients are considered to be unfit to receive chemotherapy, non-frail patients with co-morbidities may be considered for less intensive therapy. A prospective multicenter study showed at least 53% of older patients (mean age 73 years) receiving chemotherapy to experience at least one grade 3–5 toxicity, and that a risk stratification schema could be used to changes in brain activation after chemotherapy have recently been linked to an increase in cognitive complaints in patients with breast cancer [28]. [However, other issues that need to be addressed include remaining life expectancy and the impact of pre-treatment optimization based on a GA. A Norwegian study which analyzed survival in all patients curatively resected for CRC over a 10-year period showed survival to increase significantly after the implementation of national management strategies. The improvements, however, were least for those patients with colon cancer and those >75 years of age with lymph node-positive disease; both possibly being a reflection of the age cut-off of 75 years for adjuvant chemotherapy in the previous Norwegian guidelines [29]. Current evidence supports evaluating elements of the GA, especially co-morbidity, functional status, cognitive dysfunction and frailty, which are consistently associated with adverse treatment outcomes in relation to both toxicity and mortality, in both the clinical trial and routine clinical practice settings. An assessment of cognitive function is essential in order to establish whether a patient is able to consent to and comply with, their treatment and follow-up. The outcomes that need to be considered in relation to surgery and chemotherapy for older patients are presented in Table 1.
surgery in older patients with CRC Surgery remains the cornerstone of treatment for patients with CRC. The improvement in survival for patients with CRC over time has in large part been due to a decrease in post-operative mortality and, to a lesser degree, the resection of hepatic metastases in selected patients [30-35]. However, despite these improvements the survival gain is smaller in older patients than in younger patients and the gap is widening [36-39]. Survival also varies substantially between countries [40, 41]. Not only do comorbidity and emergency surgery have a negative impact on survival but age itself has been identified in several population-based studies as a negative prognostic factor [11, 42]. Malnourishment also impacts on outcome [43-45]. Decreased survival in older (≥75 years) patients post surgery has mainly been attributed to differences in early mortality [46]. Older patients with CRC who survive the first year may have the same overall cancer-related survival as younger patients [47, 48]. Thus, the treatment of older patients with CRC should focus on perioperative care and the first post-operative year [48]. Indeed, if the data are corrected for the competitive risk of dying, older CRC patients respond well to different
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establish the risk of severe chemotherapy-induced toxicity in these patients [27]. Furthermore,
6 cancer treatments [48-50]. Manceau et al. concluded that older patients with rectal cancer undergoing surgery should receive the same treatment as their younger counterparts but with an adjustment of treatment strategy in the case of co-morbidity, limited physiologic reserves, and emergency situations [50]. Currently, older patients undergoing surgery risk being under-treated, resulting in a worse oncological outcome [51], or over-treated, with the possibility of subsequent excess morbidity and mortality. Thus, it is important to optimize and individualize CRC surgery [52-54]. For example a lower morbidity rate is seen if surgery is delayed following short-course radiotherapy [55, 56]. One of the specific requirements for achieving safe and effective surgical treatment is an explicit risk assessment with CRC should be discussed by a MDT prior to the commencement of any therapy. Geriatricians are not typically members of MDTs [26, 54, 57]. However, there is clear evidence that the majority of older CRC patients can be safely treated in specialized centers where the expertise is available to provide the most favorable surgical treatment and care [57-61]. Also, where a GA is not feasible, quick screening tools for frailty can predict surgical outcomes in older patients [62]. Thus the updated recommendations for CRC patients undergoing surgery are that: A protocol should be devised to identify those patients for whom a geriatrician needs to be involved and for whom co-morbidity and frailty are a hazard. A formal GA should be considered and if this is not feasible, rapid screening tools for frailty should be used. A prehabilitation program should be considered, where necessary, which should include correction of malnutrition, and optimization of cardiovascular and pulmonary co-morbidities as well as medication use. For patients requiring prehabilitation, major resection should be postponed and emergency surgery avoided. Emergency surgery should be kept to a minimum, and, in the case of obstructive disease alternative procedures such as the construction of a diverting stoma or stenting, if cure is not the aim, must be considered [63-65]. Careful consideration should also be given to the consequences of the construction and siting of the stoma [66]. The combination of an emergency procedure with a major resection or multimodality treatment within too short a time frame should be avoided [63, 65]. Patients (especially high-risk patients) and their families need to be informed about the risks, possible functional impairment and oncological outcome before consenting to a treatment plan. High-risk patients should be offered alternative options, ranging from no tumor-controlling treatment at all, to palliative treatment, through to full treatment. Ideally, the preferences of patients if serious complications occur should be discussed.
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as stated in the previous guidelines [12], with the specific recommendation that every older patient
7
adjuvant chemotherapy The benefits of 5-fluorouracil (5-FU)-based adjuvant chemotherapy for patients with stage III colon cancer are well established for both younger and older patients [67-71], although its use in the management of patients with stage II disease remains controversial [72, 73]. An important question is: can these benefits be extended beyond 5-FU/leucovorin (LV) in older patients with high-risk stage II or stage III colon cancer? Also, does the convenience of administration achieved by replacing intravenous 5-FU with the oral fluoropyrimidine capecitabine outweigh the problems seen in elderly patients with poor renal function and the issues of under or over compliance? It is anticipated that prospective pooled analysis in >10,500 patients with stage III colon cancer, from six trials (SCOT, PRODIGE, CALGB/SWOG C80702, TOSCA, HORG and ACHIEVE), will help address some of the issues surrounding the use of oxaliplatin-based adjuvant therapy in older colon cancer patients. However, these results are not expected to be available until 2015/2016.[74] Today, based on the results of three adjuvant studies (MOSAIC, NSABP-C-07, and XELOXA), oxaliplatin-based combination chemotherapy is considered to be a standard of care in patients with stage III colon cancer [8, 67, 72, 75-77]. In the MOSAIC trial, which compared FOLFOX4 with 5FU/LV in 2,246 patients with resected stage II (40%, 25% high-risk) and III colon cancer [8], the 6year overall survival (OS) rates were 78.5% and 76.0% (HR 0.84, 95% CI: 0.71–1.00, P=0.046) respectively in favor of FOLFOX4 [67], with the benefit, attributable almost entirely to patients with stage III disease (5-FU/LV 68.7%, FOLFOX4 72.9%, HR 0.80, 95%CI: 0.65–0.97, P=0.023). Subgroup analyses showed there to be no statistically significant benefit conferred by the addition of oxaliplatin in terms of DFS or OS for either stage II or older patients (70–75 years), although female patients 70–75 years had the same oxaliplatin benefit as younger patients [72]. Interestingly, the DFS and OS benefits in patients 70-75 years were similar to those of younger patients for the first 3 years of follow up, but were lost later on due to deaths from other causes. In the NSABP-C-07 trial the addition of oxaliplatin to bolus 5-FU/LV (FLOX) improved DFS in patients with stage II/III colon cancer with the benefit still apparent after 8 years of follow-up (HR 0.82, 95% CI: 0.72–0.93, P=0.002). OS was also significantly improved for patients 12,500 patients (pts) with stage II/III colon cancer: Findings from the ACCENT Database. J Clin Oncol 2009; 27(15S): Abstract 4010.
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Table 1. Treatment considerations for older patients with CRC
Outcomes that need to be considered in Outcomes that need to be considered in relation to surgery relation to chemotherapy
1. 2.
7. 8.
QoL, quality of life.
1. Toxicity (which can be divided into numerous subcategories) 2. Completion of therapy 3. QoL 4. Functional status 5. Progression 6. Survival 7. Composite endpoints (overall treatment utility)
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3. 4. 5. 6.
Immediate post-operative morbidity 30-day post-operative morbidity and mortality Length of stay Discharge to nursing home 1-year mortality Short-term and long-term functional outcomes QoL (short- and long-term) Survival
Table 2. Outcomes of experimental (combination or oral FU) versus control arm (IV 5-FU) by treatment and age [81] Disease-free survival
*
Overall survival
*
Time to recurrence
*
Deaths within 6 months, experimental vs control
Treatment arm
HR
95% CI
HR
95% CI
HR
95% CI
%
P value
All trials Age
