Management and survival analysis of elderly patients with a cancer in the digestive system who refused to receive anticancer treatments

Management and survival analysis of elderly patients with a cancer in the digestive system who... Treatment and management of cancers in elderly patients require some special considerations. A better understanding of how cancers progress in those elderly patients who have not received any anticancer treatments could better help us in treating these patients and in making end-of-life decisions. Over the past years, we had encountered 57 elderly patients, aged 75 to 94 years (87.6 on average), with a cancer in the digestive system, who refused to accept anticancer treatment but who did receive the best available supportive and palliative care. Clinicopathological data of these patients were analyzed. Of these 57 cases, 49 were at an advanced or late stage, while the remaining eight were at an early stage at the time of diagnosis. The median overall survival time of all the patients was 11 months, and almost the entire cohort manifested multiple-organ impairments. The average number of malfunctioning organs per patient was 3.68. After carefully predicting, and then preventing or managing complications, only 54.4% of the patients eventually died of multiple-organ functional failure. Nearly 18% of the single organ dysfunctions were finally well-controlled. Our data provide the first statistical information on the survival time and the direct cause of death of the elderly patients with a cancer in the digestive system not treated with chemotherapy or other direct anticancer interventions, but who did receive the best available supportive and palliative cares. During their struggle with cancer, elderly patients clearly could benefit from prophylactic interventions on organ dysfunction. . . . . . Keywords Geriatrics Survival time Cancer Chemotherapy Surgery Radiotherapy Introduction Since even those elderly without a malignancy usually have some decline in major organ function, their cancers, especially Most countries have shown a great increase in human life over the age of 80, generally present with comorbidities. This expectancy over the last several decades. Along with this, can cause oncologists to experience some difficult treatment however, is an aging-related increase in cancer incidence [1]. decisions, as complex conditions may affect not only the ther- apy efficacy but also its tolerability. On the other hand, it is believed that cancer in the elderly usually grows and pro- gresses more slowly than in younger cancer patients [2]. * Dezhong Joshua Liao Combining these situations, both beneficial and adverse, in djliao@gmc.edu.cn the elderly, it is typically more practical to restrain, rather than * Ningzhi Xu attempt to cure, the cancer, to extend the patient’s life and xuningzhi@cicams.ac.cn quality of life (QOL) while maintaining an adequate level of * Gangshi Wang dignity. The reality is that in our clinical practice, many elderly wanggangshi@hotmail.com cancer patients simply refuse further surgery or the often de- Department of Geriatric Gastroenterology, Chinese PLA General bilitating radio- or chemotherapy routinely given to younger Hospital, Beijing 100853, People’sRepublic of China patients. Many simply prefer care-directed treatments along Department of Pathology, Guizhou Medical University Hospital, with supportive symptom-management to maintain a relative- Guiyang 550004, Guizhou, People’s Republic of China ly good QOL. In other words, palliative care plus good sup- Laboratory of Cell and Molecular Biology & State Key Laboratory of portive care is often the patient’s choice. However, this clinical Molecular Oncology, National Cancer Center/Cancer Hospital, goal is still a tremendous challenge to oncologists worldwide Chinese Academy of Medical Sciences & Peking Union Medical with many unsolved questions. For example, oncologists are College, Beijing 100021, People’s Republic of China 2334 Support Care Cancer (2018) 26:2333–2339 required to address some important issues when making man- hampered the anticancer treatment, or (4) patients and/or their agement decisions for elderly cancer patients, including how families refused to accept any anticancer therapy. to slow down or even stop progression of the cancer, how to Medical records of the patients were retrieved and prolong survival time, how to improve the QOL as the patient reviewed. The clinicopathological data identified included approaches his final days, and how to let the patient die with age, gender, tumor location, pathological findings, tumor dignity. It would be ideal if the treatment decisions were made stage at diagnosis, as well as assessments of the internal ho- collectively by the physician and the patient, as well as the meostasis and of the functions of the heart, lung, liver, kidney, patient’s family and even close friends, as already discussed in gastrointestinal tract, and hematopoietic system. Clinical stage the literature [3, 4]. of the cancer was estimated based on the results of physical When elderly cancer patients refuse to take routine antican- exams, imaging tests (x-rays, CT, and/or MRI scans), and cer treatments such as surgical removal of the tumors and tumor biopsies. Twenty-five cases of our cohort later radio- or chemotherapy, what should be the goal of their treat- underwent autopsy. Tumor staging at diagnosis was based ment and management, and what, then, would be their surviv- on the TNM classification system [7]. Stage I was classified al time, compared with that obtained from the more traditional as an early cancer, whereas stages II and above were classified and vigorous anticancer therapy given to younger patient as advanced cancers. Various managements, cause of death, groups? These questions have gradually, but increasingly, be- and survival time (from diagnosis to death) were also re- come concerns of the medical fraternity. Some clinical practi- trieved. The effects of active supportive care on survival and tioners and medical experts, especially those who deal with the maintenance of organ function were evaluated. The study geriatric and/or oncologic patients, have started to believe that was approved by the institutional ethical committee of the having a good QOL, until the very end of the life, should be hospital, and its conduction was abided by the committee’s our primary ultimate goal [5, 6]. guidelines. Since this is a retrospective statistical analysis on In our oncology practice, we have now and then encoun- deceased patients’ clinical data without disclosing the pa- tered elderly patients with a cancer of the digestive system tients’ identity, signed consent from the patients was not avail- who have refused, or could not receive, routine anticancer able and was not required according to the institutional ethical therapy. In this study, we analyzed and summarized the clin- committee. ical data of these patients, including their primary diseases, organ impairments, and direct causes of death. These latter are intriguing because, while it is well-known that cancer kills Results mainly via its metastasis to and then destruction of distant organs, little statistical information is available on what actu- Survival time of the patients ally causes the death of cancer patients. Data on the treatments during the course and on the patients’ survival time are also The cancer types of the 57 cases included esophageal squa- presented, and the strengths and weaknesses of our manage- mous cell carcinoma, gastric adenocarcinoma, duodenal ade- ment strategies for these patients are summarized and nocarcinoma, periampullary carcinoma, pancreatic ductal ade- discussed. nocarcinoma, primary hepatocellular carcinoma, intrahepatic/ perihilar/distal cholangiocarcinoma, colon cancer, and rectal cancer. Of these 57 cases, 49 were at an advanced stage (12 at stage II, 12 at stage III, and 25 at stage IV), while the Materials and methods remaining eight (including five pancreatic ductal adenocarci- nomas, two hepatocellular carcinomas, and one duodenal ade- The study involved 57 elderly patients (49 males and 8 fe- nocarcinoma) cases were at an early stage. The median overall males), from 75 to 94 years of age (87.6 on average), with a survival time was 11 months, but advanced-stage patients sur- cancer in the digestive system who were admitted into the vived for a shorter period with their median overall survival Chinese PLA General Hospital in Beijing from January being 7.28 months. The survival time of the early-stage sub- 2007 to December 2015. Patients had not received any of group was longer than that of the advanced-stage subgroup, as the usual anticancer therapies, including surgery, chemother- the median overall survival of five patients with an early-stage apy, radiotherapy, and targeted medicine. The best available pancreatic cancer was 27 months, while the remaining nine supportive care and palliative care were provided to these patients with an advanced-stage pancreatic cancer survived patients to alleviate their symptoms, protect organ function, for only 5 months. Within the advanced-stage subgroup, duo- and prevent complications. There were several different rea- denal adenocarcinoma, primary hepatocellular carcinoma, and sons for not providing an anticancer treatment: (1) the tumors colon cancer patients tended to have a relatively longer surviv- were in an advanced stage and could not be surgically re- al, while pancreatic cancer and intrahepatic cholangiocarcino- moved, (2) there were comorbidities, (3) organ status ma patients survived for the shortest time. Because we only Support Care Cancer (2018) 26:2333–2339 2335 had one case each of esophageal squamous cell carcinoma, Treatments and managements periampullary carcinoma, and rectal cancer, these cases were excluded from the comparisons. Among the advanced-stage All patients received the best available supportive care and patients, two cases of pancreatic cancer and one case of hilar palliative care to alleviate the pain and improve QOL over their bile duct carcinoma showed the shortest survival time terminal stage of life, with the comprehensive therapies (2 months). The longest survival time was 36 months in a employed summarized in Table 1. Antibiotics were adminis- patient with an advanced cancer in the distal common bile duct. tered to all patients, as they all experienced infection in the In the early-stage group, a patient with a hepatocellular carci- lung, bile duct, and/or urinary tract. Twenty-one (36.8%) pa- noma (stage Ia) survived for 61 months, which was the longest tients experienced cancer-caused pain and were given analge- in our cohort, followed by a case of an early duodenal adeno- sics, and 77.2% of the patients were administered liver protec- carcinoma who lived for 53 months. The longest survival time tive drugs due to impaired hepatic function. Bile duct stenting of early pancreatic cancer in our cohort was 35 months. through endoscopic retrograde cholangiopancreatography (ERCP), or percutaneous transhepatic cholangial drainage Changes in organ function (PTCD), was performed on 15 pancreatic, bile duct, or duode- nal cancer patients with obstructive jaundice. The median over- During the course of their diseases, almost all patients expe- all survival from the jaundice-relieving operation to death was rienced a decline in function of one or more major organs, 160 days. Tracheal intubation was done in 27 patients, and the such as heart, lung, liver, kidney, hematopoietic system, and median overall survival from this procedure to death was a gastrointestinal tract as well as total body homeostasis. As mere 12 days. Enteral and/or parenteral nutrition was applied shown in Fig. 1, imbalance of homeostasis, including acid- to all 57 patients, of whom 77.2% had a nasogastric tube or and-base imbalance and electrolytic disturbance, was the most duodenal catheterization while 96.5% received central venous common morbidity and occurred in 56 patients. The only ex- catheterization or had a peripherally inserted central catheter ception was the patient with esophageal carcinoma, who died (PICC). Plasma albumin, pre-albumin, and hemoglobin were suddenly of massive hemorrhage from the tumor. It was our determined 3 to 5 days before death, and their levels were anticipation that this patient might have shown imbalanced 27.64 ± 3.99 g/L, 13.08 ± 3.72 mg/dL, and 83.7 ± 23.1 g/L, homeostasis as well, had he survived longer. The percentage respectively. of the patients with impairments of the lung, liver, or kidneys was 89.47, 77.19, or 66.67%, respectively, suggesting that Direct cause of the death these organs might be more easily affected. Common clinical symptoms included incontrollable lung infection and ensuing Although impairment of two or more organs occurred in all respiratory failure, as well as renal or hepatic injury and dys- patients enrolled, only 54.4% of the patients eventually died of function caused by tumor invasion, infection, or the drugs multiple-organ functional failure (MOSF). After active sup- administered. All patients in our cohort manifested impair- portive and palliative cares, some patients died of single organ ment or dysfunction of two or more organ systems, with the dysfunction, including lung failure after refractory lung infec- average number of malfunctioning organs per patient being tion, bile duct infection, liver failure, heart failure, and tumor 3.68. bleeding causing hemorrhagic shock with ensuing heart Fig. 1 Percentage of organs affected in elderly patients with digestive system cancer. GI gastrointestinal tract 2336 Support Care Cancer (2018) 26:2333–2339 Table 1 Summary of comprehensive therapies employed Types of lesions Number of cases with various management Total Antibiotics Analgesics Enteral nutrition Parenteral nutrition Liver Bile duct stent Tracheal tubes tubes protection or PTCD intubation Esophageal carcinoma 1 1 0 1 1 0 0 0 Gastric adenocarcinoma 12 12 3 10 12 8 1 6 Duodenal adenocarcinoma 5 5 0 4 4 5 3 4 Periampullary carcinoma 1 1 1 1 1 1 1 0 Pancreatic ductal adenocarcinoma 14 14 7 9 14 10 5 7 Primary hepatocellular carcinoma 7 7 4 6 7 6 0 3 Cholangiocarcinoma 7 7 4 4 7 7 5 2 Colon cancer 9 9 2 8 8 6 0 4 Rectal cancer 1 1 0 1 1 1 0 1 Total 57 57 21 44 55 44 15 27 failure (Fig. 2). Functional failure of an organ is determined, respectively, were well-controlled (Fig. 3). None of our pa- as elsewhere, based on not only the patient’sclinical symp- tients died of acid/base imbalance or electrolyte disturbance. toms but also data from laboratories and relevant instruments. Direct cause of the death is defined as the primary one, such as lung infection or tumor hemorrhage, which triggers severe Discussion functional impairment of the affected organ and probably also other organ(s), eventually leading to heart failure and ensuing The significance of palliative and supportive cares death of the patient. There were 51 (89.5%) cases of lung infection, 44 (77.2%) Aging is typically associated with a higher risk of comorbid- cases of liver functional injury, and 38 (66.7%) cases of kid- ity. Elders often manifest a decline in physical and cognitive ney impairment in our cohort. There were 17.6% (nine cases), functions, and their social supports are often reduced. It is 15.9% (nine cases), and 18.4% (seven cases) of the patients more common, compared with younger patients, that tumors whose lung infection, liver injury, and kidney impairment, in elders are already at an advanced stage or even already have distant metastases at the time of diagnosis, albeit tumors in elders usually grow and progress more slowly than in younger patients. Because of these factors, elderly cancer patients usu- ally show a poorer prognosis and a shorter survival time, com- pared with younger adult patients. It has been reported that elderly cancer patients are less likely to be treated with Fig. 3 Consequences of organ impairment, with number of patients recovered from their lung, liver, or kidney injury after treatment. MOSF Fig. 2 Direct causes of the death in elderly patients with a digestive multiple-organ functional failure system cancer Support Care Cancer (2018) 26:2333–2339 2337 surgery, chemotherapy, or radiation [8]. A recent population- [14]. This recommendation is based on several randomized based study from Italy revealed that only 58 of 1183 (5.8%) clinical trials of palliative care interventions during conven- elderly patients at ages of ≥ 80 years received chemotherapy, tional anticancer treatments of patients with a metastatic can- in contrast to an average of 34.3% of their junior counterparts cer. To date, it has become possible to drive some malignan- [9]. Due to the toxicity of chemotherapy or because of other cies into a manageable, chronic, situation via current treat- concerns such as infection or other comorbidities, a higher ments and managements, making it possible for some incur- percentage of elderly patients are hospitalized than their able patients to live with the cancer in relative peace and young counterparts. Chemotherapy recipients have a substan- comfort. And, perhaps most importantly, many patients and tially higher hospitalization rate for infection or fever, hema- families have Bdying with dignity^ as their main goal. tologic complications, dehydration, and pulmonary embolism Realizing this, fulfilling this goal should also be important to (PE) or deep vein thrombosis (DVT), compared with those the oncologist. The patients in our cohort were provided with who have not received chemotherapy [10]. Modern chemo- the best available supportive and palliative care regimens in- therapy and targeted therapy have improved the overall out- stead of purely medical anticancer therapies, and thus, their comes of patients for all ages. However, the results observed Bfrom early-to-terminal-stage^ course of cancer progression is in real clinical practice are often different from those reported relatively closer to the natural one compared with the one in clinical trials, especially in elderly patients, according to our shown in those patients receiving route anticancer treatments. own experiences. Albeit most cancer patients are at a senior The median overall survival of our group is similar to that of age, there are few specific treatment-based guidelines for el- routine anticancer therapy groups reported in the literature derly cancer patients. In our opinion, this may be due to the [15–20]. The newest SEER data (from 1988 to 2012) indicates limited number of such patients recruited in clinical trials. Of that the rates of 1-year survival in liver/intrahepatic bile duct course, there are some data to support that the general health cancer and pancreatic cancer patients over 75 years of age are situation of some elderly patients is good enough to tolerate 25.6 and 15.8%, respectively [1]. In our cohort, four out of modified therapies. In fact, individualized treatment for elder- five patients with an advanced liver cancer survived 12 months ly cancer patients requires concerns other than their age. When or longer, while two patients with an advanced pancreatic treating elderly cancer patients, oncologists are advised to cancer survived 12 months after diagnosis. Therefore, our make a comprehensive assessment, using such tools as a ge- data, although just from a relatively small number of patients, riatric assessment or predictive chemotherapy toxicity tools, imply that active supportive and palliative therapies alone can as the basis for making an optimal therapy regimen. The provide a relatively good QOL and survival times comparable International Society for Geriatric Oncology and the NCCN to a traditional, aggressively treated, group of senior patients guidelines both recommend performing a geriatric assessment with a lethal and advanced malignancy. in all elderly cancer patients [11, 12]. Factors such as func- In our opinion, the word Bmanage^ may be more proper tional status of major organs, social support, patient’sprefer- than Btreat^ to describe how we should approach therapy in ence, presence of comorbidities, and life expectancy should be our daily oncological practice. Nutritional support, mainte- taken into consideration when formulating an optimal treat- nance of internal homeostasis, management of various com- ment regimen. Therefore, for elderly cancer patients, it is im- plications (pain, infection, jaundice), protection of organ func- portant to weigh the risk of dying from cancer against the risk tions, and even psychological intervention are fundamental of dying from a possible comorbidity or from a treatment- elements of a comprehensive and systematic implementation caused complication. for cancer patients. All patients in our cohort had supplemen- A large percentage of patients with an advanced cancer tal enteral and/or parenteral nutrition support, resulting in a receive a long course of aggressive treatments, including che- relatively high level of serum pre-albumin. Proper levels of motherapy and/or radiotherapy, until the moribund period of albumin and hemoglobin are important for the maintenance of the patient’s life, despite the fact that this may actually reflect a whole-body physiological function and are significant factors poor quality of care. A survey was recently conducted on the in the patients’ survival [21]. Up to two-thirds of all elderly family members of elderly lung or colorectal cancer patients patients develop pain as a result of the cancer or as a conse- who eventually died. The results show that an earlier hospice quence of its treatment [22], but in this study, only 36.8% of enrollment, avoidance of ICU admission within 30 days of the patients accepted pain-relieving drugs when apparently death, and death at a non-hospital location are associated with needed. This phenomenon may be partly because some tu- a perception of a better end-of-life care [13]. In 2012, the mors may not cause as much pain as we think, or merely American Society of Clinical Oncology (ASCO) published a because some seniors are less likely to complain of pain provisional clinical opinion (PCO) advising its members that [23]. Obstructive jaundice in patients with pancreatic cancer, B… combined standard oncology care and palliative care cholangiocarcinoma, or hepatocarcinoma may predict an un- should be considered early in the course of illness for any favorable survival, and drainage of jaundice will help to im- patient with metastatic cancer and/or a high symptom burden^ prove liver function [24, 25]. The obstructive jaundice patients 2338 Support Care Cancer (2018) 26:2333–2339 in our cohort obviously benefited from positive jaundice- It is worth noting that cancer patients at terminal stages are reducing procedures such as PTCD or bile duct stenting, since usually bedridden, which easily causes infection in the lung or the median overall survival is significantly prolonged after the urinary system, as shown in our cohort in which nearly these treatments. Less than half of our patients accepted tra- 89.5% of the patients manifested lung infection with function- cheal intubation, with the median overall survival after the al impairment. Uncontrolled infection will certainly accelerate mechanical ventilation to death being merely 12 days, sug- the patient’s death, and therefore antibiotics, in most cases gesting that such invasive manipulation was not beneficial to routed via intravenous infusion, become inevitable for most the patients and thus, in our opinion, should not often be a patients. Fortunately, about 17.6% of the patients with lung primary choice. infection were finally well controlled. Therefore, foreseeing possible dysfunction of an organ and actively preventing its occurrence are fundamental in the management of elders with The first statistical information on the direct causes an advanced cancer. These management goals can improve of cancer-caused death patients’ QOL and prolong their survival time. The complex- ity of available treatments poses a challenge to oncologists in When asked Bhow does a cancer kill the patient?^,moston- discussing the choice of cancer treatment with their patients, cologists can only give such examples as Bliver cancer patients since chemotherapy, radiotherapy, or even targeted therapy are may die of tumor hemorrhage^ and Bsome lung cancer pa- not the only important factors that influence the patients’ sur- tients may die of infection^, but few, if any, oncologists can vival and QOL. Routine chemotherapy and radiotherapy are give good statistics about how each direct cause, such as in- likely to be associated with toxicity and are thus associated fection, heart failure, or renal failure, may account for the with a significantly increased risk of organ impairment [10]. percentage of deaths for any given cancer type. This is in part Some of these weaknesses could be avoided by prophylactic because different patients with the same type of cancer may interventions. In our humble opinion, (1) foreseeing and (2) die from different causes. Textbooks of medicine generally diminishing a possible organ dysfunction should be two key describe that patients with end-stage cancer die of MOSF, elements of cancer management. which is true in a broad sense, since the body cannot survive when one or more important organs have lost function. Patients who have or have not received anticancer treatments Conclusions may die from different reasons, because the treatments them- selves likely alter, and usually damage, the functions of major In summary, we provide data, for the first time, on the course organs, including the immune system. Our report is one of the of elderly patients with a cancer in the digestive system who few, if not the only, studies of this kind to provide a percentage receive the best supportive and palliative care but never re- of common causes of death for elderly patients with a cancer ceive an anticancer treatment. All the patients eventually died in the digestive system who have not received any direct an- of dysfunction of one or more organs, but only slightly over ticancer treatments but who have received the best supportive half of them died from MOSF owing to our good prediction and palliative cares. Oncology peers can make their own eval- and pre-intervention of the problem. Our elderly patients ob- uations on the value of such cares on the patients’ survival viously benefitted from prophylactic interventions of organ time with our data as a reference. dysfunction as well as from active nutritional support and Organ failure could be regarded as the direct cause of the anti-infection treatment. It is recommended that one should patient’s death. The following are the situations often encoun- pay more attention to organ protection as one of the most tered during our clinical practice: severe infection inducing fundamental elements of comprehensive cancer management septic shock, lung infection leading to respiratory failure, bile in elderly cancer patients. duct obstruction causing liver failure, hypercoagulation prompting a myocardial infarction, tumor rupture causing Acknowledgements We wouldliketothank Dr. FredBogott atthe massive hemorrhage and ensuing hemorrhagic shock, com- Austin Medical Center-Mayo Clinic in Austin, Minnesota, and Mr. plex hematologic complications, kidney failure due to various Lucas Zellmer at the Masonic Cancer Center, University of Minnesota, for their excellent English editing of the manuscript. reasons. Many patients could have an even more complex situation, because they have more than two organs involved Compliance with ethical standards and eventually develop MOSF. However, only 54.39% of the patients in our cohort died of MOSF, with the rest dying from Conflict of interest The authors declare that they have no conflict of single organ dysfunction or from a single complication such as interest. massive hemorrhage. In our cohort, 15.9% of the patients with liver impairment were well controlled, as were 18.4% of the Ethical approval This article does not contain any study with animals. patients with kidney impairment. All procedures performed in studies involving human participants were in Support Care Cancer (2018) 26:2333–2339 2339 accordance with the ethical standards of the institutional (Chinese PLA 12. Wedding U (2015) Report on the 14th conference of the General Hospital) and/or national research committee and with the 1964 International Society of Geriatric Oncology. Future Oncol 11(6): Helsinki declaration and its later amendments or comparable ethical 893–895. https://doi.org/10.2217/fon.15.4 standards. 13. 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Management and survival analysis of elderly patients with a cancer in the digestive system who refused to receive anticancer treatments

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Medicine & Public Health; Oncology; Nursing; Nursing Research; Pain Medicine; Rehabilitation Medicine
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Abstract

Treatment and management of cancers in elderly patients require some special considerations. A better understanding of how cancers progress in those elderly patients who have not received any anticancer treatments could better help us in treating these patients and in making end-of-life decisions. Over the past years, we had encountered 57 elderly patients, aged 75 to 94 years (87.6 on average), with a cancer in the digestive system, who refused to accept anticancer treatment but who did receive the best available supportive and palliative care. Clinicopathological data of these patients were analyzed. Of these 57 cases, 49 were at an advanced or late stage, while the remaining eight were at an early stage at the time of diagnosis. The median overall survival time of all the patients was 11 months, and almost the entire cohort manifested multiple-organ impairments. The average number of malfunctioning organs per patient was 3.68. After carefully predicting, and then preventing or managing complications, only 54.4% of the patients eventually died of multiple-organ functional failure. Nearly 18% of the single organ dysfunctions were finally well-controlled. Our data provide the first statistical information on the survival time and the direct cause of death of the elderly patients with a cancer in the digestive system not treated with chemotherapy or other direct anticancer interventions, but who did receive the best available supportive and palliative cares. During their struggle with cancer, elderly patients clearly could benefit from prophylactic interventions on organ dysfunction. . . . . . Keywords Geriatrics Survival time Cancer Chemotherapy Surgery Radiotherapy Introduction Since even those elderly without a malignancy usually have some decline in major organ function, their cancers, especially Most countries have shown a great increase in human life over the age of 80, generally present with comorbidities. This expectancy over the last several decades. Along with this, can cause oncologists to experience some difficult treatment however, is an aging-related increase in cancer incidence [1]. decisions, as complex conditions may affect not only the ther- apy efficacy but also its tolerability. On the other hand, it is believed that cancer in the elderly usually grows and pro- gresses more slowly than in younger cancer patients [2]. * Dezhong Joshua Liao Combining these situations, both beneficial and adverse, in djliao@gmc.edu.cn the elderly, it is typically more practical to restrain, rather than * Ningzhi Xu attempt to cure, the cancer, to extend the patient’s life and xuningzhi@cicams.ac.cn quality of life (QOL) while maintaining an adequate level of * Gangshi Wang dignity. The reality is that in our clinical practice, many elderly wanggangshi@hotmail.com cancer patients simply refuse further surgery or the often de- Department of Geriatric Gastroenterology, Chinese PLA General bilitating radio- or chemotherapy routinely given to younger Hospital, Beijing 100853, People’sRepublic of China patients. Many simply prefer care-directed treatments along Department of Pathology, Guizhou Medical University Hospital, with supportive symptom-management to maintain a relative- Guiyang 550004, Guizhou, People’s Republic of China ly good QOL. In other words, palliative care plus good sup- Laboratory of Cell and Molecular Biology & State Key Laboratory of portive care is often the patient’s choice. However, this clinical Molecular Oncology, National Cancer Center/Cancer Hospital, goal is still a tremendous challenge to oncologists worldwide Chinese Academy of Medical Sciences & Peking Union Medical with many unsolved questions. For example, oncologists are College, Beijing 100021, People’s Republic of China 2334 Support Care Cancer (2018) 26:2333–2339 required to address some important issues when making man- hampered the anticancer treatment, or (4) patients and/or their agement decisions for elderly cancer patients, including how families refused to accept any anticancer therapy. to slow down or even stop progression of the cancer, how to Medical records of the patients were retrieved and prolong survival time, how to improve the QOL as the patient reviewed. The clinicopathological data identified included approaches his final days, and how to let the patient die with age, gender, tumor location, pathological findings, tumor dignity. It would be ideal if the treatment decisions were made stage at diagnosis, as well as assessments of the internal ho- collectively by the physician and the patient, as well as the meostasis and of the functions of the heart, lung, liver, kidney, patient’s family and even close friends, as already discussed in gastrointestinal tract, and hematopoietic system. Clinical stage the literature [3, 4]. of the cancer was estimated based on the results of physical When elderly cancer patients refuse to take routine antican- exams, imaging tests (x-rays, CT, and/or MRI scans), and cer treatments such as surgical removal of the tumors and tumor biopsies. Twenty-five cases of our cohort later radio- or chemotherapy, what should be the goal of their treat- underwent autopsy. Tumor staging at diagnosis was based ment and management, and what, then, would be their surviv- on the TNM classification system [7]. Stage I was classified al time, compared with that obtained from the more traditional as an early cancer, whereas stages II and above were classified and vigorous anticancer therapy given to younger patient as advanced cancers. Various managements, cause of death, groups? These questions have gradually, but increasingly, be- and survival time (from diagnosis to death) were also re- come concerns of the medical fraternity. Some clinical practi- trieved. The effects of active supportive care on survival and tioners and medical experts, especially those who deal with the maintenance of organ function were evaluated. The study geriatric and/or oncologic patients, have started to believe that was approved by the institutional ethical committee of the having a good QOL, until the very end of the life, should be hospital, and its conduction was abided by the committee’s our primary ultimate goal [5, 6]. guidelines. Since this is a retrospective statistical analysis on In our oncology practice, we have now and then encoun- deceased patients’ clinical data without disclosing the pa- tered elderly patients with a cancer of the digestive system tients’ identity, signed consent from the patients was not avail- who have refused, or could not receive, routine anticancer able and was not required according to the institutional ethical therapy. In this study, we analyzed and summarized the clin- committee. ical data of these patients, including their primary diseases, organ impairments, and direct causes of death. These latter are intriguing because, while it is well-known that cancer kills Results mainly via its metastasis to and then destruction of distant organs, little statistical information is available on what actu- Survival time of the patients ally causes the death of cancer patients. Data on the treatments during the course and on the patients’ survival time are also The cancer types of the 57 cases included esophageal squa- presented, and the strengths and weaknesses of our manage- mous cell carcinoma, gastric adenocarcinoma, duodenal ade- ment strategies for these patients are summarized and nocarcinoma, periampullary carcinoma, pancreatic ductal ade- discussed. nocarcinoma, primary hepatocellular carcinoma, intrahepatic/ perihilar/distal cholangiocarcinoma, colon cancer, and rectal cancer. Of these 57 cases, 49 were at an advanced stage (12 at stage II, 12 at stage III, and 25 at stage IV), while the Materials and methods remaining eight (including five pancreatic ductal adenocarci- nomas, two hepatocellular carcinomas, and one duodenal ade- The study involved 57 elderly patients (49 males and 8 fe- nocarcinoma) cases were at an early stage. The median overall males), from 75 to 94 years of age (87.6 on average), with a survival time was 11 months, but advanced-stage patients sur- cancer in the digestive system who were admitted into the vived for a shorter period with their median overall survival Chinese PLA General Hospital in Beijing from January being 7.28 months. The survival time of the early-stage sub- 2007 to December 2015. Patients had not received any of group was longer than that of the advanced-stage subgroup, as the usual anticancer therapies, including surgery, chemother- the median overall survival of five patients with an early-stage apy, radiotherapy, and targeted medicine. The best available pancreatic cancer was 27 months, while the remaining nine supportive care and palliative care were provided to these patients with an advanced-stage pancreatic cancer survived patients to alleviate their symptoms, protect organ function, for only 5 months. Within the advanced-stage subgroup, duo- and prevent complications. There were several different rea- denal adenocarcinoma, primary hepatocellular carcinoma, and sons for not providing an anticancer treatment: (1) the tumors colon cancer patients tended to have a relatively longer surviv- were in an advanced stage and could not be surgically re- al, while pancreatic cancer and intrahepatic cholangiocarcino- moved, (2) there were comorbidities, (3) organ status ma patients survived for the shortest time. Because we only Support Care Cancer (2018) 26:2333–2339 2335 had one case each of esophageal squamous cell carcinoma, Treatments and managements periampullary carcinoma, and rectal cancer, these cases were excluded from the comparisons. Among the advanced-stage All patients received the best available supportive care and patients, two cases of pancreatic cancer and one case of hilar palliative care to alleviate the pain and improve QOL over their bile duct carcinoma showed the shortest survival time terminal stage of life, with the comprehensive therapies (2 months). The longest survival time was 36 months in a employed summarized in Table 1. Antibiotics were adminis- patient with an advanced cancer in the distal common bile duct. tered to all patients, as they all experienced infection in the In the early-stage group, a patient with a hepatocellular carci- lung, bile duct, and/or urinary tract. Twenty-one (36.8%) pa- noma (stage Ia) survived for 61 months, which was the longest tients experienced cancer-caused pain and were given analge- in our cohort, followed by a case of an early duodenal adeno- sics, and 77.2% of the patients were administered liver protec- carcinoma who lived for 53 months. The longest survival time tive drugs due to impaired hepatic function. Bile duct stenting of early pancreatic cancer in our cohort was 35 months. through endoscopic retrograde cholangiopancreatography (ERCP), or percutaneous transhepatic cholangial drainage Changes in organ function (PTCD), was performed on 15 pancreatic, bile duct, or duode- nal cancer patients with obstructive jaundice. The median over- During the course of their diseases, almost all patients expe- all survival from the jaundice-relieving operation to death was rienced a decline in function of one or more major organs, 160 days. Tracheal intubation was done in 27 patients, and the such as heart, lung, liver, kidney, hematopoietic system, and median overall survival from this procedure to death was a gastrointestinal tract as well as total body homeostasis. As mere 12 days. Enteral and/or parenteral nutrition was applied shown in Fig. 1, imbalance of homeostasis, including acid- to all 57 patients, of whom 77.2% had a nasogastric tube or and-base imbalance and electrolytic disturbance, was the most duodenal catheterization while 96.5% received central venous common morbidity and occurred in 56 patients. The only ex- catheterization or had a peripherally inserted central catheter ception was the patient with esophageal carcinoma, who died (PICC). Plasma albumin, pre-albumin, and hemoglobin were suddenly of massive hemorrhage from the tumor. It was our determined 3 to 5 days before death, and their levels were anticipation that this patient might have shown imbalanced 27.64 ± 3.99 g/L, 13.08 ± 3.72 mg/dL, and 83.7 ± 23.1 g/L, homeostasis as well, had he survived longer. The percentage respectively. of the patients with impairments of the lung, liver, or kidneys was 89.47, 77.19, or 66.67%, respectively, suggesting that Direct cause of the death these organs might be more easily affected. Common clinical symptoms included incontrollable lung infection and ensuing Although impairment of two or more organs occurred in all respiratory failure, as well as renal or hepatic injury and dys- patients enrolled, only 54.4% of the patients eventually died of function caused by tumor invasion, infection, or the drugs multiple-organ functional failure (MOSF). After active sup- administered. All patients in our cohort manifested impair- portive and palliative cares, some patients died of single organ ment or dysfunction of two or more organ systems, with the dysfunction, including lung failure after refractory lung infec- average number of malfunctioning organs per patient being tion, bile duct infection, liver failure, heart failure, and tumor 3.68. bleeding causing hemorrhagic shock with ensuing heart Fig. 1 Percentage of organs affected in elderly patients with digestive system cancer. GI gastrointestinal tract 2336 Support Care Cancer (2018) 26:2333–2339 Table 1 Summary of comprehensive therapies employed Types of lesions Number of cases with various management Total Antibiotics Analgesics Enteral nutrition Parenteral nutrition Liver Bile duct stent Tracheal tubes tubes protection or PTCD intubation Esophageal carcinoma 1 1 0 1 1 0 0 0 Gastric adenocarcinoma 12 12 3 10 12 8 1 6 Duodenal adenocarcinoma 5 5 0 4 4 5 3 4 Periampullary carcinoma 1 1 1 1 1 1 1 0 Pancreatic ductal adenocarcinoma 14 14 7 9 14 10 5 7 Primary hepatocellular carcinoma 7 7 4 6 7 6 0 3 Cholangiocarcinoma 7 7 4 4 7 7 5 2 Colon cancer 9 9 2 8 8 6 0 4 Rectal cancer 1 1 0 1 1 1 0 1 Total 57 57 21 44 55 44 15 27 failure (Fig. 2). Functional failure of an organ is determined, respectively, were well-controlled (Fig. 3). None of our pa- as elsewhere, based on not only the patient’sclinical symp- tients died of acid/base imbalance or electrolyte disturbance. toms but also data from laboratories and relevant instruments. Direct cause of the death is defined as the primary one, such as lung infection or tumor hemorrhage, which triggers severe Discussion functional impairment of the affected organ and probably also other organ(s), eventually leading to heart failure and ensuing The significance of palliative and supportive cares death of the patient. There were 51 (89.5%) cases of lung infection, 44 (77.2%) Aging is typically associated with a higher risk of comorbid- cases of liver functional injury, and 38 (66.7%) cases of kid- ity. Elders often manifest a decline in physical and cognitive ney impairment in our cohort. There were 17.6% (nine cases), functions, and their social supports are often reduced. It is 15.9% (nine cases), and 18.4% (seven cases) of the patients more common, compared with younger patients, that tumors whose lung infection, liver injury, and kidney impairment, in elders are already at an advanced stage or even already have distant metastases at the time of diagnosis, albeit tumors in elders usually grow and progress more slowly than in younger patients. Because of these factors, elderly cancer patients usu- ally show a poorer prognosis and a shorter survival time, com- pared with younger adult patients. It has been reported that elderly cancer patients are less likely to be treated with Fig. 3 Consequences of organ impairment, with number of patients recovered from their lung, liver, or kidney injury after treatment. MOSF Fig. 2 Direct causes of the death in elderly patients with a digestive multiple-organ functional failure system cancer Support Care Cancer (2018) 26:2333–2339 2337 surgery, chemotherapy, or radiation [8]. A recent population- [14]. This recommendation is based on several randomized based study from Italy revealed that only 58 of 1183 (5.8%) clinical trials of palliative care interventions during conven- elderly patients at ages of ≥ 80 years received chemotherapy, tional anticancer treatments of patients with a metastatic can- in contrast to an average of 34.3% of their junior counterparts cer. To date, it has become possible to drive some malignan- [9]. Due to the toxicity of chemotherapy or because of other cies into a manageable, chronic, situation via current treat- concerns such as infection or other comorbidities, a higher ments and managements, making it possible for some incur- percentage of elderly patients are hospitalized than their able patients to live with the cancer in relative peace and young counterparts. Chemotherapy recipients have a substan- comfort. And, perhaps most importantly, many patients and tially higher hospitalization rate for infection or fever, hema- families have Bdying with dignity^ as their main goal. tologic complications, dehydration, and pulmonary embolism Realizing this, fulfilling this goal should also be important to (PE) or deep vein thrombosis (DVT), compared with those the oncologist. The patients in our cohort were provided with who have not received chemotherapy [10]. Modern chemo- the best available supportive and palliative care regimens in- therapy and targeted therapy have improved the overall out- stead of purely medical anticancer therapies, and thus, their comes of patients for all ages. However, the results observed Bfrom early-to-terminal-stage^ course of cancer progression is in real clinical practice are often different from those reported relatively closer to the natural one compared with the one in clinical trials, especially in elderly patients, according to our shown in those patients receiving route anticancer treatments. own experiences. Albeit most cancer patients are at a senior The median overall survival of our group is similar to that of age, there are few specific treatment-based guidelines for el- routine anticancer therapy groups reported in the literature derly cancer patients. In our opinion, this may be due to the [15–20]. The newest SEER data (from 1988 to 2012) indicates limited number of such patients recruited in clinical trials. Of that the rates of 1-year survival in liver/intrahepatic bile duct course, there are some data to support that the general health cancer and pancreatic cancer patients over 75 years of age are situation of some elderly patients is good enough to tolerate 25.6 and 15.8%, respectively [1]. In our cohort, four out of modified therapies. In fact, individualized treatment for elder- five patients with an advanced liver cancer survived 12 months ly cancer patients requires concerns other than their age. When or longer, while two patients with an advanced pancreatic treating elderly cancer patients, oncologists are advised to cancer survived 12 months after diagnosis. Therefore, our make a comprehensive assessment, using such tools as a ge- data, although just from a relatively small number of patients, riatric assessment or predictive chemotherapy toxicity tools, imply that active supportive and palliative therapies alone can as the basis for making an optimal therapy regimen. The provide a relatively good QOL and survival times comparable International Society for Geriatric Oncology and the NCCN to a traditional, aggressively treated, group of senior patients guidelines both recommend performing a geriatric assessment with a lethal and advanced malignancy. in all elderly cancer patients [11, 12]. Factors such as func- In our opinion, the word Bmanage^ may be more proper tional status of major organs, social support, patient’sprefer- than Btreat^ to describe how we should approach therapy in ence, presence of comorbidities, and life expectancy should be our daily oncological practice. Nutritional support, mainte- taken into consideration when formulating an optimal treat- nance of internal homeostasis, management of various com- ment regimen. Therefore, for elderly cancer patients, it is im- plications (pain, infection, jaundice), protection of organ func- portant to weigh the risk of dying from cancer against the risk tions, and even psychological intervention are fundamental of dying from a possible comorbidity or from a treatment- elements of a comprehensive and systematic implementation caused complication. for cancer patients. All patients in our cohort had supplemen- A large percentage of patients with an advanced cancer tal enteral and/or parenteral nutrition support, resulting in a receive a long course of aggressive treatments, including che- relatively high level of serum pre-albumin. Proper levels of motherapy and/or radiotherapy, until the moribund period of albumin and hemoglobin are important for the maintenance of the patient’s life, despite the fact that this may actually reflect a whole-body physiological function and are significant factors poor quality of care. A survey was recently conducted on the in the patients’ survival [21]. Up to two-thirds of all elderly family members of elderly lung or colorectal cancer patients patients develop pain as a result of the cancer or as a conse- who eventually died. The results show that an earlier hospice quence of its treatment [22], but in this study, only 36.8% of enrollment, avoidance of ICU admission within 30 days of the patients accepted pain-relieving drugs when apparently death, and death at a non-hospital location are associated with needed. This phenomenon may be partly because some tu- a perception of a better end-of-life care [13]. In 2012, the mors may not cause as much pain as we think, or merely American Society of Clinical Oncology (ASCO) published a because some seniors are less likely to complain of pain provisional clinical opinion (PCO) advising its members that [23]. Obstructive jaundice in patients with pancreatic cancer, B… combined standard oncology care and palliative care cholangiocarcinoma, or hepatocarcinoma may predict an un- should be considered early in the course of illness for any favorable survival, and drainage of jaundice will help to im- patient with metastatic cancer and/or a high symptom burden^ prove liver function [24, 25]. The obstructive jaundice patients 2338 Support Care Cancer (2018) 26:2333–2339 in our cohort obviously benefited from positive jaundice- It is worth noting that cancer patients at terminal stages are reducing procedures such as PTCD or bile duct stenting, since usually bedridden, which easily causes infection in the lung or the median overall survival is significantly prolonged after the urinary system, as shown in our cohort in which nearly these treatments. Less than half of our patients accepted tra- 89.5% of the patients manifested lung infection with function- cheal intubation, with the median overall survival after the al impairment. Uncontrolled infection will certainly accelerate mechanical ventilation to death being merely 12 days, sug- the patient’s death, and therefore antibiotics, in most cases gesting that such invasive manipulation was not beneficial to routed via intravenous infusion, become inevitable for most the patients and thus, in our opinion, should not often be a patients. Fortunately, about 17.6% of the patients with lung primary choice. infection were finally well controlled. Therefore, foreseeing possible dysfunction of an organ and actively preventing its occurrence are fundamental in the management of elders with The first statistical information on the direct causes an advanced cancer. These management goals can improve of cancer-caused death patients’ QOL and prolong their survival time. The complex- ity of available treatments poses a challenge to oncologists in When asked Bhow does a cancer kill the patient?^,moston- discussing the choice of cancer treatment with their patients, cologists can only give such examples as Bliver cancer patients since chemotherapy, radiotherapy, or even targeted therapy are may die of tumor hemorrhage^ and Bsome lung cancer pa- not the only important factors that influence the patients’ sur- tients may die of infection^, but few, if any, oncologists can vival and QOL. Routine chemotherapy and radiotherapy are give good statistics about how each direct cause, such as in- likely to be associated with toxicity and are thus associated fection, heart failure, or renal failure, may account for the with a significantly increased risk of organ impairment [10]. percentage of deaths for any given cancer type. This is in part Some of these weaknesses could be avoided by prophylactic because different patients with the same type of cancer may interventions. In our humble opinion, (1) foreseeing and (2) die from different causes. Textbooks of medicine generally diminishing a possible organ dysfunction should be two key describe that patients with end-stage cancer die of MOSF, elements of cancer management. which is true in a broad sense, since the body cannot survive when one or more important organs have lost function. Patients who have or have not received anticancer treatments Conclusions may die from different reasons, because the treatments them- selves likely alter, and usually damage, the functions of major In summary, we provide data, for the first time, on the course organs, including the immune system. Our report is one of the of elderly patients with a cancer in the digestive system who few, if not the only, studies of this kind to provide a percentage receive the best supportive and palliative care but never re- of common causes of death for elderly patients with a cancer ceive an anticancer treatment. All the patients eventually died in the digestive system who have not received any direct an- of dysfunction of one or more organs, but only slightly over ticancer treatments but who have received the best supportive half of them died from MOSF owing to our good prediction and palliative cares. Oncology peers can make their own eval- and pre-intervention of the problem. Our elderly patients ob- uations on the value of such cares on the patients’ survival viously benefitted from prophylactic interventions of organ time with our data as a reference. dysfunction as well as from active nutritional support and Organ failure could be regarded as the direct cause of the anti-infection treatment. It is recommended that one should patient’s death. The following are the situations often encoun- pay more attention to organ protection as one of the most tered during our clinical practice: severe infection inducing fundamental elements of comprehensive cancer management septic shock, lung infection leading to respiratory failure, bile in elderly cancer patients. duct obstruction causing liver failure, hypercoagulation prompting a myocardial infarction, tumor rupture causing Acknowledgements We wouldliketothank Dr. FredBogott atthe massive hemorrhage and ensuing hemorrhagic shock, com- Austin Medical Center-Mayo Clinic in Austin, Minnesota, and Mr. plex hematologic complications, kidney failure due to various Lucas Zellmer at the Masonic Cancer Center, University of Minnesota, for their excellent English editing of the manuscript. reasons. Many patients could have an even more complex situation, because they have more than two organs involved Compliance with ethical standards and eventually develop MOSF. However, only 54.39% of the patients in our cohort died of MOSF, with the rest dying from Conflict of interest The authors declare that they have no conflict of single organ dysfunction or from a single complication such as interest. massive hemorrhage. In our cohort, 15.9% of the patients with liver impairment were well controlled, as were 18.4% of the Ethical approval This article does not contain any study with animals. patients with kidney impairment. All procedures performed in studies involving human participants were in Support Care Cancer (2018) 26:2333–2339 2339 accordance with the ethical standards of the institutional (Chinese PLA 12. Wedding U (2015) Report on the 14th conference of the General Hospital) and/or national research committee and with the 1964 International Society of Geriatric Oncology. Future Oncol 11(6): Helsinki declaration and its later amendments or comparable ethical 893–895. https://doi.org/10.2217/fon.15.4 standards. 13. 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Supportive Care in CancerSpringer Journals

Published: Feb 7, 2018

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