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    -  Küçüköner M
    -  Kaplan MA
    -  Urakçı Z
    -  Sezgin Y
    -  Karhan O
    -  Işıkdoğan A

 
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ORIGINAL ARTICLE
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Survival impact of optimal treatment for elderly patients with colorectal cancer: A real world study


 Department of Medical Oncology, Dicle University Medical Faculty, Diyarbakır, Turkey

Date of Submission07-May-2019
Date of Decision27-Jun-2020
Date of Acceptance05-Oct-2020
Date of Web Publication11-May-2021

Correspondence Address:
Nadiye Akdeniz,
Department of Medical Oncology, Dicle University Medical Faculty, Diyarbakır
Turkey
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_409_19

  Abstract 


Background: In this real-life practice study, we aimed to find whether elderly colorectal cancer (CRC) patients in our center were treated optimally and also if this has an effect on overall survival (OS) or not.
Methods: We have retrospectively screened 150 CRC patients older than 65 years, diagnosed in our institution between 2010 and 2018. As study variables, patient characteristics, tumor location, tumor, nodes, metastases stage, Eastern Cooperative Oncology Group performance status (ECOG PS), comorbidities, adjuvant or metastatic chemotherapy regimens, and treatment toxicity were recorded, and the OS rate of patients was assessed.
Results: The median age was 72 (range 65 - 89) years and 48 (32%) patients had metastatic disease at the time of diagnosis. The median OS (mOS) in the suboptimal adjuvant treatment group was 31.5 (range 20.7–42.3) months, whereas mOS was not reached during the median follow-up time in the optimal treatment group (P = 0.036). The addition of oxaliplatin to chemotherapy had no benefit on mOS (P = 0.318). In the metastatic setting, the mOS in the optimal and suboptimal treatment group was 27.2 (range 10.7-43.7) months and 13.4 (range 7.5-18.8) months respectively, and was statistically significant (P = 0.001).
Conclusion: Our study revealed that optimal treatment had a significant effect on the mOS of elderly CRC patients and it was well tolerated. Advanced age alone is not a sufficient parameter for precluding effective therapy in elderly patients with CRC.


Keywords: Colorectal cancer, elderly patient, optimal treatment



How to cite this URL:
Akdeniz N, Küçüköner M, Kaplan MA, Urakçı Z, Sezgin Y, Karhan O, Işıkdoğan A. Survival impact of optimal treatment for elderly patients with colorectal cancer: A real world study. Indian J Cancer [Epub ahead of print] [cited 2021 Jul 28]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=315806





  Introduction Top


Colorectal cancer (CRC) is the third most commonly diagnosed cancer both in men and women.[1] Most cancers occur in the elderly population. At the time of diagnosis, 60% of patients are older than 65 years, and also among these patients, 36% are 75 years or older.[2] In this context, although the majority of patients with CRC are 65 years or older, this population is often less recruited in clinical trials and very likely undertreated in the clinical practice because of insufficient treatment data.[3] Undertreatment includes less aggressive diagnostic evaluation, less surgical operation, and less optimal chemotherapy, such as dose reduction or frequency modification of regimens with established efficacy.[4] Therefore, these patients are also less likely treated by adjuvant or palliative chemotherapy and radiotherapy.[5]

Treatment of elderly patients with cancer often requires greater attention due to multiple factors that they generally have, like as poor Eastern Cooperative Oncology Group (ECOG) performance status (PS), comorbidities, drug metabolism alteration in the elderly patients and decline in organs function. More severe toxicities and hospitalizations are seen during treatment in this population.[6] All these factors often influence physician's decision negatively which might lead to administered suboptimal chemotherapy.

With this real-life practice analysis, we aimed to figure out whether elderly CRC patients in our center were treated optimally and also if this has an effect on overall survival (OS).


  Materials and Methods Top


In this study, we have retrospectively screened data of CRC patients older than 65 years diagnosed in our institution between 2010 and 2018. Patient characteristics, tumor location, tumor, nodes, metastases stage, ECOG-PS, comorbidities, adjuvant or metastatic chemotherapy regimens, treatment toxicity were analyzed and OS was calculated. The clinicopathological data were collected from each patients' medical records at the institution. Inclusion criteria were: patients who were histopathologically diagnosed with colorectal adenocarcinoma and were aged 65 years or older. Patients with malignancy other than CRC were excluded. Tumors were staged according to the American Joint Committee on Cancer (AJCC) seventh edition guidelines. AJCC stages I and II were accepted as localized disease, AJCC stage III as regional disease and AJCC stage IV was accepted as metastatic disease. Toxicity evaluations were performed using the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0.

Recommended adjuvant and metastatic chemotherapy regimens and doses were shown in [Table 1]. These recommended chemotherapy regimens were classified as optimal whereas regimens with dosage or frequency modification accepted as suboptimal.[7],[8] The principles of treating metastatic CRC (mCRC) in the fit elderly are similar to young patients; however, in the adjuvant setting capecitabine is accepted as the optimal adjuvant treatment for patients older than 70 years also.[7],[8]
Table 1: Recommended adjuvant and metastatic chemotherapy regimens

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This retrospective study was conducted in accordance with the principles of the 1964 Declaration of Helsinki, including the subsequent amendments. The study was approved by the local ethics committee (permit: 241/2018).

Statistical analysis

Descriptive statistics were presented as range for discontinuous variables and as absolute numbers and percent (%) for nominal variables. The OS was defined as the duration from the date of diagnosis to the date of the last control or death. Patient survival was estimated using the Kaplan-Meier method. The log-rank test was used to compare and analyze the survival data. A P value <0.05 was considered statistically significant. All statistical analyses were performed with SPSS 18.0 software.


  Results Top


Eighty-one (54%) patients were men, and the median age was 72 (range 65–89) years. Forty-eight (32%) of patients were metastatic at the time of diagnosis. Among 150 patients, 111 (74%) had left-sided primary tumor, and 63 (42%) had rectum located disease. Sixty (40%) patients had at least one of the comorbid diseases and 106 (70.6%) patients ECOG-PS was 0 or 1. Hypertension and coronary heart disease were the most common comorbidities, which were present in 40 (26.7%) and 27 (18%) of patients, respectively. The basic demographic characteristics of the patients are shown in [Table 2].
Table 2: Demographic characteristics of the patients

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One hundred fifteen (76.7%) patients underwent surgery for primary tumors, and 15 (10%) patients underwent surgery for palliative purposes. The radiotherapy was performed on 34 (22.6%) patients. The liver was the most common site of metastatic disease involvement, and the peritoneum was the second site; their involvements at the time of diagnosis were recognized in 28 and 25 patients, respectively. Liver metastasectomy was performed in just 2 (1.3%) patients. RAS mutation status was known in 31 (20.7%) patients and 18 (12%) of them had K-RAS mutation.

Among 102 patients with localized or locally advanced-stage disease, 66 (64.7%) received chemotherapy and 32 (48.4%) received standard optimal chemotherapy. Forty-five (68.2%) of 66 patients were treated oxaliplatin-based chemotherapy regimens. Recurrence developed in 28 (27.4%) of 102 patients. Metastatic disease was detected in 76 (50.6%) patients, which included 48 patients who were metastatic at the time of diagnosis and 28 patients developed during follow-up and only 54 (71%) received at least one series of chemotherapy. Twenty-one of those 54 patients received standard optimal chemotherapy. Chemotherapy regimens that applied to these patients included single-agent capecitabine, oxaliplatin, or irinotecan-based regimens. Twenty-two (38.6%) patients were treated with chemotherapy and biological agent combination, and 17 (31.5%) of them received bevacizumab as a biologic agent. In this study, 58 deaths were reported, 92 (61.3%) patients were alive.

Primary tumor site, gender, and comorbidities had no effect on OS (P = 0.303, P = 0.981, P = 0.163, respectively). As expected, median OS (mOS) of patients with PS 0 or 1 were better than patients whose PS were 2 or more (P < 0.001) [Figure 1]. The mOS of patients who were treated with the suboptimal adjuvant treatment was 31.5 (20.7–42.3) months, whereas mOS was unreached by the time of follow-up in the standard optimal treated patients (P = 0.036) [Figure 2]a. While the rates of OS at 5 years were 59% in the standard optimal treated group, it was 37% in the suboptimal group. Addition of oxaliplatin agent to chemotherapy showed no benefit on OS (P = 0.318) [Figure 2]b. In the metastatic setting, the mOS in the standard optimal treatment and suboptimal treatment group was 27.2 (10.7-43.7) months and 13.4 (7.5-18.8) months respectively, difference between groups was statistically significant (P = 0.001) [Figure 3].
Figure 1: Overall survival according to the Eastern Cooperative Oncology Group performance status

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Figure 2: (a) Overall survival according to the adjuvant chemotherapy regimens, (b) Overall survival according to the addition of oxaliplatin

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Figure 3: Overall survival according to the metastatic chemotherapy regimens

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In the patients who had adjuvant treatment, adverse events of any grade were reported in 34 (51.5%) of 66 patients, and grade 3 or more toxicity were reported in 6 (9%) patients. In the patients with metastatic stage, adverse events of any grade were reported in 31 (59.3%) of 54 patients, and grade 3 or more toxicity were reported in 5 (9.2%) patients [Table 3].
Table 3: Adverse events

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  Discussion Top


Elderly cancer patients are a heterogeneous group and just evaluation of patients in terms of their age is not a sufficient factor for treatment decisions.[9] In frail patients' chemotherapy may cause undesirable results so physicians are usually reluctant to treat this patient's group. However, patients are mostly diagnosed at an intermediate state who are neither fit nor frail. Therefore, personalization of treatment for elderly patients with cancer is suggested.[10],[11] Elderly cancer patients should be assessed by physiological age with comprehensive geriatric assessment, modification of chemotherapy doses and symptom-based management.[9]

Chemotherapy effectiveness in elderly patients is not well known because they are generally either excluded from clinical trials or their results are pooled with younger patients. The subgroup analyses of numerous clinical trials of elderly patients have reported that elderly patients benefit from adjuvant therapy as much as young patients.[12],[13] A large cohort study of elderly patients aged ≥67 years with stage III CRC reported a survival benefit of 5-fluorouracil (5-FU)-based adjuvant chemotherapy over surgery alone.[14] Additionally, in 2006, a cohort study as well showed adjuvant chemotherapy benefit in patients older than 65 years.[15] Even if reduced dose chemotherapy was given to elderly colon cancer patients with stage III disease, the survival advantages were reported in this patients group.[16] In our study, the mOS in the suboptimal treated adjuvant treatment group was 31.5 months (20.7–42.3) whereas mOS was not reached by the time of follow-up in the standard optimal treatment group (P = 0.036). While the rates of OS at 5 years were 59% in the standard optimal treatment group, it was 37% in the suboptimal treatment group. Our study revealed in the adjuvant setting, optimally treated patients had better OS even if they are elderly.

Although published data have revealed its benefit and recommended it, adjuvant chemotherapy usage dramatically decreases as the age of patients increases. For instance, in one study 88% of younger than 55 years received chemotherapy whereas only 48% of patients aged between 75 and 84 received chemotherapy.[17] In another study, adjuvant chemotherapy was 2-fold less frequently administered in elderly patients compared with younger patients (15% versus 29%; P < 0.0001).[18] Similar to previous studies in our study, 66 (64.7%) of 102 CRC patients received adjuvant chemotherapy in the localized or locally advanced stage.

The benefit of adding oxaliplatin to 5-FU/leucovorin (LV) in the adjuvant setting for elderly patients is inconclusive.[19],[20] In the study of Doat et al., more than half of 75 years or older patients received 5-FU monotherapy in the adjuvant setting, and oxaliplatin has been administered only 41% of patients.[18] In a recent retrospective analysis, in stage III colon cancer oxaliplatin-containing regimens had only marginally survival benefit over non-oxaliplatin regimens for patients 75 years or older.[19] Adjuvant trials pooled analysis showed oxaliplatin had no significant benefit in terms of disease-free survival or OS compared to 5-FU/LV in patients older than 70 years.[20] Similarly, in our study 45 (68.2%) of 66 patients received oxaliplatin-based adjuvant chemotherapy regimens and the addition of oxaliplatin had no OS benefit (P = 0.318).

In patients with metastatic disease, OS has increased for the last 20 years.[21] The OS of elderly patients has improved as well, however, this improvement has not been as much as younger patients.[22] Similar to the adjuvant setting in disease management in metastatic, the rate of elderly patients who received chemotherapy has been less than expected. The study of Doat et al. showed that 85% of patients under 75 years were treated whereas just 48% of patients aged 75 years or older received chemotherapy (P < 0.0001). The mOS was 8.4 months for elderly patients with metastatic CRC, while the mOS among the elderly patients receiving chemotherapy was 17.1 months.[18] In another study 78% of elderly mCRC patients received chemotherapy and the mOS of these patients was 20 months however non-treated patients' mOS was 5 months.[23]

In our study in the metastatic setting, only 54 (71%) of 76 elderly patients received at least one series of chemotherapy. Among 54 patients, just 21 (38.8%) of them received standard optimal chemotherapy. In the metastatic setting, mOS in the standard optimal treatment group was 27.2 months (10.7–43.7) and in the suboptimal group, it was 13.4 months (7.5–18.8) with statistical significance (P = 0.001). In comparison to previous studies, our study revealed if elderly mCRC patients treated optimally they would have a better OS.

A recent cohort study found comorbid conditions like heart failure, diabetes, and chronic pulmonary obstructive disease had not increased toxicity-related hospitalization.[24] Furthermore, Grande et al. showed no correlation between comorbidities and OS, but patients whose PS were 2 had worse OS than 0 or 1.[23] In our study, comorbidities also had no effect on patients' survival, and the mOS of patients with PS 0 or 1 was better than patients whose PS were 2 or more (P = 0.163, P < 0.001, respectively).

Toxicity of 5-FU-based chemotherapy in elderly patients with CRC is uncertain; in some studies increased rates of stomatitis, nausea, vomiting, leukopenia, or hospitalization have been observed, whereas in others no excess toxicity has been seen.[25],[26],[27],[28],[29],[30],[31] In this study, grade 3 or more toxicity was reported in 6 (9%) patients who had adjuvant treatment. In patients with metastatic disease, grade 3 or more toxicity due to treatment was reported in 5 (9.2%) patients and there were no life-threatening toxicities that occurred during treatment.

The retrospective design, small number of patients, and lack of BRAF mutation status are limitations of our study. However, to our best knowledge, prospective randomized trials that include only elderly CRC patients are not designed and therefore we believe that our study findings would beneficial for guiding the treatment of these patients.


  Conclusions Top


In conclusion, the results of the present study show that in clinical practice, standard optimal treatment had a positive effect on OS in elderly CRC patients and it was quite well tolerated. Elderly patients with CRC should be treated with standard optimal chemotherapy regimens after whose aforementioned factors are taken into account. Advanced age alone is not a sufficient parameter for precluding effective therapy in elderly patients with CRC. For clarifying this issue, larger and prospective studies are needed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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