|Ahead of print publication
A retrospective evaluation of geriatric patients with gastric cancer receiving systemic chemotherapy
Ali Murat Tatli1, Zuhat Urakci2, Didem Tastekin3, Dogan Koca4, Sema Sezgin Goksu1, Ummugul Uyeturk5, Mehmet Ali Kaplan2, Hasan Senol Coskun1
1 Department of Medical Oncology, Akdeniz University, Antalya, Turkey
2 Department of Medical Oncology, Dicle University, Diyarbakir, Turkey
3 Department of Medical Oncology, Istanbul University, Istanbul, Turkey
4 Department of Medical Oncology, Bahcesehir University VM Medicalpark Hospital, Kocaeli, Turkey
5 Department of Medical Oncology, Bolu Abant Izzet Baysal University, Bolu, Turkey
Ali Murat Tatli,
Department of Medical Oncology, Akdeniz University, Antalya
Source of Support: None, Conflict of Interest: None
Background: The most common age at which gastric cancer is diagnosed is 70 years, and the majority of patients diagnosed are at the metastatic stage. However, although gastric cancer is a geriatric disease, there is no suggestion to discriminate treatment for the general geriatric patient population. Here, we evaluated patients receiving palliative chemotherapy for gastric cancer owing to advanced age.
Patients and Methods: Multicenter data of geriatric patients receiving palliative chemotherapy because of metastatic gastric cancer were retrospectively reviewed.
Results: In total, 262 geriatric patients with gastric cancer were included in the study. Of these, 167 patients, including 134 (51.8%) patients with metastasis at diagnosis and 33 patients with relapse after surgery, were evaluated for palliative therapy. Chemotherapy was started in 87 (52.1%) of 167 patients. The overall median survival of the patients receiving chemotherapy was 9.3 months. There was no difference in overall survival (OS) between patients aged >70 and <70 years. However, a significant difference was detected in OS of patients depending on their Eastern Cooperative Oncology Group (ECOG) performance status (PS) before treatment; survival was 15 months in the group with PS 0–1 and 7 months in the group with PS ≥2.
Conclusion: Advanced age chemotherapy receiving rates in patients with metastatic gastric cancer is decreasing. Survival is not associated with age, but pretreatment ECOG PS is important. Therefore, ECOG PS and comorbidities should be evaluated in detail, and combination therapies could contribute to patient survival.
Keywords: Geriatric patients, metastatic gastric cancer, systemic chemotherapy
|How to cite this URL:|
Tatli AM, Urakci Z, Tastekin D, Koca D, Goksu SS, Uyeturk U, Kaplan MA, Coskun HS. A retrospective evaluation of geriatric patients with gastric cancer receiving systemic chemotherapy. J Can Res Ther [Epub ahead of print] [cited 2020 Mar 31]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264702
| > Introduction|| |
Death rates due to gastric cancer rank the fourth among all cancer-related deaths. Approximately 961,000 individuals are diagnosed with gastric cancer every year. Moreover, the incidence of gastric cancer increases by age. According to the Surveillance, Epidemiology, and End Results database (http://seer. cancer.gov/csr/1975_2011), 60% of patients with gastric cancer are aged >65 years and one-third of these elderly patients are aged >75 years. Due to a rapid global increase in the elderly population, an increase in the population of elderly patients with gastric cancer is expected in the future. Therefore, it is becoming more important to find a way to better treat elderly patients with gastric cancer. The majority of elderly patients with gastric cancer are diagnosed at an inoperable or metastatic stage. The positive contribution of systemic chemotherapy on overall survival (OS) and quality of life in comparison to supportive therapy ,, is well known. The effectiveness and tolerability of systemic chemotherapy in geriatric patients with gastric cancer were shown both in adjuvant therapy and diffuse-stage disease treatment in recent studies.,,,,, Nevertheless, most oncologists refrain from implementing treatment for geriatric patients. Analyses of the current studies which were specifically conducted on these patients revealed that age was not considered as a prognostic indicator., Moreover, the meta-analysis of some studies indicated that elderly patients benefited as well from systemic treatment as younger patients.,,,, However, there are insufficient data on which combination therapies may be used for geriatric patients and what doses would be more effective and tolerable.
In our study, our goal was to identify prognostic factors by assessing clinicopathological characteristics and treatment-receiving rates as well as treatment options for geriatric patients with metastatic gastric cancer. We aimed to improve the selection of optimal treatment methods and patients among geriatric patients with metastatic gastric cancer.
| > Patients and Methods|| |
Multicenter (five centers) data of geriatric patients diagnosed with gastric cancer who received palliative chemotherapy and follow-up due to metastatic gastric cancer, including age, performance state, chemotherapy initiation rates, chemotherapy regimens, dependent toxicity, and survival between January 2011 and December 2016, were reviewed retrospectively. A total of 262 geriatric patients (aged ≥65 years) with histologically confirmed advanced or recurrent adenocarcinoma of the stomach or gastroesophageal junction were enrolled in this study. Among these, 167 patients were evaluated for palliative chemotherapy, and the results of 87 patients who received chemotherapy were reviewed retrospectively.
Statistical analyses were performed using SPSS (version 18.0; SPSS Inc., Chicago, IL, USA). Gender, surgical treatments, Eastern Cooperative Oncology Group (ECOG) performance status (PS), and age were compared by Pearson's Chi-square test. Descriptive analyses were used for demographic data and the Kaplan–Meier test for survival analysis. OS was estimated using the Kaplan–Meier method, and the log-rank test was used for comparison of the study groups for survival.
Multivariate logistic regression was used to assess the factors associated with the administration of chemotherapy. The prognostic factors for OS were evaluated using the Cox proportional hazards regression. For all analyses, P = <0.05 was considered to indicate a statistically significant difference.
| > Results|| |
A total of 262 geriatric patients with gastric cancer, comprising 179 men (68.3%) and 83 women (31.7%), were examined. Of these, 167 patients were examined for palliative treatment, including 134 (51.8%) patients with metastasis at the time of the diagnosis and 33 patients with postoperative relapse [Table 1]. Chemotherapy was started for 87 (52.1%) of these 167 patients; any of 80 patients weren't received chemotherapy for palliative purposes. Single-agent fluoropyrimidine-based treatment was implemented on 17 (19.5%) patients, whereas 70 (80.5%) patients received combination chemotherapy; 63 (72%) of these patients were treated with cisplatin-based regimens. The most common combination regimen was cisplatin-based chemotherapy although the age group was geriatric. In all, 30 (34.5%) of the patients receiving chemotherapy were aged between 65 and 70 years and 57 (65.5%) patients were aged >70 years; 6 patients who were 80 or above received palliative chemotherapy. Among the chemotherapy patients, 33 had an ECOG PS between 0 and 1, whereas 54 patients had an ECOG PS of 2 and above [Table 2].
|Table 1: Demographic characteristics of geriatric gastric cancer patients|
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Treatment and outcomes
The median OS of patients who received chemotherapy was 9.3 months (95% confidence interval [CI]: 6.7–11.8). The evaluation of treatment responses revealed 22 (25%) patients with partial response, 2 (2.3%) patients with complete response, 17 (19.3%) patients with stable condition, and 28 (31.8%) patients with progression; 19 (21.6%) patients were not evaluated. The total response rate was observed as 46.6% (41 patients). There was no difference in OS between patients above and below 70 years of age. However, there was a significant difference in the OS of the patients with a PS of 1 and patients with a PS of 2 and above; analyses showed a survival of 15 months in the PS 0–1 group (95% CI: 12.6–19.1) and 7 months in the PS 2 group (95% CI: 4.9–9.1; P = 0.001) [Figure 1] and [Figure 2]. Furthermore, there was no difference in univariate and multivariate analyses in terms of age, gender, and chemotherapy combination.
|Figure 1: Overall survival of geriatric advanced gastric cancer patients with chemotherapy|
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|Figure 2: Overall survival analysis in geriatric gastric cancer patients according to the performance status|
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There was no difference in survival between geriatric patients who had primary tumor surgery (7.1 months; 95% CI: 5.3–8.9) at the time of diagnosis and those who did not undergo any surgical procedure (10.2 months; 95% CI: 5.6–14.7; P = 0.311). Furthermore, the combination regimens with cisplatin, which were implemented for majority of the patients, were not superior in terms of survival, with patients having a survival period of 10 months (95% CI: 5.7–14.2) in the cisplatin group versus a survival period of 5 months (95% CI: 2.9–7) in the cisplatin-free group (P = 0.084). Age did not have any prognostic significance in geriatric patients with gastric cancer regardless of whether they were grouped as <70 years, ≥75 years, or <75 years. When patients were grouped as ≥70 versus <70 years, there was no significant statistical difference in survival (9.2 months; 95% CI: 5.6–12.9 vs. 8.1 months; 95% CI: 4.2–12; P = 0.409). In addition, in the analyses for ≥75 versus <75 years, no significant statistical difference in survival was observed (10.2 months; 95% CI: 5.7–14.7 vs. 7.3 months; 95% CI: 4.7–9.9; P = 0.193). The performance state was the most important prognostic indicator for the survival of geriatric patients with metastatic gastric cancer in both univariate and multivariate analyses (15 vs. 7 months; P = 0.001) [Table 3].
|Table 3: Prognostic factors in geriatric patients with advanced gastric cancer using the Cox proportional hazards model|
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The most common toxicities observed due to chemotherapy were anemia and neutropenia. More than half of the patients experienced anemia during follow-up. Multiple blood transfusions were needed in 20 (23%) patients who presented Grade 3–4 toxicity. Among 23 (26.4%) patients with Grade 3–4 neutropenia, which was classified as a hematological toxicity, 4 patients were hospitalized because of febrile neutropenia and received treatment. In all, 3 patients received treatment because of pneumonia and 1 patient was treated due to a urinary system infection. The rarest hematological toxicity was thrombocytopenia, which occurred in 7 (8%) patients. The most challenging toxicity cases among the nonhematological toxicities were nausea and vomiting. Grade 3–4 nausea and vomiting rates were 20.7% (18) and 13.8% (12), respectively. Another nonhematological toxicity, mucositis, was observed as Grade 3–4 in 2 (2.3%) patients [Table 4].
| > Discussion|| |
Although positive responses to chemotherapy were obtained for metastatic disease, none of the patients had longer survival rates. The recent increase in the geriatric population and peak incidence levels of gastric cancer in this age group are important aspects to consider for the treatment approach for this patient group. Gastric cancer is ranked the first among all gastrointestinal cancers in Japan, Mexico, and other Latin America countries, in particular, and the peak incidence is comprised the seventh decade. The majority of patients with metastatic gastric cancer are geriatric. However, there is no standardized treatment approach for patients of this age group. The current literature mainly consists of retrospective studies, which are limited and have conflicting outcomes, as well as a few small-scope Phase 2 studies.
In the present study, we evaluated some characteristics of 87 geriatric patients who had palliative chemotherapy, such as age, gender, primary tumor, surgery, chemotherapy procedures, and PS, and we tried to make improvements in the treatment of these patients through a comparison with the literature.
There is no prospective, randomized, Phase 3 study comparing geriatric patients with advanced stage gastric cancer and younger patients with gastric cancer. There were two pooled analyses as wide-scope studies with an indirect approach., Trumper et al. compared patients <70 and >70 years in a pooled analysis of three clinical studies. In the aforementioned study, 1080 patients were evaluated and the number of patients aged >70 years was 257 (23.8%). There was no statistically significant difference between the two geriatric age groups in terms of overall response rate (ORR) and OS. In another pooled analysis study conducted by Jatoi et al. 4 years later, 367 patients were evaluated in a pooled analysis of 8 studies. Patients aged ≤65 and >65 years were compared. Of the 367 patients, 154 (41.9%) were aged >65 years. Although severe side effects were detected in the group of patients aged ≤65 years (73% vs. 66%, P = 0.02), survival (OS and progression-free survival) results were observed to be comparable in both the groups.
Although chemotherapy effects in geriatric advanced stage patients were equal to those in younger patients, due to the higher comorbidity ratios and age-dependent changes in the pharmacokinetic and pharmacodynamic drug interactions, we observed a reduced ratio of treatments in this group of patients in many oncology clinics. We observed that chemotherapy was started in 87 (52.1%) of 167 patients who were assessed for palliative chemotherapy; almost half of the patients did not receive any treatment. Therefore, the treatment of the patients in this age group should be supported with more study results.
One of the most important issues is deciding on a combination treatment for patients with gastric cancer. The first study that evaluated the effectiveness and tolerability of palliative chemotherapy was a pooled study on 1080 patients who were treated between 1992 and 2001. In the aforementioned study, patients were divided into two groups, below and above 70 years of age, and the patients who received cisplatin combination (epirubicin and cisplatin plus protracted venous infusion of 5-fluorouracil [PVI 5-FU]; ECF or mitomycin C [MMC], cisplatin, and PVI 5-FU; MCF) and those who did not receive combination therapy (PVI 5-FU alone or in combination with MMC or methotrexate and 5-FU followed by doxorubicin [FAMXT]) were compared. The survival of the groups receiving cisplatin combination was better in both age groups. In the patients receiving oxaliplatin treatment (ECF or MCF) in both age groups (<70 vs. >70 years), the OS was 8.8 versus 7.9 months; in the PVI 5-FU ± MMC group, OS was 5.2 versus 6.6 months; and in the FAMXT group, OS was 6.1 versus 5.0 months. Similarly, we detected that the patients who received cisplatin combination treatment had better OS than those not treated with cisplatin. The survival period of the group treated with cisplatin combination was 10 months (95% CI: 5.7–14.2), whereas that of the group not treated with cisplatin was 5 months (95% CI: 2.9–7; P = 0.084). Although this was not statistically significant, we see a trend favoring the association between cisplatin combination treatment and longer survival.
Furthermore, one of the most important findings of Trumper et al. was that the effectiveness of palliative chemotherapy was similar in both geriatric patients aged <70 years and ≥70 years. When the survival periods of the patients aged <70 years were compared to those aged ≥70 years (9.2 months; 95% CI: 5.6–12.9 vs. 8.1 months; 95% CI: 4.2–12; P = 0.409), no difference was detected; similar results were obtained in the present study.
Oxaliplatin, a third-generation platinum analog, is active against gastric cancer and has a favorable toxicity profile as compared to cisplatin. There are many Phase 2,,,,,, and retrospective studies,, in which oxaliplatin was combined with 5-FU or capecitabine. The results of the present study showed that oxaliplatin-based combination therapies were effective in this age group (ORR of 34.9%–52.5% and median OS of 9.0–10.5 months).
In a Phase 3 study performed by Al-Batran et al., there was no statistically significant difference in median OS when 5-FU/leucovorin and oxaliplatin (FLO) and 5-FU/leucovorin and cisplatin (FLP) regimens were compared. However, a statistically significant difference was detected between FLO and FLP regimens in the analysis of subgroups in terms of ORR (41.3% vs. 16.7%) and OS (13.9 vs. 7.2 months) in patients above 65 years of age. Despite these results, there was no exact conclusion for an optimal treatment approach and combination for geriatric patients with gastric cancer. However, based on our study and the literature, age was not significant in itself in geriatric patients with cancer, and the patients in this age group benefited from systemic treatment similar to younger patients. It should be considered that patients with a good PS would be the best prognostic group that could benefit from such treatments. In the present study, the most important difference for the analysis of all subgroups was observed to be PS. The group with patients of PS of 2 and above (survival of 7 months; 95% CI: 4.9–9.1) was the group with the highest statistically significant difference when compared to the groups with patients of PS of 0–1 (survival of 15 months; 95% CI: 12.6–19.1; P = 0.001). The retrospective design of the present study was one of its important disadvantages. The number of patients who received chemotherapy was 87, whereas the majority of these patients were those who received cisplatin-based combined treatment. We need prospective, randomized studies where preplanned subgroups and chemotherapy protocols are compared to obtain precise results on this subject.
| > Conclusion|| |
The current information for the patients of this age group includes Phase 3, prospective, randomized study subgroup analysis, small-scale Phase 2 studies, and retrospective data. The information from the literature for treatment approaches for patients with gastric cancer appears to be insufficient. However, in line with the outcomes of the present study and especially of the two pooled analyses as well as all other studies, we can conclude that elderly patients with good PS benefitted from palliative chemotherapy like younger patients. Therefore, elderly patients with gastric cancer should be assessed for combination therapies if the performance state of these patients is adequate for systemic treatment, disregarding the age limitations of these patients. Platinum/fluoropyrimidine combination treatment may be preferred. It should be considered that oxaliplatin combination would be less toxic than cisplatin combinations. Consequently, geriatric patients with a good PS and sufficient organ function should be assessed for systemic therapies like younger patients. However, a guideline should be created for the optimal treatment approach for patients of this age group through further studies.
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Conflicts of interest
There are no conflicts of interest.
| > References|| |
Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al.
Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 2015;136:E359-86.
Jung KW, Won YJ, Kong HJ, Oh CM, Lee DH, Lee JS. Prediction of cancer incidence and mortality in Korea, 2014. Cancer Res Treat 2014;46:124-30.
Pyrhönen S, Kuitunen T, Nyandoto P, Kouri M. Randomised comparison of fluorouracil, epidoxorubicin and methotrexate (FEMTX) plus supportive care with supportive care alone in patients with non-resectable gastric cancer. Br J Cancer 1995;71:587-91.
Murad AM, Santiago FF, Petroianu A, Rocha PR, Rodrigues MA, Rausch M. Modified therapy with 5-fluorouracil, doxorubicin, and methotrexate in advanced gastric cancer. Cancer 1993;72:37-41.
Glimelius B, Hoffman K, Haglund U, Nyrén O, Sjödén PO. Initial or delayed chemotherapy with best supportive care in advanced gastric cancer. Ann Oncol 1994;5:189-90.
Catalano V, Bisonni R, Graziano F, Giordani P, Alessandroni P, Baldelli AM, et al.
A phase II study of modified FOLFOX as first-line chemotherapy for metastatic gastric cancer in elderly patients with associated diseases. Gastric Cancer 2013;16:411-9.
Jin Y, Qiu MZ, Wang DS, Zhang DS, Ren C, Bai L, et al.
Adjuvant chemotherapy for elderly patients with gastric cancer after D2 gastrectomy. PLoS One 2013;8:e53149.
Kim JH, Kim HS, Han AR, Moh IH, Chung DC, Choi DR, et al.
Irinotecan, leucovorin and 5-fluorouracil (modified FOLFIRI) as salvage chemotherapy for frail or elderly patients with advanced gastric cancer. Oncol Lett 2012;4:751-4.
Koizumi W, Akiya T, Sato A, Sakuyama T, Sasaki E, Tomidokoro T, et al.
Phase II study of S-1 as first-line treatment for elderly patients over 75 years of age with advanced gastric cancer: The Tokyo cooperative oncology group study. Cancer Chemother Pharmacol 2010;65:1093-9.
Lee JL, Kang YK, Kang HJ, Lee KH, Zang DY, Ryoo BY, et al.
A randomised multicentre phase II trial of capecitabine vs. S-1 as first-line treatment in elderly patients with metastatic or recurrent unresectable gastric cancer. Br J Cancer 2008;99:584-90.
Trumper M, Ross PJ, Cunningham D, Norman AR, Hawkins R, Seymour M, et al.
Efficacy and tolerability of chemotherapy in elderly patients with advanced oesophago-gastric cancer: A pooled analysis of three clinical trials. Eur J Cancer 2006;42:827-34.
Kawaguchi T, Komatsu S, Ichikawa D, Kubota T, Okamoto K, Konishi H, et al.
Clinical significance of chemotherapy for geriatric patients with advanced or recurrent gastric cancer. Mol Clin Oncol 2015;3:83-8.
Polee MB, Hop WC, Kok TC, Eskens FA, van der Burg ME, Splinter TA, et al.
Prognostic factors for survival in patients with advanced oesophageal cancer treated with cisplatin-based combination chemotherapy. Br J Cancer 2003;89:2045-50.
Chau I, Norman AR, Cunningham D, Waters JS, Oates J, Ross PJ, et al.
Multivariate prognostic factor analysis in locally advanced and metastatic esophago-gastric cancer – Pooled analysis from three multicenter, randomized, controlled trials using individual patient data. J Clin Oncol 2004;22:2395-403.
Jatoi A, Foster NR, Egner JR, Burch PA, Stella PJ, Rubin J, et al.
Older versus younger patients with metastatic adenocarcinoma of the esophagus, gastroesophageal junction, and stomach: A pooled analysis of eight consecutive North Central Cancer Treatment Group (NCCTG) trials. Int J Oncol 2010;36:601-6.
Saito H, Osaki T, Murakami D, Sakamoto T, Kanaji S, Tatebe S, et al.
Effect of age on prognosis in patients with gastric cancer. ANZ J Surg 2006;76:458-61.
Santini D, Graziano F, Catalano V, Di Seri M, Testa E, Baldelli AM, et al.
Weekly oxaliplatin, 5-fluorouracil and folinic acid (OXALF) as first-line chemotherapy for elderly patients with advanced gastric cancer: Results of a phase II trial. BMC Cancer 2006;6:125.
Choi IS, Oh DY, Kim BS, Lee KW, Kim JH, Lee JS. Oxaliplatin, 5-FU, folinic acid as first-line palliative chemotherapy in elderly patients with metastatic or recurrent gastric cancer. Cancer Res Treat 2007;39:99-103.
Liu ZF, Guo QS, Zhang XQ, Yang XG, Guan F, Fu Z, et al.
Biweekly oxaliplatin in combination with continuous infusional 5-fluorouracil and leucovorin (modified FOLFOX-4 regimen) as first-line chemotherapy for elderly patients with advanced gastric cancer. Am J Clin Oncol 2008;31:259-63.
Dong N, Jiang W, Li H, Liu Z, Xu X, Wang M. Triweekly oxaliplatin plus oral capecitabine as first-line chemotherapy in elderly patients with advanced gastric cancer. Am J Clin Oncol 2009;32:559-63.
Zhao JG, Qiu F, Xiong JP, Zhang L, Xiang XJ, Yu F, et al.
A phase II study of modified FOLFOX as first-line chemotherapy in elderly patients with advanced gastric cancer. Anticancer Drugs 2009;20:281-6.
Xiang XJ, Zhang L, Qiu F, Yu F, Zhan ZY, Feng M, et al.
A phase II study of capecitabine plus oxaliplatin as first-line chemotherapy in elderly patients with advanced gastric cancer. Chemotherapy 2012;58:1-7.
Nardi M, Azzarello D, Maisano R, Del Medico P, Giannicola R, Raffaele M, et al.
FOLFOX-4 regimen as fist-line chemotherapy in elderly patients with advanced gastric cancer: A safety study. J Chemother 2007;19:85-9.
Cho YH, Kim SY, Hong Lee M, Yoo MW, Bang HY, Lee KY, et al.
Comparative analysis of the efficacy and safety of chemotherapy with oxaliplatin plus fluorouracil/leucovorin between elderly patients over 65 years and younger patients with advanced gastric cancer. Gastric Cancer 2012;15:389-95.
Al-Batran SE, Hartmann JT, Probst S, Schmalenberg H, Hollerbach S, Hofheinz R, et al.
Phase III trial in metastatic gastroesophageal adenocarcinoma with fluorouracil, leucovorin plus either oxaliplatin or cisplatin: A study of the arbeitsgemeinschaft internistische onkologie. J Clin Oncol 2008;26:1435-42.
[Figure 1], [Figure 2]
[Table 1], [Table 2], [Table 3], [Table 4]