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Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer
JGO-00812; No. of pages: 5; 4C: Journal of Geriatric Oncology xxx (2019) xxx
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Journal of Geriatric Oncology
Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer Terufumi Kawamoto a,⁎, Naoto Shikama a, Masaki Oshima a, Yasuo Kosugi a, Masahiko Tsurumaru b, Keisuke Sasai a a b
Department of Radiation Oncology, Juntendo University, Graduate School of Medicine, Japan Department of Esophageal and Gastroenterological Surgery, Juntendo University, Graduate School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 18 June 2019 Received in revised form 27 July 2019 Accepted 21 August 2019 Available online xxxx Keywords: Esophageal cancer Chemoradiotherapy Older patients
a b s t r a c t Objectives: Considering that therapeutic strategies for older adult patients with esophageal cancer (EC) remain controversial, we aimed to assess the safety of radiotherapy with concurrent docetaxel (DOC-RT) among older adult patients with EC. Materials and Methods: Eligible patients included those aged ≥76 years who were diagnosed with esophageal squamous cell carcinoma. Patients received radiotherapy (60 Gy in 30 fractions) and concurrent docetaxel (10 mg/m2 weekly for six cycles). Survival, toxicity, and treatment completion rates were retrospectively evaluated. Results: Among 84 older adult patients receiving radical radiotherapy or chemoradiotherapy, 73 receiving DOC-RT were studied. Median follow-up duration was 14 months (range, 2–101 months). The 1-, 3-, and 5year overall survival rates were 63%, 33%, and 13%, respectively, with a median survival time of 21 months. Grade 3 acute toxicities included esophagitis (7%), esophageal fistula (3%), pneumonitis (1%), leukopenia (10%), and anemia (8%). Grade 3 late toxicities included esophageal stenosis (4%), pleural effusion (3%), pericardial effusion (1%), and pneumonitis (1%). Grade 4 and 5 toxicities were not observed. DOC-RT was discontinued due to deterioration in the general condition (6%), esophageal fistula (3%), pneumonia (1%), and pain (1%), resulting in a DOC-RT completion rate of 89% (65/73 patients). The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished [geriatric nutritional risk index (GNRI b92)] patients than the completion group. Conclusion: DOC-RT can be a safe regimen for older adult patients with EC. Nonetheless, old age (≥80 years) and undernourishment (GNRI b92) should be considered prior to DOC-RT administration. © 2019 Elsevier Ltd. All rights reserved.
1. Introduction Esophageal cancer (EC) is the eighth most common type of cancer worldwide and the sixth leading cause of cancer-related death [1]. Owing to increased life expectancy, the number of older adult patients with EC has also grown significantly over recent decades, with approximately 30–34% of patients aged ≥75 years at diagnosis [2,3]. In Japan, neoadjuvant chemotherapy followed by esophagectomy has been the standard treatment for resectable EC [4,5]. However, due Abbreviations: CCI, Charlson Comorbidity Index; CI, confidence interval; CRT, chemoradiotherapy; DOC, docetaxel; EC, esophageal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FP, 5-fluorouracil and cisplatin; GNRI, geriatric nutritional risk index; HR, hazard ratio; MST, median survival time; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; UMIN, University Hospital Medical Information Network. ⁎ Corresponding author at: Department of Radiation Oncology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: [email protected] (T. Kawamoto).
to limitations related to their physiological condition, older adults are generally not considered fit for surgery. Chemoradiotherapy (CRT) has been shown to provide significantly better survival benefits in patients with EC compared to radiotherapy (RT) alone, with 5-fluorouracil and cisplatin (FP) being designated as the standard regimen [6,7]. However, clinical trials supporting these standard treatments did not include older adults aged ≥76 years. Moreover, a retrospective comparison of the outcomes of RT with concurrent FP between older and non-older adults with stage II/III (non-T4) EC demonstrated that older adults had more frequent hematological adverse events, poorer compliance, and significantly inferior survival [8]. Thus, a standard CRT regimen with lower toxicity and higher efficacy needs to be established for older adults with EC. Docetaxel (DOC) is an active chemotherapeutic agent for advanced EC [9,10]. Apart from its cytotoxic activity, DOC possesses radiosensitizing properties through its ability to induce G2-M cell cycle blockade [11,12]. Accordingly, studies on EC, non-small-cell lung cancer, and head and neck cancer have shown that CRT with DOC
https://doi.org/10.1016/j.jgo.2019.08.009 1879-4068/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
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T. Kawamoto et al. / Journal of Geriatric Oncology xxx (2019) xxx
(DOC-RT) offers promising activity and manageable toxicity [13–18]. Moreover, a previous phase 1 study in Japan revealed that DOC-RT was tolerable and effective in patients with localized EC aged 20–79 years, with the recommended DOC dose being 10 mg/m2 weekly [19]. However, a phase 2 study on DOC-RT in older adults with locally advanced EC was prematurely terminated due to slow accrual [20]. Therefore, the efficacy and safety of DOC-RT among older adults with EC remains unclear. Thus, the present retrospective study primarily aimed to assess the safety of DOC-RT in older adults with EC. 2. Materials and Methods 2.1. Study Population We retrospectively reviewed the medical records, RT treatment plans, and diagnostic images of patients with EC who satisfied the following criteria: (i) ≥76 years of age with pathologically proven esophageal squamous cell carcinoma; (ii) Eastern Cooperative Oncology Group performance status (ECOG PS) [21] of 0–2; (iii) clinical stage of I–IVA and IVB (M1 lymph node) based on the 8th Union for International Cancer Control TNM classification [22]; (iv) treatment with definitive concurrent DOC-RT; and (v) no other active cancer. Patients with para-aortic lymph node metastasis were excluded. EC was diagnosed comprehensively through upper gastrointestinal endoscopy, computed tomography, positron emission tomography, and physical examination.
as acute or late, respectively. Treatment completion was defined as having completed the scheduled RT and DOC. After evaluating treatment completion rates, Fisher's exact test was used to compare the proportions of categorical variables between the non-completion and completion groups. Comorbidities were estimated using the Charlson Comorbidity Index (CCI), which is based on 12 disease comorbidity categories, with scores ranging from 1 to 6 based on the relative risk of 1-year mortality [24,25]. Nutritional status was estimated using the geriatric nutritional risk index (GNRI) [26], which combines two nutritional indicators, albumin and actual compared with ideal body weight, and was developed by modifying the nutritional risk index for older adults. The GNRI formula is as follows: GNRI = [1.487 × pretreatment serum albumin (g/L)] + [41.7 × pretreatment weight (kg)/ideal body weight (kg)]. The participants were classified according to the following cut-offs: high risk, b92; moderate risk, 92–98; and no risk, N98 [27]. All statistical analyses were performed using EZR version 1.37 [28], and p values b.05 (two-sided) were considered statistically significant. The retrospective study protocol was reviewed and approved by the Juntendo Hospital review board (approval number: 19–039). 3. Results 3.1. Patients and Tumor Characteristics
2.2. Treatment External RT was administered using 6- or 10-MV X-rays from a linear accelerator. The daily RT fraction size was 2.0 Gy to the International Commission on Radiation Units and Measurements reference point administered 5 days per week for a total dose of 60 Gy. Elective nodal irradiation including the bilateral supraclavicular and mediastinal lymph node regions was performed in 47 patients, while involved-field irradiation covering the primary tumor and lymph node metastases with a margin of 2–4 cm was performed in 26 patients. Elective nodal irradiation tended to be used in patients with more advanced cancer. All patients underwent threedimensional conformal RT using 2–4 fields to avoid the spinal cord. Among those receiving 2-field irradiation, the beam direction was changed after 40 Gy of irradiation. The percentage of total lung volume exceeding 20 Gy and mean lung dose did not exceed the constraints of 35% and 20 Gy, respectively. Mean heart dose did not exceed the constraints of 40 Gy. In conjunction with RT, all patients received a chemotherapy regimen consisting of DOC at a weekly dose of 10 mg/m2 for 6 consecutive weeks. DOC was administered on an outpatient basis. After treatment completion, the patients were followed up at 1- or 3-month intervals. Follow-up evaluations included a history and physical examination, blood test, upper gastrointestinal endoscopy, computed tomography, and positron emission tomography. The blood test included complete blood cell count; biochemical marker levels (albumin, electrolytes, creatinine, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase); and tumor marker levels (squamous cell carcinoma antigen). 2.3. Statistical Analyses Overall survival (OS) and progression-free survival (PFS) from the treatment start date were measured using the Kaplan–Meier method. Death from any cause was defined as an event when calculating OS, while disease progression at any site or death from any cause was defined as an event when calculating PFS. Toxicity was assessed and documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [23]. Toxicities occurring within 3 months or N3 months after treatment were defined
Between January 2009 and May 2018, 84 patients with EC aged ≥76 years received radical RT or CRT at our hospital. Among these 84 older adults, 4 (5%) received RT with concurrent FP, 7 (8%) received RT alone, and the remaining 73 (87%) received definitive concurrent DOC-RT. Table 1 provides a summary of the patient and tumor characteristics. The median follow-up duration was 14 (range, 2–101) months for the entire cohort and 24 (range, 3–101) months for the 27 survivors, 10 of whom were lost to follow-up. Among the included patients, 32 (44%) underwent outpatient treatment, 35 (48%) underwent inpatient treatment, and the remaining 6 (8%) underwent temporary inpatient treatment due to dysphagia and esophagitis. The median hospitalization period for the inpatients was 85 (range, 7–178) days. 3.2. Survival The 1-, 3-, and 5-year PFS rates were 41% [95% confidence interval (CI), 29–52], 24% (95% CI, 14–36), and 8% (95% CI, 2–21), respectively. The 1-, 3-, and 5-year OS rates were 63% (95% CI, 50–73), 33% (95% CI, 21–45), and 13% (95% CI, 4–28), respectively, with a median survival time (MST) of 21 months (Fig. 1). Moreover, 40 patients died of tumor progression, while 6 died of other causes, including gastric bleeding (1 patient), heart failure (1 patient), suicide (1 patient), alcoholic cirrhosis (1 patient), and aspiration pneumonia from cerebral infarction (2 patients). 3.3. Toxicity and Completion Rates Table 2 summarizes the toxicities associated with DOC-RT. DOC and RT were discontinued due to deterioration in the general condition (6%), esophageal fistula (3%), pneumonia (1%), and pain (1%), resulting in a DOC-RT completion rate of 89% (65/73 patients). The remaining 65 patients received RT and DOC as scheduled. 3.4. Comparison Between the Non-completion and Completion Groups Table 3 provides a comparison between the non-completion and completion groups. The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished (GNRI b92)
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
T. Kawamoto et al. / Journal of Geriatric Oncology xxx (2019) xxx Table 1 Patient and tumor characteristics.
Age (years), median (range) ≥80 years b80 years Sex Male Female ECOG PS 0 1 2 Location of primary tumor Cervix Upper thorax Middle thorax Lower thorax Abdomen T factor 1 2 3 4 N factor 0 1 2 3 cStage I II III IVA IVB (M1 lymph node) History of smoking Yes No CCr (mL/min) ≥60 b60 CCI 2 3 4 5 GNRI b92 92–98 N98 Radiation field ENI IFI Median follow-up time (months), median (range)
Table 2 Treatment toxicities. No. (%)
CTCAEv4.0
80 (76–90) 31 (42) 42 (58)
Acute toxicities
61 (84) 12 (16) 41 (56) 22 (30) 10 (14) Late toxicities 9 (12) 8 (11) 40 (55) 14 (19) 2 (3) 19 (26) 5 (7) 22 (30) 27 (37) 29 (40) 12 (16) 17 (23) 15 (21) 19 (26) 9 (12) 15 (21) 24 (33) 6 (8) 48 (66) 25 (34) 24 (33) 49 (67) 41 (56) 16 (22) 14 (19) 2 (3) 28 (38) 22 (30) 23 (32) 47 (64) 26 (36) 14 (2−101)
CCI, Charlson Comorbidity Index; CCr, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; GNRI, geriatric nutritional risk index; IFI, involved-field irradiation.
Fig. 1. Kaplan–Meier estimates of survivals.
3
Nausea Malaise Dysphagia Esophagitis Esophageal fistula Dermatitis Pneumonitis Leukopenia Anemia Thrombocytopenia Esophageal stenosis Pleural effusion Pericardial effusion Pneumonitis
Grade 1/2, no. (%)
Grade 3, no. (%)
1 (1) 6 (8) 2 (3) 29 (40) 4 (5) 11 (15) 8 (11) 33 (45) 47 (64) 32 (44) 2 (3) 28 (38) 16 (22) 5 (7)
5 (7) – 3 (4) 5 (7) 2 (3) – 1 (1) 7 (10) 6 (8) – 3 (4) 2 (3) 1 (1) 1 (1)
patients than the completion group (p b .001 and p = .004, respectively). Among the 16 undernourished patients aged ≥80 years, 7 discontinued DOC-RT. No other baseline factors, including sex, ECOG PS, clinical stage, smoking status, creatinine clearance, CCI, and radiation field, were associated with the completion rate. Table 3 Comparison between the non-completion and completion groups. Patient and tumor characteristics
Non-completion group
Completion group
p-Value
Total Age, no. (%) ≥80 years b80 years Sex, no. (%) Male Female ECOG PS, no. (%) 0 1 2 T factor, no. (%) 1 2 3 4 N factor, no. (%) 0 1–3 cStage, no. (%) I II III IVA IVB (M1 lymph node) History of smoking Yes No CCr (mL/min) ≥60 b60 CCI 2 3 4 5 GNRI, no. (%) ≥92 b92 Radiation field ENI IFI
8
65
8 (100) 0
23 (35) 42 (65)
b0.001
7 (87) 1 (13)
54 (83) 11 (17)
1
2 (25) 4 (50) 2 (25)
39 (60) 18 (28) 8 (12)
0.137
2 (25) 0 3 (37.5) 3 (37.5)
17 (26) 5 (8) 19 (29) 24 (37)
1
2 (25) 6 (75)
27 (42) 38 (58)
0.47
2 (25) 0 3 (37.5) 3 (37.5) 0
17 (26) 9 (14) 12 (19) 21 (32) 6 (9)
0.7
7 (87) 1 (13)
41 (63) 24 (37)
0.25
2 (25) 6 (75)
22 (34) 43 (66)
1
3 (37) 2 (25) 2 (25) 1 (13)
38 (58) 14 (21) 12 (19) 1 (2)
0.23
1 (13) 7 (87)
44 (68) 21 (32)
0.004
7 (87) 1 (13)
40 (62) 25 (38)
0.25
CCI, Charlson Comorbidity Index; CCr, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; GNRI, geriatric nutritional risk index; IFI, involved-field irradiation.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
7 0 0 26/12/21/41 40 26/7/30/37
28/32/32/8 20/16/40/24 NA Watanabe
2019 73 Our report
2018 25
2018 55 Walter31
32
2016 16 Ohba20
5FU, 5-fluorouracil; DOC, docetaxel; FP, 5-fluorouracil plus cisplatin; MST, median survival time; NA, information not available; RT, radiotherapy.
10 21 89
8 32 28 72 24 84
4 7 5 33 12 66
FP or mitomycin C 59.4 Gy/33 fr. + 5FU Nedaplatine 50.4 Gy/28 fr. +5FU DOC 60 Gy/30 fr. NA 46 2/20/58/20
31 6 0 6 27.7 88 60 Gy/30 fr. DOC 0/34/56/0 19 25/6/69/0
33 52 70 14.7 67 60 Gy/30 fr. FP 0/54/46/0 43 6/6/88/0 2007 33 Takeuchi8
74 (71–79) 77 (73–81) 75 (70–85) 79 (76–85) 80 (76–90)
Thrombo–cytopenia Grade 3–4 (%) Anemia Grade 3–4 (%) Leukopenia Grade 3–4 (%) MST (months) Treatment completion rate (%) Median prescribed dose Chemotherapy regimen cStage I/II/III/IV (%) T1/2/3/4 (%) N0 (%) No. Median age years (range) Year
Table 4 Literature review of results for radiotherapy in elderly patients with esophageal cancer.
The present study was designed to assess the safety of DOC-RT among older adults with EC (age, ≥76 years). When comparing our results with those of other similar studies, three important factors need to be addressed; 1) hematological toxicity, 2) radiation-induced esophagitis, and 3) patients' underlying conditions including nutritional status and comorbidities. Our results showed that CRT at 60 Gy with 10 mg/m2 of DOC weekly for 6 consecutive weeks produced grade 3/4 leukopenia in 10%, anemia in 8%, and esophagitis in 7% of the patients, with a completion rate of 89%. A separate retrospective study among older adults with EC receiving CRT at 60 Gy with concurrent FP showed grade 3/4 leukopenia in 70%, anemia in 52%, thrombocytopenia in 33%, and esophagitis in 9% of the patients, with a completion rate of 67%. Moreover, older adults developed leukopenia and anemia more frequently and had lower CRT completion rates than non-older adults [8]. Another retrospective study involving older adults with EC receiving CRT with concurrent cisplatin and S-1 observed that those aged 75 years had a significantly higher incidence of severe leukopenia than those aged between 70 and 75 years (41.9% vs. 72.0%, respectively) [29]. These reports suggest that cisplatinum-based CRT places older adults at high risk for severe leukopenia. Conversely, the results of a prospective trial demonstrated promising and acceptable toxicity profiles for DOC-RT in patients with inoperable EC aged between 41 and 88 years, in which grade 3/4 toxicities included leukopenia in 9%, anemia in 6%, thrombocytopenia in 3%, and esophagitis in 17% of the patients. DOC-RT was discontinued due to progressive disease (four patients), deteriorating performance status (one patient), pneumonia (one patient), and an acute abdominal episode (one patient), resulting in a DOC-RT completion rate of 79% (27/34 patients) [18]. Moreover, a phase 2 study on DOC-RT in older adults with locally advanced EC showed grade 3/4 leukopenia in 6% and thrombocytopenia in 6% of the patients, with a treatment completion rate of 88% [20]. Considering the aforementioned findings, the present study demonstrated that DOC-RT had lower hematological toxicity rates than cisplatinum-based CRT in older adults with EC. Thus, DOCRT can be a safer regimen for older adults with EC in terms of hematological toxicities. The phase 2 study of DOC-RT in older adults with locally advanced EC reported a high rate of grade 3/4 acute esophagitis (31.3%) and a total radiation dose reduction was recommended [20]. A reduction in the total radiation dose is generally considered to decrease the incidence of esophagitis, particularly in older adults. A prospective study on patients with EC aged over 80 treated with RT alone delivered at 66 Gy showed a low rate of grade 3/4 acute esophagitis (4%) [30]. In addition to this, the rate of grade 3/4 acute esophagitis in our study was generally favorable compared with the outcomes of previous studies (Table 4) [8,20,31,32]. Thus, it may not be necessary to reduce the total radiation dose for DOC-RT in all older adults. In older adults, there are sometimes problems that must be considered in treatment decisions, such as comorbidities and nutritional status. However, only few reports focused on comorbidities and nutritional status in the treatment decisions of older adults with EC [31,33–36]. Malnutrition, which is a common condition at diagnosis in older adults, often impaired performance status, quality of life, response to treatment, and even survival [37]. Bo et al. reported that the risk of mortality increased by 68.8% [hazard ratio (HR) = 1.688; 95% CI, 1.019–2.798] for the moderate-risk group (GNRI 92–98) and by 169.9% (HR = 2.699; 95% CI, 1.512–4.819) for the high-risk group (GNRI b92) compared with the non-nutritional risk group (GNRI N98) in older adults with EC treated with RT [34]. CCI—a tool used to predict mortality by classifying or weighting comorbidities—has been utilized widely by health researchers to measure the burden of disease [25]. The CCI is associated with OS as well as with treatment-related death in older adults with EC [31,36]. In our study, we compared the proportions of categorical variables between the non-completion and
Esophagitis Grade 3–4 (%)
4. Discussion
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Author
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Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
T. Kawamoto et al. / Journal of Geriatric Oncology xxx (2019) xxx
completion groups to analyze which older adults with EC may be unfit for DOC-RT. The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished (GNRI b92) patients than the completion group, but the CCI was not associated. Thus, older adults and undernourished patients may need therapy with less toxicity burden, such as RT alone or palliative treatment. The present study has several limitations associated with its retrospective design. First, we could not demonstrate a benefit of treatment with DOC-RT compared with RT alone. A previous retrospective study suggested that platinum- or taxane-based concurrent CRT (MST, 22.3 months) is superior to sequential CRT (MST, 18.0 months) and RT alone (MST, 12.4 months) in older adults with stage I–IV EC [38]. In our study, the MST was 21 months for older adults. In terms of survival, DOC-RT might be a recommended treatment for older adults with EC. Second, this study has selection biases. We enrolled patients with stage I–IV EC in a single institution and some of the patients were fit for FP-RT. Therefore, a prospective study with a uniform strategy, such as inclusion of older adults with stage II/III EC who are medically unfit for surgery or FP-RT, in a multi-institutional setting is essential. In conclusion, DOC-RT can be a safe regimen for older adults with EC. Nonetheless, older age (over 80 years) and undernourishment (GNRI b92) should be considered in determining the administration of DOCRT. To establish a new treatment option, Japanese study groups are conducting a phase I/II clinical trial assessing taxane-based concurrent CRT in older adults with EC [the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000020397]. Author Contributions TK prepared the manuscript and conducted the literature search; TK reviewed and edited the manuscript; and TK, NS, MO, YK, MT, and KS reviewed the manuscript. All authors have read and approved the final manuscript. Declaration of Competing Interest None. References [1] Di Pardo BJ, Bronson NW, Diggs BS, Thomas Jr CR, Hunter JG, Dolan JP. The global burden of esophageal cancer: a disability-adjusted life-year approach. World J Surg 2016;40(2):395–401. [2] Faiz Z, Lemmens VE, Siersema PD, Nieuwenhuijzen GA, Wouters MW, Rozema T, et al. Increased resection rates and survival among patients aged 75 years and older with esophageal cancer: a Dutch nationwide population-based study. World J Surg 2012;36(12):2872–8. [3] National Cancer Center in Japan. Center for Cancer Control and in- formation services. Available at http://ganjoho.jp/reg_stat/index.html; 2017. [4] Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19(1):68–74. [5] Kato K, Muro K, Minashi K, Ohtsu A, Ishikura S, Boku N, et al. Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906). Int J Radiat Oncol Biol Phys 2011;81 (3):684–90. [6] Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson Jr JA, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. Jama 1999;281(17):1623–7. [7] Kato K, Nakajima TE, Ito Y, Katada C, Ishiyama H, Tokunaga SY, et al. Phase II study of concurrent chemoradiotherapy at the dose of 50.4 Gy with elective nodal irradiation for Stage II-III esophageal carcinoma. Jpn J Clin Oncol 2013;43(6):608–15. [8] Takeuchi S, Ohtsu A, Doi T, Kojima T, Minashi K, Mera K, et al. A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer. Am J Clin Oncol 2007;30(6):607–11. [9] Einzig AI, Neuberg D, Remick SC, Karp DD, O'Dwyer PJ, Stewart JA, et al. Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: the Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol 1996;13(2): 87–93.
5
[10] Rigas JR, Dragnev KH, Bubis JA. Docetaxel in the treatment of esophageal cancer. Semin Oncol 2005;32(2):S39–51 Suppl 4. [11] Hennequin C, Giocanti N, Favaudon V. Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res 1996; 56(8):1842–50. [12] Dunne AL, Mothersill C, Robson T, Wilson GD, Hirst DG. Radiosensitization of colon cancer cell lines by docetaxel: mechanisms of action. Oncol Res 2004;14(9):447–54. [13] Mauer AM, Masters GA, Haraf DJ, Hoffman PC, Watson SM, Golomb HM, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 1998;16 (1):159–64. [14] Kushida T, Nohara S, Yoshino K, Fujiwara D, Ouchi K, Amano T, et al. Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis. Dis Esophagus 2014;27(4):368–73. [15] Koukourakis MI, Kourousis C, Kamilaki M, Koukouraki S, Giatromanolaki A, Kakolyris S, et al. Weekly docetaxel and concomitant boost radiotherapy for non-small cell lung cancer. A phase I/II dose escalation trial. Eur J Cancer 1998;34(6):838–44. [16] Calais G, Bardet E, Sire C, Alfonsi M, Bourhis J, Rhein B, et al. Radiotherapy with concomitant weekly docetaxel for Stages III/IV oropharynx carcinoma. Results of the 9802 GORTEC Phase II trial. Int J Radiat Oncol Biol Phys 2004;58(1):161–6. [17] Fujii M, Tsukuda M, Satake B, Kubota A, Kida A, Kohno N, et al. Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck. Int J Clin Oncol 2004;9(2):107–12. [18] Font A, Arellano A, Fernandez-Llamazares J, Casas D, Boix J, Cardenal J, et al. Weekly docetaxel with concomitant radiotherapy in patients with inoperable oesophageal cancer. Clin Transl Oncol 2007;9(3):177–82. [19] Hokamura N, Kawano N, Takmaki Y. A phase I study of docetaxel with concurrent radiotherapy in patients with esophageal cancer; 2008. [20] Ohba A, Kato K, Ito Y, Katada C, Ishiyama H, Yamamoto S, et al. Chemoradiation therapy with docetaxel in elderly patients with stage II/III esophageal cancer: a phase 2 trial. Adv Radiat Oncol 2016;1(4):230–6. [21] Common toxicity criteria, Version2.0 publish date; April 30 1999. [22] Brierley J, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. . 8th ed.Chichester, West Sussex, UK; Hoboken, NJ: John Wiley & Sons, Inc; 2017. [23] National Cancer Institute (U.S.). In: Bethesda Md, editor. Common terminology criteria for adverse events (CTCAE). Rev. National Cancer Institute: U.S. Dept. of Health and Human Services, National Institutes of Health; 2009. [24] Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 2011;173(6):676–82. [25] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373–83. [26] Bouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, et al. Geriatric nutritional risk index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr 2005;82(4):777–83. [27] Cereda E, Pedrolli C. The geriatric nutritional risk index. Curr Opin Clin Nutr Metab Care 2009;12(1):1–7. [28] Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48(3):452–8. [29] Wang H, Li G, Chen L, Duan Y, Zou C, Hu C. Definitive concurrent chemoradiotherapy with S-1 and cisplatin in elderly esophageal squamous cell carcinoma patients. J Thorac Dis 2017;9(3):646–54. [30] Kawashima M, Kagami Y, Toita T, Uno T, Sugiyama M, Tamura Y, et al. Prospective trial of radiotherapy for patients 80 years of age or older with squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 2006;64(4): 1112–21. [31] Walter F, Bockle D, Schmidt-Hegemann NS, Kopple R, Gerum S, Boeck S, et al. Clinical outcome of elderly patients (N/= 70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis. Radiat Oncol 2018;13(1):93. [32] Watanabe A, Katada C, Komori S, Moriya H, Yamashita K, Harada H, et al. Feasibility of definitive chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma: a retrospective study. Adv Radiat Oncol 2018;3(3):305–13. [33] Yin H, E M, Zhang H, Wang C. The outcomes of radiotherapy and factors that predict overall survival in elderly patients with esophageal squamous cell carcinoma. Clin Transl Oncol 2017;19(6):742–9. [34] Bo Y, Wang K, Liu Y, You J, Cui H, Zhu Y, et al. The geriatric nutritional risk index predicts survival in elderly esophageal squamous cell carcinoma patients with radiotherapy. PLoS One 2016;11(5):e0155903. [35] Song T, Du D, Zhang X, Fang M, Wu S. Comparative study of radiotherapy plus erlotinib versus chemoradiotherapy for elderly patients with esophageal cancer: a propensity score-matched analysis. Dis Esophagus 2017;30(9):1–10. [36] Tougeron D, Di Fiore F, Thureau S, Berbera N, Iwanicki-Caron I, Hamidou H, et al. Safety and outcome of definitive chemoradiotherapy in elderly patients with oesophageal cancer. Br J Cancer 2008;99(10):1586–92. [37] Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur J Oncol Nurs 2005;9(Suppl. 2):S51–63. [38] Li X, Zhao LJ, Liu NB, Zhang WC, Pang QS, Wang P, et al. Feasibility and efficacy of concurrent chemoradiotherapy in elderly patients with esophageal squamous cell carcinoma: a respective study of 116 cases from a single institution. Asian Pac J Cancer Prev 2015;16(4):1463–9.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
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Journal of Geriatric Oncology
Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer Terufumi Kawamoto a,⁎, Naoto Shikama a, Masaki Oshima a, Yasuo Kosugi a, Masahiko Tsurumaru b, Keisuke Sasai a a b
Department of Radiation Oncology, Juntendo University, Graduate School of Medicine, Japan Department of Esophageal and Gastroenterological Surgery, Juntendo University, Graduate School of Medicine, Japan
a r t i c l e
i n f o
Article history: Received 18 June 2019 Received in revised form 27 July 2019 Accepted 21 August 2019 Available online xxxx Keywords: Esophageal cancer Chemoradiotherapy Older patients
a b s t r a c t Objectives: Considering that therapeutic strategies for older adult patients with esophageal cancer (EC) remain controversial, we aimed to assess the safety of radiotherapy with concurrent docetaxel (DOC-RT) among older adult patients with EC. Materials and Methods: Eligible patients included those aged ≥76 years who were diagnosed with esophageal squamous cell carcinoma. Patients received radiotherapy (60 Gy in 30 fractions) and concurrent docetaxel (10 mg/m2 weekly for six cycles). Survival, toxicity, and treatment completion rates were retrospectively evaluated. Results: Among 84 older adult patients receiving radical radiotherapy or chemoradiotherapy, 73 receiving DOC-RT were studied. Median follow-up duration was 14 months (range, 2–101 months). The 1-, 3-, and 5year overall survival rates were 63%, 33%, and 13%, respectively, with a median survival time of 21 months. Grade 3 acute toxicities included esophagitis (7%), esophageal fistula (3%), pneumonitis (1%), leukopenia (10%), and anemia (8%). Grade 3 late toxicities included esophageal stenosis (4%), pleural effusion (3%), pericardial effusion (1%), and pneumonitis (1%). Grade 4 and 5 toxicities were not observed. DOC-RT was discontinued due to deterioration in the general condition (6%), esophageal fistula (3%), pneumonia (1%), and pain (1%), resulting in a DOC-RT completion rate of 89% (65/73 patients). The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished [geriatric nutritional risk index (GNRI b92)] patients than the completion group. Conclusion: DOC-RT can be a safe regimen for older adult patients with EC. Nonetheless, old age (≥80 years) and undernourishment (GNRI b92) should be considered prior to DOC-RT administration. © 2019 Elsevier Ltd. All rights reserved.
1. Introduction Esophageal cancer (EC) is the eighth most common type of cancer worldwide and the sixth leading cause of cancer-related death [1]. Owing to increased life expectancy, the number of older adult patients with EC has also grown significantly over recent decades, with approximately 30–34% of patients aged ≥75 years at diagnosis [2,3]. In Japan, neoadjuvant chemotherapy followed by esophagectomy has been the standard treatment for resectable EC [4,5]. However, due Abbreviations: CCI, Charlson Comorbidity Index; CI, confidence interval; CRT, chemoradiotherapy; DOC, docetaxel; EC, esophageal cancer; ECOG PS, Eastern Cooperative Oncology Group performance status; FP, 5-fluorouracil and cisplatin; GNRI, geriatric nutritional risk index; HR, hazard ratio; MST, median survival time; OS, overall survival; PFS, progression-free survival; RT, radiotherapy; UMIN, University Hospital Medical Information Network. ⁎ Corresponding author at: Department of Radiation Oncology, Juntendo University, Graduate School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan. E-mail address: [email protected] (T. Kawamoto).
to limitations related to their physiological condition, older adults are generally not considered fit for surgery. Chemoradiotherapy (CRT) has been shown to provide significantly better survival benefits in patients with EC compared to radiotherapy (RT) alone, with 5-fluorouracil and cisplatin (FP) being designated as the standard regimen [6,7]. However, clinical trials supporting these standard treatments did not include older adults aged ≥76 years. Moreover, a retrospective comparison of the outcomes of RT with concurrent FP between older and non-older adults with stage II/III (non-T4) EC demonstrated that older adults had more frequent hematological adverse events, poorer compliance, and significantly inferior survival [8]. Thus, a standard CRT regimen with lower toxicity and higher efficacy needs to be established for older adults with EC. Docetaxel (DOC) is an active chemotherapeutic agent for advanced EC [9,10]. Apart from its cytotoxic activity, DOC possesses radiosensitizing properties through its ability to induce G2-M cell cycle blockade [11,12]. Accordingly, studies on EC, non-small-cell lung cancer, and head and neck cancer have shown that CRT with DOC
https://doi.org/10.1016/j.jgo.2019.08.009 1879-4068/© 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
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(DOC-RT) offers promising activity and manageable toxicity [13–18]. Moreover, a previous phase 1 study in Japan revealed that DOC-RT was tolerable and effective in patients with localized EC aged 20–79 years, with the recommended DOC dose being 10 mg/m2 weekly [19]. However, a phase 2 study on DOC-RT in older adults with locally advanced EC was prematurely terminated due to slow accrual [20]. Therefore, the efficacy and safety of DOC-RT among older adults with EC remains unclear. Thus, the present retrospective study primarily aimed to assess the safety of DOC-RT in older adults with EC. 2. Materials and Methods 2.1. Study Population We retrospectively reviewed the medical records, RT treatment plans, and diagnostic images of patients with EC who satisfied the following criteria: (i) ≥76 years of age with pathologically proven esophageal squamous cell carcinoma; (ii) Eastern Cooperative Oncology Group performance status (ECOG PS) [21] of 0–2; (iii) clinical stage of I–IVA and IVB (M1 lymph node) based on the 8th Union for International Cancer Control TNM classification [22]; (iv) treatment with definitive concurrent DOC-RT; and (v) no other active cancer. Patients with para-aortic lymph node metastasis were excluded. EC was diagnosed comprehensively through upper gastrointestinal endoscopy, computed tomography, positron emission tomography, and physical examination.
as acute or late, respectively. Treatment completion was defined as having completed the scheduled RT and DOC. After evaluating treatment completion rates, Fisher's exact test was used to compare the proportions of categorical variables between the non-completion and completion groups. Comorbidities were estimated using the Charlson Comorbidity Index (CCI), which is based on 12 disease comorbidity categories, with scores ranging from 1 to 6 based on the relative risk of 1-year mortality [24,25]. Nutritional status was estimated using the geriatric nutritional risk index (GNRI) [26], which combines two nutritional indicators, albumin and actual compared with ideal body weight, and was developed by modifying the nutritional risk index for older adults. The GNRI formula is as follows: GNRI = [1.487 × pretreatment serum albumin (g/L)] + [41.7 × pretreatment weight (kg)/ideal body weight (kg)]. The participants were classified according to the following cut-offs: high risk, b92; moderate risk, 92–98; and no risk, N98 [27]. All statistical analyses were performed using EZR version 1.37 [28], and p values b.05 (two-sided) were considered statistically significant. The retrospective study protocol was reviewed and approved by the Juntendo Hospital review board (approval number: 19–039). 3. Results 3.1. Patients and Tumor Characteristics
2.2. Treatment External RT was administered using 6- or 10-MV X-rays from a linear accelerator. The daily RT fraction size was 2.0 Gy to the International Commission on Radiation Units and Measurements reference point administered 5 days per week for a total dose of 60 Gy. Elective nodal irradiation including the bilateral supraclavicular and mediastinal lymph node regions was performed in 47 patients, while involved-field irradiation covering the primary tumor and lymph node metastases with a margin of 2–4 cm was performed in 26 patients. Elective nodal irradiation tended to be used in patients with more advanced cancer. All patients underwent threedimensional conformal RT using 2–4 fields to avoid the spinal cord. Among those receiving 2-field irradiation, the beam direction was changed after 40 Gy of irradiation. The percentage of total lung volume exceeding 20 Gy and mean lung dose did not exceed the constraints of 35% and 20 Gy, respectively. Mean heart dose did not exceed the constraints of 40 Gy. In conjunction with RT, all patients received a chemotherapy regimen consisting of DOC at a weekly dose of 10 mg/m2 for 6 consecutive weeks. DOC was administered on an outpatient basis. After treatment completion, the patients were followed up at 1- or 3-month intervals. Follow-up evaluations included a history and physical examination, blood test, upper gastrointestinal endoscopy, computed tomography, and positron emission tomography. The blood test included complete blood cell count; biochemical marker levels (albumin, electrolytes, creatinine, aspartate aminotransferase, alanine aminotransferase, lactate dehydrogenase, and alkaline phosphatase); and tumor marker levels (squamous cell carcinoma antigen). 2.3. Statistical Analyses Overall survival (OS) and progression-free survival (PFS) from the treatment start date were measured using the Kaplan–Meier method. Death from any cause was defined as an event when calculating OS, while disease progression at any site or death from any cause was defined as an event when calculating PFS. Toxicity was assessed and documented according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [23]. Toxicities occurring within 3 months or N3 months after treatment were defined
Between January 2009 and May 2018, 84 patients with EC aged ≥76 years received radical RT or CRT at our hospital. Among these 84 older adults, 4 (5%) received RT with concurrent FP, 7 (8%) received RT alone, and the remaining 73 (87%) received definitive concurrent DOC-RT. Table 1 provides a summary of the patient and tumor characteristics. The median follow-up duration was 14 (range, 2–101) months for the entire cohort and 24 (range, 3–101) months for the 27 survivors, 10 of whom were lost to follow-up. Among the included patients, 32 (44%) underwent outpatient treatment, 35 (48%) underwent inpatient treatment, and the remaining 6 (8%) underwent temporary inpatient treatment due to dysphagia and esophagitis. The median hospitalization period for the inpatients was 85 (range, 7–178) days. 3.2. Survival The 1-, 3-, and 5-year PFS rates were 41% [95% confidence interval (CI), 29–52], 24% (95% CI, 14–36), and 8% (95% CI, 2–21), respectively. The 1-, 3-, and 5-year OS rates were 63% (95% CI, 50–73), 33% (95% CI, 21–45), and 13% (95% CI, 4–28), respectively, with a median survival time (MST) of 21 months (Fig. 1). Moreover, 40 patients died of tumor progression, while 6 died of other causes, including gastric bleeding (1 patient), heart failure (1 patient), suicide (1 patient), alcoholic cirrhosis (1 patient), and aspiration pneumonia from cerebral infarction (2 patients). 3.3. Toxicity and Completion Rates Table 2 summarizes the toxicities associated with DOC-RT. DOC and RT were discontinued due to deterioration in the general condition (6%), esophageal fistula (3%), pneumonia (1%), and pain (1%), resulting in a DOC-RT completion rate of 89% (65/73 patients). The remaining 65 patients received RT and DOC as scheduled. 3.4. Comparison Between the Non-completion and Completion Groups Table 3 provides a comparison between the non-completion and completion groups. The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished (GNRI b92)
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
T. Kawamoto et al. / Journal of Geriatric Oncology xxx (2019) xxx Table 1 Patient and tumor characteristics.
Age (years), median (range) ≥80 years b80 years Sex Male Female ECOG PS 0 1 2 Location of primary tumor Cervix Upper thorax Middle thorax Lower thorax Abdomen T factor 1 2 3 4 N factor 0 1 2 3 cStage I II III IVA IVB (M1 lymph node) History of smoking Yes No CCr (mL/min) ≥60 b60 CCI 2 3 4 5 GNRI b92 92–98 N98 Radiation field ENI IFI Median follow-up time (months), median (range)
Table 2 Treatment toxicities. No. (%)
CTCAEv4.0
80 (76–90) 31 (42) 42 (58)
Acute toxicities
61 (84) 12 (16) 41 (56) 22 (30) 10 (14) Late toxicities 9 (12) 8 (11) 40 (55) 14 (19) 2 (3) 19 (26) 5 (7) 22 (30) 27 (37) 29 (40) 12 (16) 17 (23) 15 (21) 19 (26) 9 (12) 15 (21) 24 (33) 6 (8) 48 (66) 25 (34) 24 (33) 49 (67) 41 (56) 16 (22) 14 (19) 2 (3) 28 (38) 22 (30) 23 (32) 47 (64) 26 (36) 14 (2−101)
CCI, Charlson Comorbidity Index; CCr, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; GNRI, geriatric nutritional risk index; IFI, involved-field irradiation.
Fig. 1. Kaplan–Meier estimates of survivals.
3
Nausea Malaise Dysphagia Esophagitis Esophageal fistula Dermatitis Pneumonitis Leukopenia Anemia Thrombocytopenia Esophageal stenosis Pleural effusion Pericardial effusion Pneumonitis
Grade 1/2, no. (%)
Grade 3, no. (%)
1 (1) 6 (8) 2 (3) 29 (40) 4 (5) 11 (15) 8 (11) 33 (45) 47 (64) 32 (44) 2 (3) 28 (38) 16 (22) 5 (7)
5 (7) – 3 (4) 5 (7) 2 (3) – 1 (1) 7 (10) 6 (8) – 3 (4) 2 (3) 1 (1) 1 (1)
patients than the completion group (p b .001 and p = .004, respectively). Among the 16 undernourished patients aged ≥80 years, 7 discontinued DOC-RT. No other baseline factors, including sex, ECOG PS, clinical stage, smoking status, creatinine clearance, CCI, and radiation field, were associated with the completion rate. Table 3 Comparison between the non-completion and completion groups. Patient and tumor characteristics
Non-completion group
Completion group
p-Value
Total Age, no. (%) ≥80 years b80 years Sex, no. (%) Male Female ECOG PS, no. (%) 0 1 2 T factor, no. (%) 1 2 3 4 N factor, no. (%) 0 1–3 cStage, no. (%) I II III IVA IVB (M1 lymph node) History of smoking Yes No CCr (mL/min) ≥60 b60 CCI 2 3 4 5 GNRI, no. (%) ≥92 b92 Radiation field ENI IFI
8
65
8 (100) 0
23 (35) 42 (65)
b0.001
7 (87) 1 (13)
54 (83) 11 (17)
1
2 (25) 4 (50) 2 (25)
39 (60) 18 (28) 8 (12)
0.137
2 (25) 0 3 (37.5) 3 (37.5)
17 (26) 5 (8) 19 (29) 24 (37)
1
2 (25) 6 (75)
27 (42) 38 (58)
0.47
2 (25) 0 3 (37.5) 3 (37.5) 0
17 (26) 9 (14) 12 (19) 21 (32) 6 (9)
0.7
7 (87) 1 (13)
41 (63) 24 (37)
0.25
2 (25) 6 (75)
22 (34) 43 (66)
1
3 (37) 2 (25) 2 (25) 1 (13)
38 (58) 14 (21) 12 (19) 1 (2)
0.23
1 (13) 7 (87)
44 (68) 21 (32)
0.004
7 (87) 1 (13)
40 (62) 25 (38)
0.25
CCI, Charlson Comorbidity Index; CCr, creatinine clearance; ECOG PS, Eastern Cooperative Oncology Group performance status; ENI, elective nodal irradiation; GNRI, geriatric nutritional risk index; IFI, involved-field irradiation.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
7 0 0 26/12/21/41 40 26/7/30/37
28/32/32/8 20/16/40/24 NA Watanabe
2019 73 Our report
2018 25
2018 55 Walter31
32
2016 16 Ohba20
5FU, 5-fluorouracil; DOC, docetaxel; FP, 5-fluorouracil plus cisplatin; MST, median survival time; NA, information not available; RT, radiotherapy.
10 21 89
8 32 28 72 24 84
4 7 5 33 12 66
FP or mitomycin C 59.4 Gy/33 fr. + 5FU Nedaplatine 50.4 Gy/28 fr. +5FU DOC 60 Gy/30 fr. NA 46 2/20/58/20
31 6 0 6 27.7 88 60 Gy/30 fr. DOC 0/34/56/0 19 25/6/69/0
33 52 70 14.7 67 60 Gy/30 fr. FP 0/54/46/0 43 6/6/88/0 2007 33 Takeuchi8
74 (71–79) 77 (73–81) 75 (70–85) 79 (76–85) 80 (76–90)
Thrombo–cytopenia Grade 3–4 (%) Anemia Grade 3–4 (%) Leukopenia Grade 3–4 (%) MST (months) Treatment completion rate (%) Median prescribed dose Chemotherapy regimen cStage I/II/III/IV (%) T1/2/3/4 (%) N0 (%) No. Median age years (range) Year
Table 4 Literature review of results for radiotherapy in elderly patients with esophageal cancer.
The present study was designed to assess the safety of DOC-RT among older adults with EC (age, ≥76 years). When comparing our results with those of other similar studies, three important factors need to be addressed; 1) hematological toxicity, 2) radiation-induced esophagitis, and 3) patients' underlying conditions including nutritional status and comorbidities. Our results showed that CRT at 60 Gy with 10 mg/m2 of DOC weekly for 6 consecutive weeks produced grade 3/4 leukopenia in 10%, anemia in 8%, and esophagitis in 7% of the patients, with a completion rate of 89%. A separate retrospective study among older adults with EC receiving CRT at 60 Gy with concurrent FP showed grade 3/4 leukopenia in 70%, anemia in 52%, thrombocytopenia in 33%, and esophagitis in 9% of the patients, with a completion rate of 67%. Moreover, older adults developed leukopenia and anemia more frequently and had lower CRT completion rates than non-older adults [8]. Another retrospective study involving older adults with EC receiving CRT with concurrent cisplatin and S-1 observed that those aged 75 years had a significantly higher incidence of severe leukopenia than those aged between 70 and 75 years (41.9% vs. 72.0%, respectively) [29]. These reports suggest that cisplatinum-based CRT places older adults at high risk for severe leukopenia. Conversely, the results of a prospective trial demonstrated promising and acceptable toxicity profiles for DOC-RT in patients with inoperable EC aged between 41 and 88 years, in which grade 3/4 toxicities included leukopenia in 9%, anemia in 6%, thrombocytopenia in 3%, and esophagitis in 17% of the patients. DOC-RT was discontinued due to progressive disease (four patients), deteriorating performance status (one patient), pneumonia (one patient), and an acute abdominal episode (one patient), resulting in a DOC-RT completion rate of 79% (27/34 patients) [18]. Moreover, a phase 2 study on DOC-RT in older adults with locally advanced EC showed grade 3/4 leukopenia in 6% and thrombocytopenia in 6% of the patients, with a treatment completion rate of 88% [20]. Considering the aforementioned findings, the present study demonstrated that DOC-RT had lower hematological toxicity rates than cisplatinum-based CRT in older adults with EC. Thus, DOCRT can be a safer regimen for older adults with EC in terms of hematological toxicities. The phase 2 study of DOC-RT in older adults with locally advanced EC reported a high rate of grade 3/4 acute esophagitis (31.3%) and a total radiation dose reduction was recommended [20]. A reduction in the total radiation dose is generally considered to decrease the incidence of esophagitis, particularly in older adults. A prospective study on patients with EC aged over 80 treated with RT alone delivered at 66 Gy showed a low rate of grade 3/4 acute esophagitis (4%) [30]. In addition to this, the rate of grade 3/4 acute esophagitis in our study was generally favorable compared with the outcomes of previous studies (Table 4) [8,20,31,32]. Thus, it may not be necessary to reduce the total radiation dose for DOC-RT in all older adults. In older adults, there are sometimes problems that must be considered in treatment decisions, such as comorbidities and nutritional status. However, only few reports focused on comorbidities and nutritional status in the treatment decisions of older adults with EC [31,33–36]. Malnutrition, which is a common condition at diagnosis in older adults, often impaired performance status, quality of life, response to treatment, and even survival [37]. Bo et al. reported that the risk of mortality increased by 68.8% [hazard ratio (HR) = 1.688; 95% CI, 1.019–2.798] for the moderate-risk group (GNRI 92–98) and by 169.9% (HR = 2.699; 95% CI, 1.512–4.819) for the high-risk group (GNRI b92) compared with the non-nutritional risk group (GNRI N98) in older adults with EC treated with RT [34]. CCI—a tool used to predict mortality by classifying or weighting comorbidities—has been utilized widely by health researchers to measure the burden of disease [25]. The CCI is associated with OS as well as with treatment-related death in older adults with EC [31,36]. In our study, we compared the proportions of categorical variables between the non-completion and
Esophagitis Grade 3–4 (%)
4. Discussion
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Author
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Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009
T. Kawamoto et al. / Journal of Geriatric Oncology xxx (2019) xxx
completion groups to analyze which older adults with EC may be unfit for DOC-RT. The non-completion group comprised a higher proportion of older adults (age ≥ 80 years) and undernourished (GNRI b92) patients than the completion group, but the CCI was not associated. Thus, older adults and undernourished patients may need therapy with less toxicity burden, such as RT alone or palliative treatment. The present study has several limitations associated with its retrospective design. First, we could not demonstrate a benefit of treatment with DOC-RT compared with RT alone. A previous retrospective study suggested that platinum- or taxane-based concurrent CRT (MST, 22.3 months) is superior to sequential CRT (MST, 18.0 months) and RT alone (MST, 12.4 months) in older adults with stage I–IV EC [38]. In our study, the MST was 21 months for older adults. In terms of survival, DOC-RT might be a recommended treatment for older adults with EC. Second, this study has selection biases. We enrolled patients with stage I–IV EC in a single institution and some of the patients were fit for FP-RT. Therefore, a prospective study with a uniform strategy, such as inclusion of older adults with stage II/III EC who are medically unfit for surgery or FP-RT, in a multi-institutional setting is essential. In conclusion, DOC-RT can be a safe regimen for older adults with EC. Nonetheless, older age (over 80 years) and undernourishment (GNRI b92) should be considered in determining the administration of DOCRT. To establish a new treatment option, Japanese study groups are conducting a phase I/II clinical trial assessing taxane-based concurrent CRT in older adults with EC [the University Hospital Medical Information Network (UMIN) Clinical Trials Registry as UMIN000020397]. Author Contributions TK prepared the manuscript and conducted the literature search; TK reviewed and edited the manuscript; and TK, NS, MO, YK, MT, and KS reviewed the manuscript. All authors have read and approved the final manuscript. Declaration of Competing Interest None. References [1] Di Pardo BJ, Bronson NW, Diggs BS, Thomas Jr CR, Hunter JG, Dolan JP. The global burden of esophageal cancer: a disability-adjusted life-year approach. World J Surg 2016;40(2):395–401. [2] Faiz Z, Lemmens VE, Siersema PD, Nieuwenhuijzen GA, Wouters MW, Rozema T, et al. Increased resection rates and survival among patients aged 75 years and older with esophageal cancer: a Dutch nationwide population-based study. World J Surg 2012;36(12):2872–8. [3] National Cancer Center in Japan. Center for Cancer Control and in- formation services. Available at http://ganjoho.jp/reg_stat/index.html; 2017. [4] Ando N, Kato H, Igaki H, Shinoda M, Ozawa S, Shimizu H, et al. A randomized trial comparing postoperative adjuvant chemotherapy with cisplatin and 5-fluorouracil versus preoperative chemotherapy for localized advanced squamous cell carcinoma of the thoracic esophagus (JCOG9907). Ann Surg Oncol 2012;19(1):68–74. [5] Kato K, Muro K, Minashi K, Ohtsu A, Ishikura S, Boku N, et al. Phase II study of chemoradiotherapy with 5-fluorouracil and cisplatin for stage II-III esophageal squamous cell carcinoma: JCOG trial (JCOG 9906). Int J Radiat Oncol Biol Phys 2011;81 (3):684–90. [6] Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson Jr JA, Al-Sarraf M, et al. Chemoradiotherapy of locally advanced esophageal cancer: long-term follow-up of a prospective randomized trial (RTOG 85-01). Radiation Therapy Oncology Group. Jama 1999;281(17):1623–7. [7] Kato K, Nakajima TE, Ito Y, Katada C, Ishiyama H, Tokunaga SY, et al. Phase II study of concurrent chemoradiotherapy at the dose of 50.4 Gy with elective nodal irradiation for Stage II-III esophageal carcinoma. Jpn J Clin Oncol 2013;43(6):608–15. [8] Takeuchi S, Ohtsu A, Doi T, Kojima T, Minashi K, Mera K, et al. A retrospective study of definitive chemoradiotherapy for elderly patients with esophageal cancer. Am J Clin Oncol 2007;30(6):607–11. [9] Einzig AI, Neuberg D, Remick SC, Karp DD, O'Dwyer PJ, Stewart JA, et al. Phase II trial of docetaxel (Taxotere) in patients with adenocarcinoma of the upper gastrointestinal tract previously untreated with cytotoxic chemotherapy: the Eastern Cooperative Oncology Group (ECOG) results of protocol E1293. Med Oncol 1996;13(2): 87–93.
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[10] Rigas JR, Dragnev KH, Bubis JA. Docetaxel in the treatment of esophageal cancer. Semin Oncol 2005;32(2):S39–51 Suppl 4. [11] Hennequin C, Giocanti N, Favaudon V. Interaction of ionizing radiation with paclitaxel (Taxol) and docetaxel (Taxotere) in HeLa and SQ20B cells. Cancer Res 1996; 56(8):1842–50. [12] Dunne AL, Mothersill C, Robson T, Wilson GD, Hirst DG. Radiosensitization of colon cancer cell lines by docetaxel: mechanisms of action. Oncol Res 2004;14(9):447–54. [13] Mauer AM, Masters GA, Haraf DJ, Hoffman PC, Watson SM, Golomb HM, et al. Phase I study of docetaxel with concomitant thoracic radiation therapy. J Clin Oncol 1998;16 (1):159–64. [14] Kushida T, Nohara S, Yoshino K, Fujiwara D, Ouchi K, Amano T, et al. Utility of weekly docetaxel combined with preoperative radiotherapy for locally advanced esophageal cancer from pathological analysis. Dis Esophagus 2014;27(4):368–73. [15] Koukourakis MI, Kourousis C, Kamilaki M, Koukouraki S, Giatromanolaki A, Kakolyris S, et al. Weekly docetaxel and concomitant boost radiotherapy for non-small cell lung cancer. A phase I/II dose escalation trial. Eur J Cancer 1998;34(6):838–44. [16] Calais G, Bardet E, Sire C, Alfonsi M, Bourhis J, Rhein B, et al. Radiotherapy with concomitant weekly docetaxel for Stages III/IV oropharynx carcinoma. Results of the 9802 GORTEC Phase II trial. Int J Radiat Oncol Biol Phys 2004;58(1):161–6. [17] Fujii M, Tsukuda M, Satake B, Kubota A, Kida A, Kohno N, et al. Phase I/II trial of weekly docetaxel and concomitant radiotherapy for squamous cell carcinoma of the head and neck. Int J Clin Oncol 2004;9(2):107–12. [18] Font A, Arellano A, Fernandez-Llamazares J, Casas D, Boix J, Cardenal J, et al. Weekly docetaxel with concomitant radiotherapy in patients with inoperable oesophageal cancer. Clin Transl Oncol 2007;9(3):177–82. [19] Hokamura N, Kawano N, Takmaki Y. A phase I study of docetaxel with concurrent radiotherapy in patients with esophageal cancer; 2008. [20] Ohba A, Kato K, Ito Y, Katada C, Ishiyama H, Yamamoto S, et al. Chemoradiation therapy with docetaxel in elderly patients with stage II/III esophageal cancer: a phase 2 trial. Adv Radiat Oncol 2016;1(4):230–6. [21] Common toxicity criteria, Version2.0 publish date; April 30 1999. [22] Brierley J, Gospodarowicz MK, Wittekind C. TNM classification of malignant tumours. . 8th ed.Chichester, West Sussex, UK; Hoboken, NJ: John Wiley & Sons, Inc; 2017. [23] National Cancer Institute (U.S.). In: Bethesda Md, editor. Common terminology criteria for adverse events (CTCAE). Rev. National Cancer Institute: U.S. Dept. of Health and Human Services, National Institutes of Health; 2009. [24] Quan H, Li B, Couris CM, Fushimi K, Graham P, Hider P, et al. Updating and validating the Charlson comorbidity index and score for risk adjustment in hospital discharge abstracts using data from 6 countries. Am J Epidemiol 2011;173(6):676–82. [25] Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis 1987;40(5):373–83. [26] Bouillanne O, Morineau G, Dupont C, Coulombel I, Vincent JP, Nicolis I, et al. Geriatric nutritional risk index: a new index for evaluating at-risk elderly medical patients. Am J Clin Nutr 2005;82(4):777–83. [27] Cereda E, Pedrolli C. The geriatric nutritional risk index. Curr Opin Clin Nutr Metab Care 2009;12(1):1–7. [28] Kanda Y. Investigation of the freely available easy-to-use software 'EZR' for medical statistics. Bone Marrow Transplant 2013;48(3):452–8. [29] Wang H, Li G, Chen L, Duan Y, Zou C, Hu C. Definitive concurrent chemoradiotherapy with S-1 and cisplatin in elderly esophageal squamous cell carcinoma patients. J Thorac Dis 2017;9(3):646–54. [30] Kawashima M, Kagami Y, Toita T, Uno T, Sugiyama M, Tamura Y, et al. Prospective trial of radiotherapy for patients 80 years of age or older with squamous cell carcinoma of the thoracic esophagus. Int J Radiat Oncol Biol Phys 2006;64(4): 1112–21. [31] Walter F, Bockle D, Schmidt-Hegemann NS, Kopple R, Gerum S, Boeck S, et al. Clinical outcome of elderly patients (N/= 70 years) with esophageal cancer undergoing definitive or neoadjuvant radio(chemo)therapy: a retrospective single center analysis. Radiat Oncol 2018;13(1):93. [32] Watanabe A, Katada C, Komori S, Moriya H, Yamashita K, Harada H, et al. Feasibility of definitive chemoradiation therapy with nedaplatin and 5-fluorouracil in elderly patients with esophageal squamous cell carcinoma: a retrospective study. Adv Radiat Oncol 2018;3(3):305–13. [33] Yin H, E M, Zhang H, Wang C. The outcomes of radiotherapy and factors that predict overall survival in elderly patients with esophageal squamous cell carcinoma. Clin Transl Oncol 2017;19(6):742–9. [34] Bo Y, Wang K, Liu Y, You J, Cui H, Zhu Y, et al. The geriatric nutritional risk index predicts survival in elderly esophageal squamous cell carcinoma patients with radiotherapy. PLoS One 2016;11(5):e0155903. [35] Song T, Du D, Zhang X, Fang M, Wu S. Comparative study of radiotherapy plus erlotinib versus chemoradiotherapy for elderly patients with esophageal cancer: a propensity score-matched analysis. Dis Esophagus 2017;30(9):1–10. [36] Tougeron D, Di Fiore F, Thureau S, Berbera N, Iwanicki-Caron I, Hamidou H, et al. Safety and outcome of definitive chemoradiotherapy in elderly patients with oesophageal cancer. Br J Cancer 2008;99(10):1586–92. [37] Van Cutsem E, Arends J. The causes and consequences of cancer-associated malnutrition. Eur J Oncol Nurs 2005;9(Suppl. 2):S51–63. [38] Li X, Zhao LJ, Liu NB, Zhang WC, Pang QS, Wang P, et al. Feasibility and efficacy of concurrent chemoradiotherapy in elderly patients with esophageal squamous cell carcinoma: a respective study of 116 cases from a single institution. Asian Pac J Cancer Prev 2015;16(4):1463–9.
Please cite this article as: T. Kawamoto, N. Shikama, M. Oshima, et al., Safety of radiotherapy with concurrent docetaxel in older patients with esophageal cancer, J Geriatr Oncol, https://doi.org/10.1016/j.jgo.2019.08.009