|Ahead of print
Sequential chemotherapy after definitive radiotherapy in markedly elderly patients with advanced esophageal cancer
Shigenobu Watanabe1, Ichiro Ogino1, Chikara Kunisaki2, Masaharu Hata3
1 Department of Radiation Oncology, Yokohama City University Medical Center, Yokohama, Japan
2 Gastroenterological Center, Yokohama City University Medical Center, Yokohama, Japan
3 Department of Radiology, Yokohama City University, Graduate School of Medicine, Yokohama, Japan
|Date of Submission||29-Aug-2019|
|Date of Decision||01-Sep-2019|
|Date of Acceptance||17-Jan-2020|
|Date of Web Publication||10-Dec-2020|
Department of Radiation Oncology, Yokohama City University Medical Center, Yokohama
Source of Support: None, Conflict of Interest: None
Background: Concurrent chemoradiotherapy (CCRT) is the standard treatment for advanced esophageal cancer, but it may be more invasive in the elderly and definitive radiotherapy (RT) alone may be selected. This study assessed the significance of sequential chemoradiotherapy (SCRT) in elderly esophageal cancer patients.
Methods: We reviewed 87 patients aged 75 years and older, who were treated using definitive radiotherapy without concurrent chemotherapy for esophageal cancer. A total dose ranging from 50.4 to 63 Gy (median, 58.8) was delivered to the primary lesion and the involved lymph nodes. This study compared patients who received SCRT with those who received RT alone among 40 patients with stage III or IVA cancer. Descriptive statistics were calculated using Cox proportional hazards regression analysis and the generalized Wilcoxon test.
Results: The total progression-free survival (TPFS), progression-free survival outside the irradiation field, and overall survival were significantly longer after SCRT (n = 15) than after definitive RT alone (n = 25; P = 0.0041 and 0.0098), whereas the progression-free survival in the irradiation field was not significantly different between the two groups. The TPFS was significantly shorter in patients who received RT alone than in those who received SCRT (P = 0.0372). There were no grade 4 or higher adverse events in the patients who received SCRT.
Conclusion: SCRT was associated with a reduced relapse rate, suggesting that it should be considered for markedly elderly patients with advanced esophageal cancer.
Keywords: Advanced esophageal cancer, markedly elderly, sequential chemoradiotherapy
Key Message Sequential chemoradiotherapy is associated with a reduced relapse rate and longer overall survival in markedly elderly patients with advanced esophageal cancer. Sequential chemoradiotherapy should be considered for these patients.
|How to cite this URL:|
Watanabe S, Ogino I, Kunisaki C, Hata M. Sequential chemotherapy after definitive radiotherapy in markedly elderly patients with advanced esophageal cancer. Indian J Cancer [Epub ahead of print] [cited 2021 Apr 14]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=302943
| » Introduction|| |
Esophageal cancer is the seventh most common malignancy in males and the thirteenth most common malignancy in females. Globally, more than 572,000 new cases and approximately 508,600 patients were expected to die from esophageal cancer in 2018., Over 90% of all esophageal cancer cases occur in East and Southeast Asia, sub-Saharan Africa, and Central Asia.
Radiotherapy (RT) and chemoradiotherapy (CRT) are effective and considered as alternatives to surgery for locally advanced squamous cell carcinoma of the esophagus., In addition, concurrent CRT (CCRT) is recommended for the treatment of esophageal cancer. However, frailty can hinder the completion of CCRT in elderly patients, who, therefore, need a more carefully planned treatment strategy and/or multidisciplinary supportive care. Although several studies have reported elderly patients with esophageal cancer who received RT alone or CRT,,, treatment approaches for esophageal cancer have not been established for elderly patients. It is necessary to examine the treatment methods used in elderly patients with esophageal cancer for whom CCRT has not been adopted due to their frailty. In the present study, we compared outcomes in markedly elderly patients (age ≥75 years) with esophageal cancer who underwent RT alone or sequential CRT (SCRT).
| » Subjects and Methods|| |
Patient data collection
In this retrospective study, we reviewed the medical records of patients who received definitive RT without CCRT between January 2010 and November 2018. In total, 87 patients who were 75 years of age or older, whom we defined as markedly elderly patients, at the start of RT were included in this study. All patients were restaged using the eighth edition of the Union for International Cancer Control TNM classification. Of the 87 patients, 40 had stage III or IVA disease without evidence of distant metastasis at the end of radiotherapy. This study compared patients who received SCRT with those who received RT alone among the 40 patients.
The follow-up time was defined as the period from the date of RT completion to the date of death or final confirmation of survival. The median follow-up of the study cohort was 9.5 months (range, 1–48 months).
Gastroscopy and computed tomography (CT) were performed for pretreatment staging on all patients. Evaluations after treatment were performed every 3 to 6 months, and comprised provisional medical history and physical examination, laboratory tests, and CT or positron emission tomography/CT. At each follow-up visit, treatment-related toxicities were assessed and scored according to the National Cancer Institute's common terminology criteria for adverse events version 4.0.
This retrospective study was conducted in accordance with the code of ethics (approval number: B170700047). All patients included in the study provided written informed consent for treatment.
Radiotherapy and chemotherapy
All patients received definitive RT. RT was delivered 5 days per week, with daily doses ranging from 1.8 to 2.0 Gy. A prophylactic dose ranging from 41.4 to 51.3 Gy (median, 44.0 Gy) was delivered to regional lymph nodes. A total dose ranging from 50.4 to 63 Gy (median, 58.8 Gy) was delivered to the primary lesion and the affected lymph nodes. During RT, for simulation and treatment, all patients were immobilized in a supine position. Planning CT images of the entire chest were obtained using a Lightspeed RT Scanner (GE Healthcare UK) with a 2.5 mm slice thickness under shallow breathing. During the planning of three-dimensional treatment, contouring of the target lesion and organs-at-risk was performed by radiation oncologists. Dose distributions were calculated using the Pinnacle 3 software program (Philips, Amsterdam, Netherlands).
No patients received induction chemotherapy. Patients with impaired liver or kidney function, or those with a performance status (PS) of 3 or 4 at the end of RT were excluded from SCRT. All patients with medical indication were offered SCRT. The standard sequential chemotherapy regimen was of two courses of standard-dose cisplatin and 5-fluorouracil (sFP) followed by 3 courses of docetaxel and cisplatin (DC). Sequential chemotherapy was discontinued for patients who had a PS that deteriorated to 3 or 4, who became unable to tolerate chemotherapy due to impaired liver or kidney function, or who refused to continue chemotherapy during sequential chemotherapy.
The following definitions were used in this study. Overall survival (OS) was defined as the period from the last day of radiotherapy to the day of death regardless of cause. Disease-specific survival was defined as the period from the last day of radiotherapy to the day of death due to esophageal cancer. Total progression-free survival (TPFS) was defined as the period from the last day of radiotherapy to the day when a re-increase in the size of the remaining lesion or development of a new lesion was confirmed. The progression-free survival period in the irradiation field (IFPFS) was defined as the period from the last day of radiotherapy to the day when a re-increase in the size of the remaining lesion or the development of a new lesion in the irradiation field was confirmed. The progression-free survival period out of the irradiation field (OFPFS) was defined as the period from the last day of radiotherapy to the day of a new lesion developing outside the irradiation field.
The Mann–Whitney U test was used to evaluate associations between the treatment and examined characteristics. Descriptive statistics were calculated, and time-to-event analyses were performed using Cox's proportional hazards regression analysis. The Kaplan–Meier method was used to calculate the cumulative incidence of disease progression, disease-specific death, and mortality rate in the two groups, and the generalized Wilcoxon test was used to analyze the differences in these parameters between the two groups. For all analyses, a two-tailed P value of <0.05 was considered statistically significant. All statistical analyses were performed using the JMP pro version 12.2 software package (SAS Institute, Tokyo, Japan).
| » Results|| |
This study included 30 men and 10 women, with a median age of 79.6 (range: 75 - 88) years. The pathological type was squamous cell carcinoma in all patients. The therapeutic effects at the end of radiotherapy were complete remission, partial remission, and stable disease in 5, 33, and 2 patients, respectively. Nine patients had a history of other cancers. However, the history of other cancers did not affect treatment choice. The detailed characteristics of the two groups are presented in [Table 1]. Briefly, the median age was significantly lower and the PS score was significantly higher in the SCRT group. None of the remaining characteristics differed significantly between the two groups.
Characteristics of the patients who received sequential CRT
Fifteen patients were treated using SCRT. Among them, contrary to the standard regimen, 2 received 3 course of DC and 1 received Gimeracil and Oteracil Porassium (S-1) medication for 3 months. The remaining 12 patients were started on standard sequential chemotherapy, which was 2 courses of sFP followed by 3 courses of DC. However, only 3 patients were able to complete the planned regimen. They were all under age 77 and PS0 at the end of radiotherapy. The other 9 patients were unable to complete the regimen due to PS deterioration (3 or 4), grade 3 cytopenia, or refusal for treatment. Among the 9 patients, 4 received only 1 course of sFP and 5 received 2 courses.
One patient developed grade 3 cytopenia, but all other adverse events were grade 2 or lower in this group.
Characteristics of patients who received RT alone
Thirty-five patients were treated using RT alone. Among them, 13 did not receive SCRT for medical reasons, such as heart failure, maintenance dialysis, or poor PS (3 or 4), at the end of RT, and 6 patients refused sequential CRT due to personal or family preferences. The reason why the remaining 6 patients did not receive SCRT was not recorded.
In this group, 2 patients developed grade 5 esophago-aortic fistula and 2 patients developed grade 3 pneumonitis. The remaining adverse events were grade 2 or lower.
Comparison of prognosis between patients who received SCRT and RT alone
The 2-year TPFS and OFPFS rates were significantly higher in the SCRT group than in the RT alone group (25.2% versus 0%, P = 0.0041; [Figure 1]). Similarly, the 2-year IFPFS rate was higher in the SCRT group, albeit insignificantly (29.2% versus 0%, P = 0.1079). Furthermore, the 2-year OFPFS rate was significantly higher in the SCRT group than in the RT alone group (60.0% versus 26.7%, P = 0.0098; [Figure 2]). The 2-year OS rate was also significantly higher in the SCRT group (38.0% versus 15.0%, P = 0.0295; [Figure 3]), and the 2-year DSS was higher in the SCRT group than in the RT alone group, but not significantly (49.9% versus 19.9%, P = 0.1261).
|Figure 1: Kaplan–Meier curves for total progression-free survival in 15 patients who underwent sequential chemotherapy and 25 patients who did not undergo sequential chemotherapy (P = 0.0041). *Chemoradiotherapy, †Radiotherapy|
Click here to view
|Figure 2: Kaplan–Meier curves for progression-free survival outside the field in 15 patients who underwent sequential chemotherapy and 25 patients who did not undergo sequential chemotherapy (P = 0.0098). *Chemoradiotherapy, †Radiotherapy|
Click here to view
|Figure 3: Kaplan–Meier curves for overall survival in 15 patients who underwent sequential chemotherapy and 25 patients who did not undergo sequential chemotherapy (P = 0.0295)|
Click here to view
By the Cox's proportional hazards regression model-based univariate analysis, younger age and a good PS score were significantly associated with a longer TPFS. In the multivariate analysis, the TPFS of the patients who received RT alone was significantly shorter than that of the patients who received SCRT [Table 2]. In addition, younger age and a good PS score were significantly associated with a longer OFPFS in the univariate analysis. However, in the multivariate analysis, neither was significantly associated with prolonged OFPFS [Table 3]. None of the other evaluated factors were associated with a significantly longer IFPFS, OS, or DSS.
|Table 2: Univariate and multivariate analyses of factors associated with total progression-free survival|
Click here to view
|Table 3: Univariate and multivariate analyses of the factors associated with progression-free survival outside the field|
Click here to view
Prognosis of patients with lymph node metastasis
Among the study cohort of 40 patients, 36 had lymph node metastases; of these, 13 patients received SCRT, whereas the remaining 23 patients received RT alone. Survival analyses based on the lymph node metastasis status revealed that the 2-year TPFS rate was significantly higher in the subgroup with SCRT than in the subgroup with RT alone (43.3% versus 0%, P = 0.0146). Similarly, the 2-year IFPFS rate was higher in the subgroup with SCRT than in the subgroup with RT alone, although the difference was not significant (52.7% versus 0%, P = 0.2223). In addition, the 2-year OFPFS rate was significantly higher in the subgroup with SCRT than in the subgroup with RT alone (53.6% versus 25.6%, P = 0.0165). Furthermore, the 2-year OS rate was higher in the subgroup with SCRT than in the subgroup with RT alone, although not significantly (31.2% versus 17.1%, P = 0.0547). The 2-year DSS rate was also higher in the subgroup with SCRT than in the subgroup with RT alone, although not significantly (42.7% versus 23.3%, P = 0.2163).
In the subgroup of 4 patients without lymph node metastases, there were no significant differences in TPFS (P = 0.1025), IFPFS (P = 0.1573), OFPFS (P = 0.3173), OS (P = 0.3173), or DSS (P = 0.3173) between those who received SCRT and those who received RT alone.
| » Discussion|| |
CCRT is the standard treatment for inoperable advanced esophageal cancer, and CCRT and cisplatin-based chemotherapy are recommended over radiotherapy alone. However, treatment outcomes using this approach are not satisfactory. In addition, the incidence of treatment-related adverse events remains high in patients who are administered CCRT. Therefore, CCRT should be performed following consideration of the potential risks and benefits and the patient's general condition.,,
In elderly patients, the use of chemotherapy is often limited due to age-associated decline in functional reserve, increased rates of comorbid conditions, and concomitant medication use. Therefore, CCRT is often not feasible due to excessive tumor invasion in elderly patients. For patients precluded from CCRT based on choice or comorbidities, there is minimal evidence regarding optimal doses and dose fractions. Most studies were performed using conventional fractions (1.8–2 Gy/fraction). RT alone or in combination with chemotherapy as SCRT are treatment options for patients who cannot receive CCRT, and treatment outcomes of patients with esophageal cancer who receive SCRT and those who receive CCRT remain controversial. One study reported that CCRT and SCRT groups exhibited similar survival outcomes, whereas another found that CCRT was superior to SCRT in terms of survival outcomes. However, RT alone and SCRT are considered reasonable treatment strategies for elderly patients with esophageal cancer who cannot receive CCRT. In the present study, all patients who completed the planned SCRT regimen were under 77 and PS0 at the end of radiotherapy. This criterion may be a selection criterion to choose patients for SCRT.
Several studies have evaluated the outcomes of RT and CRT for esophageal cancer. In the studies that investigated RT alone, the 1-, 2-, and 3-year OS rates were 33.9%–38%, 9.7%–17%, and 0%–21%, respectively.,, Conversely, the studies assessing outcomes of CCRT found that the 1-, 2-, and 3-year OS rates were 47%–62.3%, 21%–36.1%, and 26.1%–44.7%, respectively,,,, whereas the 1- and 3-year OS rates of SCRT were 65.6% and 34.4%, respectively. In the present study, the 2-year OS rates of the patients who received CRT and RT alone were 38.0% and 15.0%, respectively, which were comparable with those reported in the previous studies. Moreover, comparison of the SCRT and RT alone groups revealed that the difference in OFPFS was larger than that in IFPFS. This suggests that SCRT is effective in controlling micrometastases outside of the irradiation field in markedly elderly patients with esophageal cancer.
The previous studies reported that chemotherapy suppressed the development of clinical distant metastases by eradicating subclinical distant metastases. Chemotherapy is a systemic treatment, whereas radiotherapy and surgery are local treatments. Therefore, the addition of chemotherapy after surgery is comparable to the addition of chemotherapy after RT. Postoperative chemotherapy is effective in suppressing recurrence and significantly prolonging DFS. In addition, risk reduction by postoperative chemotherapy was previously reported to be significant in patients with lymph node metastasis.
In the current study, SCRT was more effective in patients with lymph node metastases than in those without. Specifically, SCRT improved the OFPFS significantly but did not improve the IFPFS in the patients with lymph node metastasis. Similar to surgical cases, SCRT may be effective for patients with lymph node metastases who have a higher risk of micrometastases to lymph nodes and distant metastasis outside the irradiation field.
In the current study, we also found that the patients who underwent SCRT had a better PFS and OS than those who received RT alone; however, these differences were not significant. Furthermore, adverse events in the patients who received SCRT were not worse than those in patients who received RT alone. In the elderly, hospitalization is associated with a decline in activities of daily living and leads to frailty and increased mortality., However, SCRT is considered to be more beneficial despite its adverse effects and accompanying hospitalization.
To the best of our knowledge, this is the first study reporting the significant prognostic benefits of SCRT in markedly elderly patients with advanced esophageal cancer for whom the adoption of CCRT is challenging. Although there are limitations due to the small cohort size and observational study design at a single center, the current study suggested that SCRT can suppress recurrence after radiotherapy and improve survival. Additional studies, such as interventional clinical trials, are necessary for conclusive results.
| » Conclusions|| |
SCRT was associated with a reduced relapse rate and longer OS in markedly elderly patients with advanced esophageal cancer. SCRT should be considered for these patients, who are expected to have a poor prognosis with RT alone, especially under age 77 and PS0 at the end of radiotherapy.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| » References|| |
Cools-Lartigue J, Spicer J, Ferri LE. Current status of management of malignant disease: Current management of esophageal cancer. J Gastrointest Surg 2015;19:964-72.
Short MW, Burgers KG, Fry VT. Esophageal cancer. Am Fam Physician 2017;95:22-8.
Blais E, Vendrely V, Sargos P, Créhange G, Huguet F, Maingon P, et al
. Chemoradiation for oesophageal cancer: A critical review of the literature. Cancer Radiother 2019;123:62-72.
Fan XW, Wu JL, Wang HB, Liang F, Jiang GL, Wu KL. Three-dimensional conformal radiation therapy alone for esophageal squamous cell carcinoma: 10-year survival outcomes. Thorac Cancer 2019;10:519-25.
Spyropoulou D, Pallis AG, Leotsinidis M, Kardamakis D. Completion of radiotherapy is associated with the Vulnerable Elders Survey-13 score in elderly patients with cancer. J Geriatr Oncol 2014;5:20-5.
Xing L, Liang Y, Zhang J, Wu P, Xu D, Liu F, et al
. Definitive chemoradiotherapy with capecitabine and cisplatin for elder patients with locally advanced squamous cell esophageal cancer. J Cancer Res Clin Oncol 2014;140:867-72.
Zhang XB, Xie CY, Li WF, Zhang P, Wu SX. Phase II study of radiotherapy plus erlotinib for elder patients with esophageal carcinoma. Zhonghua Yi Xue Za Zhi 2012;92:1615-7.
Bollschweiler E, Plum P, Monig SP, Holscher AH. Current and future treatment options for esophageal cancer in the elderly. Expert Opin Pharmacother 2017;18:1001-10.
Shinoda M, Ando N, Kato K, Ishikura S, Kato H, Tsubosa Y, et al
. Randomized study of low-dose versus standard-dose chemoradiotherapy for unresectable esophageal squamous cell carcinoma (JCOG0303). Cancer Sci 2015;106:407-12.
Zhu Y, Zhang W, Li Q, Li Q, Qiu B, Liu H, et al
. A phase II randomized controlled trial: Definitive concurrent chemoradiotherapy with docetaxel plus cisplatin versus 5-fluorouracil plus cisplatin in patients with oesophageal squamous cell carcinoma. J Cancer 2017;8:3657-66.
Song GM, Tian X, Liu XL, Chen H, Zhou JG, Bian W, et al
. Concurrent chemo-radiotherapy with S-1 as an alternative therapy for elderly Chinese patients with non-metastatic esophageal squamous cancer: Evidence based on a systematic review and meta-analysis. Oncotarget 2017;8:37963-73.
Wong RK, Malthaner RA, Zuraw L, Rumble RB. Combined modality radiotherapy and chemotherapy in nonsurgical management of localized carcinoma of the esophagus: A practice guideline. Int J Radiat Oncol Biol Phys 2003;55:930-42.
Ishida K, Ando N, Yamamoto S, Ide H, Shinoda M. Phase II study of cisplatin and 5-fluorouracil with concurrent radiotherapy in advanced squamous cell carcinoma of the esophagus: A Japan esophageal oncology group (JEOG)/Japan clinical oncology group trial (JCOG9516). Jpn J Clin Oncol 2004;34:615-9.
Nishimura Y, Suzuki M, Nakamatsu K, Kanamori S, Yagyu Y, Shigeoka H. Prospective trial of concurrent chemoradiotherapy with protracted infusion of 5-fluorouracil and cisplatin for T4 esophageal cancer with or without fistula. Int J Radiat Oncol Biol Phys 2002;53:134-9.
Talarico L, Chen G, Pazdur R. Enrollment of elderly patients in clinical trials for cancer drug registration: A 7-year experience by the US Food and Drug Administration. J Clin Oncol 2004;22:4626-31.
Chen H, Zhou L, Yang Y, Yang L, Chen L. Clinical effect of radiotherapy combined with chemotherapy for non-surgical treatment of the esophageal squamous cell carcinoma. Med Sci Monit 2018;24:4183-91.
Li F, Li T, Liu L, Lv J, Song Y, Li C, et al
. Concurrent versus sequential chemoradiotherapy for esophageal cancer among Chinese population: A meta-analysis. Tumori 2015;101:353-9.
Cooper JS, Guo MD, Herskovic A, Macdonald JS, Martenson JA Jr, 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;281:1623-7.
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;64:1112-21.
Wong R, Malthaner R. Combined chemotherapy and radiotherapy (without surgery) compared with radiotherapy alone in localized carcinoma of the esophagus. Cochrane Database Syst Rev 2006;CD002092.
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;81:684-90.
Ando N, Iizuka T, Ide H, Ishida K, Shinoda M, Nishimaki T, et al
. Surgery plus chemotherapy compared with surgery alone for localized squamous cell carcinoma of the thoracic esophagus: A Japan clinical oncology group study--JCOG9204. J Clin Oncol 2003;21:4592-6.
Boltz M, Resnick B, Capezuti E, Shuluk J, Secic M. Functional decline in hospitalized older adults: Can nursing make a difference? Geriatr Nurs 2012;33:272-9.
Rozzini R, Sabatini T, Cassinadri A, Boffelli S, Ferri M, Barbisoni P, et al
. Relationship between functional loss before hospital admission and mortality in elderly persons with medical illness. J Gerontol A Biol Sci Med Sci 2005;60:1180-3.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3]