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    -  Watanabe S
    -  Ogino I
    -  Kunisaki C
    -  Hata M

 
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ORIGINAL ARTICLE
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Sequential chemotherapy after definitive radiotherapy in markedly elderly patients with advanced esophageal cancer


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 Submission29-Aug-2019
Date of Decision01-Sep-2019
Date of Acceptance17-Jan-2020
Date of Web Publication10-Dec-2020

Correspondence Address:
Shigenobu Watanabe,
Department of Radiation Oncology, Yokohama City University Medical Center, Yokohama
Japan
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ijc.IJC_768_19

PMID: 33402604

  Abstract 


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 Jan 24]. Available from: https://www.indianjcancer.com/preprintarticle.asp?id=302943





  Introduction Top


Esophageal cancer is the seventh most common malignancy in males and the thirteenth most common malignancy in females.[1] Globally, more than 572,000 new cases and approximately 508,600 patients were expected to die from esophageal cancer in 2018.[2],[3] Over 90% of all esophageal cancer cases occur in East and Southeast Asia, sub-Saharan Africa, and Central Asia.[4]

Radiotherapy (RT) and chemoradiotherapy (CRT) are effective and considered as alternatives to surgery for locally advanced squamous cell carcinoma of the esophagus.[5],[6] 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.[7] Although several studies have reported elderly patients with esophageal cancer who received RT alone or CRT,[8],[9],[10] 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 Top


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)[11] followed by 3 courses of docetaxel and cisplatin (DC).[12] 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.

Statistical analysis

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 Top


Patient characteristics

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.
Table 1: Patient characteristics

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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)[13] 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

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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

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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)

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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

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Table 3: Univariate and multivariate analyses of the factors associated with progression-free survival outside the field

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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 Top


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.[14],[15],[16]

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.[17] 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,[18] whereas another found that CCRT was superior to SCRT in terms of survival outcomes.[19] 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.[20],[21],[22] 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,[15],[20],[22],[23] whereas the 1- and 3-year OS rates of SCRT were 65.6% and 34.4%, respectively.[18] 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.[20] 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.[24]

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.[25],[26] 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 Top


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

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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