Efficacy and safety of concurrent radiotherapy and chemotherapy for locally advanced esophageal squamous cell carcinoma: a randomized controlled trial

Abstract

Background

Neoadjuvant concurrent chemoradiotherapy (CCRT) has become the preferred modality for patients with inoperable locally advanced esophageal squamous cell carcinoma (ESCC). To investigate whether the CCRT regimen of paclitaxel plus 5-fluorouracil (TF) increases the efficacy when compared with a regimen of cisplatin plus 5-fluorouracil (PF) in the locally advanced ESCC patient treatment.

Methods

A total of 103 ESCC patients were randomly divided into study group (TF, n=52) and control group (PF, n=51), treated in Affiliated Hospital of Jiangnan University from July 2014 to June 2016. These patients were followed up for 2 years in our department by performing certain examinations to evaluate their survival state. The primary endpoint was overall survival (OS). Local control (LC), progression-free survival (PFS) and adverse effects were secondary endpoints.

Results

A total of 103 patients were enrolled. The 1-, 2-year OS for TF group was 76.9%, 59.6% versus 74.5% (χ²=0.134, P=0.72), 56.9% (χ²=0.151, P=0.70) for PF group. The 1-, 2-year LPS for TF group and PF group were 71.2%, 61.5% and 66.7% (χ²=0.065, P=0.80), 58.8% (χ²=0.079, P=0.78) respectively. The serious leukopenia (grade 3–4) incidence rate for TF group was 36.5% versus 17.6% for PF group (χ²=4.642, P<0.05).

Conclusions

When compared with the PF regimen, the TF regimen shows no survival benefit but exhibited a trend to a better control rate and a decreased distant metastasis rate. Both regimens showed tolerable toxicity.

Trial Registration

Chinese Clinical Trial Registry ChiCTR2500100712.

Introduction

Esophageal carcinoma (EC) is currently a common cancer in China, has an estimated 90% of cases classified as squamous cell carcinoma (1). The treatment of EC includes preoperative chemoradiation (chemoRT), definitive chemoradiotherapy (dCRT), or pre-esophagectomy for small or well-differentiated lesions. According to the results of the CROSS trial and some other clinical studies (2,3), neoadjuvant concurrent chemoradiotherapy (CCRT) followed by surgery is considered a standard of care for patients with operable esophageal or junctional cancer, especially in western countries. In recent years, based on the promising results of some randomized trials, CCRT has become the preferred modality for patients with inoperable locally advanced esophageal squamous cell carcinoma (ESCC). Compared with radiotherapy alone, the superiority of CCRT has been demonstrated by improved local control (LC) and overall survival (OS) (4). According to the Radiation Therapy Oncology Group (RTOG) 8501, cisplatin combined with a continuous 5-fluorouracil infusion (PF) is still the dominant CCRT regimen (5). Nonetheless, paclitaxel has shown an advantage in the treatment of EC (6). Paclitaxel is a new antineoplastic drug which has been reported to enhance radio-sensitivity. In recent years, paclitaxel has been increasingly utilized in CCRT.

The MD Anderson Cancer Center (MDACC) reported that 5-fluorouracil/paclitaxel combined radiotherapy in patients with esophagus and gastroesophageal junction carcinoma, and they found that the toxicity of the regimen was tolerable. Compared two paclitaxel-based regimens with the PF regimen from the RTOG 9405 trial in dCRT for localized EC patients, the results showed that the paclitaxel-based regimen had a trend to increase OS compared with PF regimen (1-year OS, 76% vs. 69%, P=0.104) (7,8). Since then, several single-arm II trials of the paclitaxel plus 5-fluorouracil (TF) regimen for ESCC patients have shown good efficacy, with 3-year OS rating from 35.8% to 42.0% (9,10).

In this study, we designed a phase 3 trial to compare the efficacy and safety between two CCRT regimens in the treatment of locally advanced ESCC patients. We present the following article in accordance with the CONSORT reporting checklist (available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-524/rc).

Methods

Patients

A total of 103 patients aged from 18 to 75 years and pathologically diagnosed with locally advanced ESCC (T2N0M0-TxNxM1a, AJCC 2002) were selected at the Department of Radiation Oncology, Affiliated Hospital of Jiangnan University from July 2014 to June 2016. Patients were identified before participation in this two-parallel study as having not received surgery, radiotherapy, or chemotherapy, having an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 to 2, adequate renal, hepatic, cardiac, pulmonary, and hematological function, and having a life expectancy of at least three months. If patients were determined to be at a high risk of death in case of severe esophageal defect (deep esophageal ulcer, esophageal obstruction, esophageal perforation), organ failure or infection, if they had a history of surgery, radiotherapy, or chemotherapy for ESCC, or if they had distant metastasis, they are excluded, according to the American Joint Committee on Cancer (AJCC) 2002. The flow chart of patient selection is as follows (Figure 1).

Figure 1.

Flow chart of patient selection. TF, paclitaxel plus 5-fluorouracil; PF, cisplatin plus 5-fluorouracil.

Patients who underwent CCRT were assigned to TF or PF chemotherapy regimen group. Use the statistical analysis system to generate a random sequence and assignment numbers. As was shown in Table 1, there was not found difference between the two groups.

Table 1. Patient characteristics.

Characteristics	TF group (n=52)	PF group (n=51)	P value
Gender			0.47
Male	40 (76.9)	36 (70.6)
Female	12 (23.1)	15 (29.4)
Age (years)
Average [range]	63.73 [47–75]	63.45 [46–75]	0.46
18–59	8 (15.4)	10 (19.6)	0.58
≥60	44 (84.6)	41 (80.4)
Tumor location			0.63
Upper	16 (30.8)	18 (35.3)
Middle	24 (46.2)	25 (49.0)
Lower	12 (23.1)	8 (15.7)
Lymph nodes status			0.22
Positive	43 (82.7)	37 (72.5)
Negative	9 (17.3)	14 (27.5)
Clinical stage			0.85
IIa	5 (9.6)	3 (5.9)
IIb	10 (19.2)	12 (23.5)
III	28 (53.8)	26 (51.0)
IVa	9 (17.3)	10 (19.6)

Data are presented as n (%) unless otherwise specified. TF, paclitaxel plus 5-fluorouracil; PF, cisplatin plus 5-fluorouracil.

These studies involving human participants were reviewed and approved by the Affiliated Hospital of Jiangnan University (No. LS2024308). The participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Treatment modalities

Chemotherapy

Participants were randomly assigned to two groups, the experimental group (TF group) and control group (PF group). Concurrent as well as consolidation chemotherapy were included. The participants in the TF group underwent 5 weeks of CCRT followed by two cycles of consolidated chemotherapy once every 4 weeks. For patients in the PF group, 2 cycles of CCRT were included once every 4 weeks followed by 2 cycles of consolidated chemotherapy of the same regimen.

Radiotherapy

We used the intensity-modulated radiotherapy (IMRT) technique based on the computed tomography (CT) simulation planning system to perform radiotherapy. Participants were treated 5 days a week, 1.8 Gy per day. The total dose of 34 fractions was 61.2 Gy. The target volumes were defined as follows: (I) gross tumor volume (GTV): visible tumor and metastatic lymph nodes; (II) clinical target volume (CTV): GTV+ 30 mm in the superior and inferior direction for esophageal tumor but no extension circumferentially, neither for the metastatic lymph nodes; and (III) planning target volume (PTV): CTV+ 10 mm in all directions, slightly shrunk to protect the spinal cord if necessary.

Observation

With a global alpha risk of 5% and 80%, the follow-up period was 24 months, and patient loss 10%, requiring the inclusion of 103 patients (randomly assignment at 1:1) to demonstrate a 2-year OS improvement. The study would be terminated when all the surviving patients were followed-up more than 2 years.

Patient characteristics were observed according to the following variables: gender (male or female), age (continuous), tumor location, lymph nodes’ status (negative or positive), and clinical stage status.

The primary endpoint was OS. The secondary endpoints included LC, progression-free survival (PFS), and adverse effects. Patient characteristics were compared using chi-squared and Fisher’s exact tests. The treatment-related toxicities were calculated and analyzed, including hematologic side effects (leukopenia, hyperhemoglobinemia, and thrombocytopenia), acute pneumonia and esophagitis, gastroenteric reactions (nausea and vomiting, anorexia), peripheral neuropathy, myalgia, and arthralgia. The hematologic toxicities were evaluated based on the World Health Organization (WHO) criteria and the remaining toxicities were evaluated based on the RTOG/European Organization for Research and Treatment of Cancer (EORTC) criteria, using the Chi-squared test. Actuarial OS and PFS curves used the Kaplan-Meier method and log-rank test. The OS and PFS data of 2-year and median were reported.

Statistical analyses

Statistical analysis using the software SPSS 20.0 (IBM Corp., Armonk, NY, USA). Significant values were defined as those with a P<0.05.

Results

Patient characteristics

One hundred and three patients enrolled in our research, of which 52 (50.5%) were randomly assigned to the TF group, and 51 (49.5%) were assigned to the PF group (Figure 1). In the TF group, 32 (61.5%) participants completed the whole treatment, including 2 (3.8%) who did not complete their radiotherapy. In the PF group, 33 (64.7%) patients completed the whole treatment, and there was 1 (2%) patient who did not finish the radiotherapy. The median ages of the TF and PF groups were 63.73 and 63.45 years, respectively. Other characteristics such as gender, tumor location, lymph nodes’ status, and tumor stage between the TF and PF groups are shown in Table 1. As can be seen, there was no statistical significance between the two groups.

OS

Median follow-up was 23.3 months [95% confidence interval (CI): 21.41 to 25.22]. The OS was no difference in different chemotherapy regimens. The median, 1- and 2-year OS for the TF group were 20.0 months, 76.9%, and 59.6%, respectively, and 19.3 months, 74.5%, and 56.9%, respectively, for PF group (P=0.72 and P=0.70). These results showed that the TF regimen combined with radiotherapy had no survival benefit compared with the PF regimen [hazard ratio (HR) =0.890, 95% CI: 0.489 to 1.618; P=0.70]. Further details are available in Table 2 and Figure 2.

Table 2. Patient survival data.

Endpoint	TF group (n=52), n (%)	PF group (n=51), n (%)	P value	HR (95% CI)
OS
1-year	40 (76.9)	38 (74.5)	0.72	0.866 (0395–1.897)
2-year	31 (59.6)	29 (56.9)	0.70	0.890 (0.489–1.618)
PFS
1-year	33 (63.5)	32 (62.7)	0.80	0.922 (0.488–1.742)
2-year	27 (51.9)	20 (39.2)	0.25	0.735 (0.434–1.245)

TF, paclitaxel plus 5-fluorouracil; PF, cisplatin plus 5-fluorouracil; HR, hazard ratio; CI, confidence interval; OS, overall survival; PFS, progression-free survival.

Figure 2.

Kaplan-Meier curves for OS for patients of both groups. OS, overall survival; TF, paclitaxel plus 5-fluorouracil; PF, cisplatin plus 5-fluorouracil.

PFS and LC

In TF group, the 1- and 2-year PFS rates were 63.5%, and 51.9%, respectively, and 62.7% and 39.2%, respectively, for the PF group. Similarly in PFS (HR =0.922, 95% CI: 0.488 to 1.742, P=0.80, and HR =0.735, 95% CI: 0.434 to 1.245, P=0.25), no significant difference. Further details are available in Table 2 and Figures 3,4.

Figure 3.

Kaplan-Meier curves for PFS for patients of both groups. PFS, progression-free survival; TF, paclitaxel plus 5-fluorouracil; PF, cisplatin plus 5-fluorouracil.

Figure 4.

Analysis for OS and PFS of both groups. CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival; PF, cisplatin plus 5-fluorouracil; TF, paclitaxel plus 5-fluorouracil.

Analogous results were found on the local (L) PFS rates. The 1- and 2-year LPFS rates were 71.2% and 61.5%, respectively, for the TF group compared with 66.7% and 58.8%, respectively, for the PF group, showing no obvious difference (P=0.623 and P=0.778). During a 2-year follow-up period, 20 participants were found to have a local recurrence and 5 participants had distant metastasis in the TF group. The number of patients who experienced locoregional and distant failure was 21 and 10, respectively in the PF group. Further details are available in Table 3.

Table 3. Patient recurrence and metastasis data.

Endpoint	TF group (n=52)	PF group (n=51)	P value
1-year local recurrence			0.62
Yes	15 (28.8)	17 (33.3)
No	37 (71.2)	34 (66.7)
2-year local recurrence			0.78
Yes	20 (38.5)	21 (41.2)
No	32 (61.5)	30 (58.8)
1-year distant metastasis			0.41
Yes	4 (7.7)	2 (3.9)
No	48 (92.3)	49 (96.1)
2-year distant metastasis			0.15
Yes	5 (9.6)	10 (19.6)
No	47 (90.4)	41 (80.4)

Data are presented as n (%). PF, cisplatin plus 5-fluorouracil; TF, paclitaxel plus 5-fluorouracil.

Adverse effects

The occurrence of the toxicities is displayed in Table 4, and the incidence rate is shown in Table 5. Our results indicated that the most common treatment-related severe toxicity (grade 3–4) was leukopenia in the TF group (36.5%), significantly higher than that in the PF group (17.6%, χ²=4.642, P=0.003). Furthermore, patients in the TF group more frequently experienced severe acute pneumonia (grade 3–4) than those in the PF group (15.4% vs. 3.9%, χ²=3.859, P=0.049). Nevertheless, patients in the PF group had a higher risk of experiencing severe nausea and vomiting (grade 3–4) than those in the TF group (17.6% vs. 1.9%, χ²=7.262, P=0.007). No significant difference was found in severe hyperhemoglobinemia, thrombocytopenia, acute esophagitis myalgia, arthralgia, and peripheral neuropathy between the two groups. No treatment-related deaths occurred during the study period.

Table 4. Occurrence of the toxicities.

AEs	Grade 0			Grade 1			Grade 2			Grade 3
	TF	PF		TF	PF		TF	PF		TF	PF
Leukopenia	3	6		17	10		13	26		17	7
Hypohemoglobinemia	21	17		5	26		24	7		2	1
Thrombocytopenia	38	18		6	22		7	9		1	1
Acute pneumonia	13	25		14	17		17	7		7	1
Acute esophagitis	4	12		15	29		30	8		2	2
Nausea and vomiting	39	25		11	8		1	9		1	8
Anorexia	35	15		11	12		3	16		3	6
Myalgia and arthralgia	41	49		5	1		5	1		1	0
Peripheral neuropathy	39	37		4	11		9	3		0	0

AEs, adverse events; PF, cisplatin plus 5-fluorouracil; TF, paclitaxel plus 5-fluorouracil.

Table 5. Comparison of adverse effects between two groups.

AEs	TF group (n=52)	PF group (n=51)	χ2	P value
Leukopenia			4.642	0.03
Grade 0–2	33 (63.5)	42 (82.4)
Grade 3–4	19 (36.5)	9 (17.6)
Hypohemoglobinemia			0.324	0.57
Grade 0–2	50 (96.2)	50 (98.0)
Grade 3–4	2 (3.8)	1 (2.0)
Thrombocytopenia			0.364	0.55
Grade 0–2	51 (98.1)	49 (96.1)
Grade 3–4	1 (1.9)	2 (3.9)
Acute pneumonia			3.859	0.049
Grade 0–2	44 (84.6)	49 (96.1)
Grade 3–4	8 (15.4)	2 (3.9)
Acute esophagitis			0.190	0.66
Grade 0–2	49 (94.2)	49 (96.1)
Grade 3–4	3 (5.8)	2 (3.9)
Nausea and vomiting			7.262	0.007
Grade 0–2	51 (98.1)	42 (82.4)
Grade 3–4	1 (1.9)	9 (17.6)
Anorexia			2.655	0.10
Grade 0–2	49 (94.2)	43 (84.3)
Grade 3–4	3 (5.8)	8 (15.7)
Myalgia and arthralgia			0.990	0.32
Grade 0–2	51 (98.1)	51 (100.0)
Grade 3–4	1 (1.9)	0 (0.0)
Peripheral neuropathy			6.310	0.04
Grade 0–2	52 (100.0)	51 (100.0)
Grade 3–4	0 (0.0)	0 (0.0)

Data are presented as n (%). AEs, adverse events; PF, cisplatin plus 5-fluorouracil; TF, paclitaxel plus 5-fluorouracil.

Discussion

Comprehensive treatment including surgery is the standard regimen in the treatment of ESCC (11,12). Unfortunately, the majority of Chinese patients are diagnosed with locally advanced tumors, for which surgery is not the most appropriate treatment strategy and the prognosis is unfavorable. With the development of more advanced radiation techniques, including three-dimensional conformal radiation therapy (3D-CRT) and IMRT, radiotherapy has become a preferred choice for these patients. New studies have been focused on CCRT for potentially curative intent. Better LC and OS have been found in combined therapy than in radiotherapy or chemotherapy alone (13,14). Application of chemotherapeutic drugs can not only reduce the distant metastasis rate but also enhance the radio-sensitivity during the period of radiotherapy.

PF was the classic regimen for CCRT in the past decades. However, treatments based on paclitaxel have been used frequently since the beginning of this century. The new antineoplastic drug paclitaxel has unique advantages. When paclitaxel is involved, tumor cells cycle are blocked at the G2/M phase, which interferes with mitosis. The irradiated tumor cells arrested at the G2/M phase are more sensitive to radiotherapy. In addition, paclitaxel induces the apoptosis of the tumor cells (15). In 2000, Adelstein et al. reported a retrospective study on the basis of paclitaxel and cisplatin, the median survival was 15 months, lower than that of our TF regimen, but severe nausea and neutropenia were observed. Compared with the fluorouracil-based regimen, no additional benefit was found (16). However, researchers did not stop their attempts to utilize the paclitaxel-based regimen. In 2001, MDACC performed a regimen: continuous infusion of fluorouracil plus weekly PTX and combined with radiotherapy was used to treat esophagus and gastroesophageal junction carcinoma pattients, showing that this regimen was well tolerated (7). Yang et al. reported that the regimen based on paclitaxel/lobaplatin improved patients’ treatment response rates and decreased the overall toxicity (17). In their study, the PFS in the paclitaxel/lobaplatin and cisplatin/5-fluorouracil groups were 13.0 and 6.5 months, respectively. Besides, the former group demonstrated decreased side effects on patients’ digestive and hematological system. In addition, Tamtai et al. reported that CCRT based on carboplatin (CP) and paclitaxel had less toxicity than the platinum/5-fluorouracil regimen and the efficacy was comparable (18). The median OS between the CP and PF groups was 21.3 and 16.3 months, respectively, and the difference was not statistically significant (P=0.61). The hematological reactions were similarly reported in both groups. The phase 2 randomized control study RTOG 0113 based on the administration of paclitaxel has shown higher 1-year OS than that in RTOG 9405 based on cisplatin and 5-fluorouracil (9).

In our study, the TF regimen may lead to better survival and tumor control, as listed in Table 2 and Figures 2-4. Unfortunately, there was no significant statistical difference between the two regimens in OS, PFS, and LPFS in our study. However, the OS rate is acceptable. Reported by Polee et al., the regimen was paclitaxel 180 mg/m² and cisplatin 60 mg/m² every 2 weeks. The 1-year OS was 43% (19). In another randomized phase II study reported by Nishimura et al., patients were randomly enrolled in two groups with low-dose protracted infusion PF chemotherapy regimen or full-dose short-term infusion chemotherapy regimen combined with radiotherapy. The 2-year survival rates were 46% and 44%, respectively (20). To improve patients’ survival, regimens including three agents may be feasible. As reported by Satake et al. in a prospective study, 33 patients received the induction chemotherapy regimen on the basis of docetaxel, cisplatin, and fluorouracil followed by CCRT. The median survival time was 26.0 months and no treatment-related deaths were reported (21). Furthermore, radiotherapy may have an effect. In Nayan et al.’s prospective randomized study, high-dose radiotherapy with concurrent chemotherapy may probably be more effective than a standard-dose regimen for its higher response rates (71% vs. 64%, P=0.38) and the toxic reactions were acceptable (22). In another Japanese study, proton beam therapy seemed to be feasible for a spread-out Bragg peak and more desirable dose distribution to the target volume. The complete response (CR) rates for patients with stage I, II, and III tumors were 88%, 89%, and 56%, respectively (23).

When observing the side effects, clinical practitioners frequently focus on severe toxicities (grade 3–4) because they sometimes threaten patients’ lives. Leukopenia is one incident which occurs more often when paclitaxel is involved than other antineoplastic drugs (24). In our trial, the occurrence rate of leukopenia from grade 3–4 was 36.5% when paclitaxel was used, statistically significantly higher than that in the control group (17.6%). However, in a phase 2 study established by Xia et al., only 24.5% of the total patients experienced severe neutropenia (grade 3–4) when a weekly paclitaxel and 5-fluorouracil regimen was involved (25). The discrepancy was obvious, and the ECOG score of the patients may be the reason. In our trial, patients were assigned to each group with their ECOG score 0–2, but in Xia’s study, the patients’ ECOG score was 0–1.

Acute pneumonia is an incident that occurs when patients’ lungs are exposed to radioactive rays. Severe pneumonia may lead to extensive pulmonary fibrosis and respiratory failure that finally threaten patients’ lives. Therefore, doctors must pay more attention to radiation-induced pneumonia. In our trial, more patients in the TF group experienced severe pneumonia (15.4%) than in the PF group (3.9%), and the difference was statistically significant (P=0.049). Compared with the chemotherapy regimen based on paclitaxel and cisplatin, the TF regimen may signify higher risk of incurring pneumonia and the time pneumonia is incurred may be earlier. Analogously, acute esophagitis was observed during the period of radiotherapy as it can bring about esophageal perforation, hemorrhage, or an inflammatory response. Fortunately, only 5 of the total participants experienced severe esophagitis. No great distinction was found between the two groups. All participants who experienced pneumonia or esophagitis had completed the whole treatment course when corticosteroids were added.

Nausea and vomiting were frequently observed when cisplatin was intravenously infused, and patients’ quality of life was impaired. As expected, 17.6% of the patients in the PF group experienced grade 3–4 vomiting, which was obviously more than those in the other group (1.9%, P=0.007). However, when the antagonist of the 5-HT3 receptor was used, nausea and vomiting were controlled satisfactorily.

There were several important limitations to our study. First, the sample size was small, and the follow-up time was not long enough. The TF chemoradiotherapy regimen showed a trend towards a better control rate and a decreased distant metastasis rate, though the result was not significant. An expanded sample size and follow-up period might provide a more precise conclusion. In addition, the disease stage of patients enrolled in the study varied from T2N0M0 to TxNxM1a, subgroup analysis may be needed to obtain adequately powered outcomes. We also did not perform a stratified analysis of other factors. Furthermore, it is unknown whether other paclitaxel-based chemotherapy regimens, for example, paclitaxel plus CP or paclitaxel plus cisplatin, may lead to more positive outcomes compared with the TF regimen. Further studies may be needed to explore the paclitaxel-based CCRT regime role in the treatment of locally advanced ESCC. As for adverse effects, patients’ severe leukopenia and acute pneumonia must be scrutinized when paclitaxel and 5-fluorouracil are involved, and symptomatic treatment is necessary to avoid serious consequences. Meanwhile, digestive system discomfort, especially nausea and vomiting, is frequently observed when the PF regimen is carried out, in this instance, antiemetic drugs are necessary to improve patients’ quality of life and satisfaction.

Conclusions

Compared with the PF chemoradiotherapy regimen, the TF chemoradiotherapy regimen showed no survival benefit, but exhibited a trend to a better control rate and a decreased distant metastasis rate, though the result was not significant. Both regimens showed tolerable toxicity, though they have different behaviors.

Supplementary

The article’s supplementary files as

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The studies involving human participants were reviewed and approved by the Affiliated Hospital of Jiangnan University (No. LS2024308). The participants provided their written informed consent to participate in this study. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Data Sharing Statement

Available at https://jgo.amegroups.com/article/view/10.21037/jgo-22-524/dss

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DOI: 10.21037/jgo-22-524