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ORIGINAL ARTICLE
Year : 2016  |  Volume : 12  |  Issue : 1  |  Page : 90-95

The clinical efficacy of consolidation chemotherapy for resectable esophageal squamous cell cancer after trimodality therapy


1 Department of Radiation Oncology, Red Cross Blood Center of Henan, 9 Tongle Road, Zhengzhou 450053, Henan Province, China
2 Red Cross Blood Center of Henan, 9 Tongle Road, Zhengzhou 450053, Henan Province, China

Date of Web Publication13-Apr-2016

Correspondence Address:
Hong Ge
Department of Radiation Oncology, The Affiliated Cancer Hospital of Zhengzhou University, Zhengzhou 450008
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.148687

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 > Abstract 


Purpose: We aimed to assess the clinical outcome of consolidation chemotherapy for resectable esophageal squamous cell cancer (ESCC) after trimodality therapy.
Materials and Methods: From January 2005 to December 2012, a total of 192 consecutive locally advanced ESCC patients who underwent trimodality therapy successfully was included. Grouping was based on the degree of myelosuppression occurred during preoperative chemoradiotherapy. Of the 192 patients, 120 patients underwent trimodality therapy only (TT group), while 72 patients received consolidation chemotherapy additionally after trimodality therapy (TC group). Preoperative chemoradiotherapy included two cycles of chemotherapy concurrently with radiotherapy. The chemotherapy regimen consisted of cisplatin 20 mg/m2/day and fluorouracil 400 mg/m2/day administered intravenously infusion on days 1–5 of a 21 days cycle. Concurrent radiotherapy was delivered in a total of 40 Gy in 20 fractions. All patients underwent surgery successfully. For 72 patients in TC group, additional 1–4 cycles of consolidation chemotherapy were administered, and chemotherapy regimen was as before.
Results: The 5-year survival rate was 43.5% in TT group, as compared with 48.8% in TC group. (P = 0.238). The 5.year progression.free survival. (PFS) rates were 34.0% in TT group and 38.8% in TC group. (P = 0.049). Risk reduction in PFS was remarkable for males and those who did not achieve pathologic complete response. (pCR). The incidence rate of disease progression did not differ significantly. (P = 0.200).
Conclusions: The addition of consolidation chemotherapy demonstrates no survival benefit for patients with locally advanced ESCC, but PFS is significantly improved, especially for males and those who did not achieve pCR.

Keywords: Consolidation chemotherapy, locally advanced esophageal squamous cell cancer, overall survival, progression-free survival, trimodality therapy


How to cite this article:
Sun Y, Cheng S, Lu Y, Zheng X, Ye K, Ge H. The clinical efficacy of consolidation chemotherapy for resectable esophageal squamous cell cancer after trimodality therapy. J Can Res Ther 2016;12:90-5

How to cite this URL:
Sun Y, Cheng S, Lu Y, Zheng X, Ye K, Ge H. The clinical efficacy of consolidation chemotherapy for resectable esophageal squamous cell cancer after trimodality therapy. J Can Res Ther [serial online] 2016 [cited 2020 Oct 30];12:90-5. Available from: https://www.cancerjournal.net/text.asp?2016/12/1/90/148687




 > Introduction Top


Esophageal squamous cell cancer (ESCC) is the most prevailing histological subtype in the endemic regions of the world, particularly accounting for more than 90% of all the esophageal malignancies in China.[1] More than 50% of esophageal cancer extends beyond the local regional confines at the time of diagnosis, and fewer than 60% of patients with local regional disease can undergo curative surgical resection.[2],[3] Surgery alone remains a disappointing prognosis for these patients, and the 5-year survival rate was <25% in the worldwide.[4]

The management of esophageal cancer has undergone a continuing evolution in order to improve the survival rate of esophageal cancer patients. With extensive clinical study on preoperative chemoradiotherapy followed by surgery (trimodality therapy), overall survival (OS) of patients with local-regional esophageal cancer were improved and the 5-year survival rates were reported as 17–47%.[5],[6],[7],[8],[9],[10],[11],[12] However, local recurrence and distant metastasis remain an issue for locally advanced esophageal cancer (LAEC) patients who had undergone trimodality therapy. Therefore, systemic therapy after trimodality therapy may have a role in the treatment of this cohort of patients.

To our knowledge, there are few published studies on whether consolidation chemotherapy could improve local control rate for resectable esophageal cancer after trimodality therapy or not. Therefore, we performed this study to assess the clinical outcome of consolidation chemotherapy for resectable ESCC after trimodality therapy.


 > Materials and Methods Top


Esophageal cancer patients who were treated by trimodality therapy from January 1, 2005 to December 31, 2012 were reviewed at our institution. Staging of ESCC was defined according to the American Joint Committee on Cancer 7th edition.[13] Each patient signed specific informed consent and received routine blood assays, endoscopy, imaging examination prior to the initial treatment. This retrospective study was approved by our institutional review board.

The inclusion criteria of patients was as follows: (1) Pathologically confirmed squamous cell cancer of the thoracic esophagus; (2) clinically diagnosed as LAEC (IIA-IIIB) before all treatment; (3) an Eastern Cooperative Oncology Group performance status of 0 or 1; (4) no more than 75 years old; (5) adequate bone marrow reserve, normal liver, and kidney function as well as heart and lung function; (6) no evidence of supraclavicular lymph nodes, celiac lymph nodes, or distant hematogenous metastasis; (7) no microscopic residual tumor (R0) after surgery. The exclusion criteria of the patients form this study was as follows: (1) Patients with cervical or gastroesophageal junction cancer; (2) patients with serious perioperative comorbidity; (3) patients with additional synchronous or metachronous cancer; (4) patients who underwent postoperative radiotherapy combined with or without consolidation chemotherapy.

Grouping was based on the degree of myelosuppression during preoperative chemoradiotherapy. Patients who did not show Grade 2 or more myelosuppression were given postoperative consolidation chemotherapy. Remaining patients who showed Grade 2 or more myelosuppression did not receive any other treatments after trimodality therapy.

Preoperative chemoradiotherapy

Preoperative chemoradiotherapy included two cycles of chemotherapy concurrently with radiotherapy. The chemotherapy regimen consisted of cisplatin 20 mg/m 2/day and fluorouracil 400 mg/m 2/day administered intravenously infusion on days 1–5 of a 21 days cycle. A prophylactic antiemetic therapy was given during chemotherapy, and other supportive and symptomatic treatments were also provided. Radiotherapy began within 24 h after the administration of first chemotherapy course. Radiation therapy was performed using three-dimensional conformal technique. A total radiation dose of 40 Gy was delivered with 6 MV photons in 20 fractions within 4 weeks. The radiation dose in all cases was prescribed to the isocenter. The principle of gross target volume (GTV) contour included the esophagus wall whose thickness ≥0.5 cm. Clinical target volume (CTV) margins added to GTV were 0.5–0.8 cm in lateral and anterior-posterior directions and 1.5–3.0 cm in superior-inferior direction. Planned target volume (PTV) margins added to CTV were 0.5–1.0 cm in all directions. Contour of metastatic lymph nodes in mediastinum included the ones whose short diameter ≥1.0 cm. But for lymph nodes located at special places such as tracheoesophageal groove and cardio-diaphragmatic angle, contour of lymph nodes included the ones whose short diameter ≥0.5 cm. CTV margins added to GTV were 0.5 cm in all directions. PTV margins added to CTV were 0.5–0.8 cm in all directions. The bilateral supraclavicular area was usually treated for proximal esophageal tumor. Prophylactic irradiation to other lymph node stations like lymph nodes in the neck and abdomen were not routinely recommended.

Surgery

After preoperative chemoradiotherapy, potentially resectable candidates were restaged by computed tomography (CT) to exclude progression. The choice of surgical procedure was based on the location of the tumor and the available type for conduit, as well as surgeon's experience and preference. Resectable candidates then underwent left transthoracic or thoracoabdominal approaches with anastomosis in chest or neck, using the stomach as the conduit. All resected specimens were submitted for pathologic examination. Tumor pathologic response was classified according to the grading system developed specifically for esophageal cancer.[14]

Consolidation chemotherapy and toxicity

Consolidation chemotherapy regimen was the same as preoperative chemotherapy, every 21 days for 1–4 cycles. The first cycle of chemotherapy started in 3–4 weeks after surgery. Toxicity occurred during consolidation chemotherapy was evaluated by World Health Organization grading system for chemotherapy toxicity. Once the toxicity occurred, systemic and supportive therapy was provided.

Follow-up

Each patient was required to return for periodical examination every 3–6 months for the first 2 years and at 1-year interval thereafter. The closing date was December 31, 2013. Follow-up data were documented for each patient, including physical examination, chest and abdomen CT imaging, and upper gastrointestinal radiography.

All patients' information were collected and analyzed. Extracted information included preoperative factors (age and gender), tumor features (tumor location, tumor length, and tumor differentiation), and postoperative events (pathologic response after trimodality treatment, pathologic lymph node status, pathologic T-staging, disease progression, survival status and toxicity). Disease progression included local-regional lymph nodes recurrence, anastomotic recurrence, and distant metastasis.

Statistical analysis

All statistical calculations were carried out using Statistical Package for Social Sciences 17.0 (SPSS Inc., Chicago, IL). Comparison of the qualitative data, such as patient and tumor characteristics, treatment factors, in two groups adopted χ2 test or Fisher's exact test. OS was calculated from the time of diagnosis to the date of death or the last follow-up. Progression-free survival (PFS) was calculated from the time of diagnosis to the date of disease progression or the last follow-up. Survival rates were determined by Kaplan–Meier method with log-rank test. The end-points of this study is PFS and OS. All statistical tests were two-sided, and statistical significance was established as P < 0.05.

Cox proportional-hazard regression model was employed to identify prognostic factors. First, univariate analyses were performed to explore potential significant prognostic factors. Variables with statistical significance (P < 0.10) on univariate analyses were incorporated into multivariate analyses. Then, multivariate Cox proportional-hazard regression model was employed to identify prognostic factors. Moreover, subgroup analyses were used to detect possible interactions in PFS between subgroups, both with and without adjustment for prognostic factors. Subgroups were predefined to: Gender, tumor length, pathologic response, and pathologic lymph node status.


 > Results Top


Patient characteristics

A total of 283 patients received preoperative chemoradiotherapy followed by surgery. However, 71 patients received postoperative radiotherapy additionally, and they were excluded. Among the remaining 212 patients, 2 patients were diagnosed with metachronous cancer (one with rectal cancer and one with lung cancer), 16 patients experienced margin-positive resection (14 patients with microscopically residual tumor after resection and 2 patients with macroscopically residual tumor after resection), and 2 patients died immediately after the surgery. These 20 patients were also excluded. Eventually, 192 patients were included in the current study. 72 patients received consolidation chemotherapy after trimodality therapy (defined as TC group), and 120 patients received trimodality therapy only (defined as TT group). After the surgery, a total of 2919 resected lymph nodes (range: 7–32; mean: 15.2/patient) was sent to Pathology Department for pathologic diagnosis. One or more positive lymph nodes detected in 1 patient were deemed as pathologically positive. The baseline characteristics of patients and tumors are summarized in [Table 1]. The percentage of patients with tumor length no more than 5 cm was significantly large in TT group (χ2= 4.642; P = 0.031). Remaining characteristics did not differ significantly between two groups. After surgery, patients in TC group received 1–4 cycles of chemotherapy.
Table 1: Patient and tumor baseline characteristics

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Overall survival

The median follow-up was 28.5 months (range: 8–88 months) for TT group and 31 months (range: 2–81 months) for TC group. All patients were followed-up until their death or December 31, 2013 except 5 (2.6%) patients due to loss to follow-up. There were 97 (50.5%) patients still alive and 89 patients (46.4%) dead until the deadline of follow-up. The 1-, 3-, and 5-year survival rate was 87.4%, 51.9%, and 43.5% in the TT group, as compared with 93.0%, 58.5%, and 48.8% in the TC group [Figure 1] (χ2= 1.390; P = 0.238). No statistically significant improvement in OS was found to be correlated with the addition of consolidation chemotherapy after trimodality therapy. On univariate analysis, examined prognostic factors included age, gender, tumor location, tumor length, tumor differentiation, pathologic response, pathologic lymph node status, and pathologic T-stage. Only pathologic complete response (pCR) (P = 0.016; hazard ratio [HR]: 1.405 [1.065, 1.854]) and negative lymph node (P = 0.007; HR: 1.947 [1.202, 3.155]) were found to be significantly associated with better OS. On multivariate analysis, pCR (P = 0.014; HR: 1.420 [1.074, 1.878]) and negative lymph node (P = 0.006; HR: 1.979 [1.221, 3.209]) were also found to be significantly associated with better OS.
Figure 1: Overall survival in two groups by Kaplan–Meier method

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Progression-free survival

Until the end of the study, there were 73 patients (60.8%) who were diagnosed as disease progression in TT group and 33 patients (51.4%) in TC group. The 5-year PFS rates were 34.0% in TT group and 38.8% in TC group (χ2= 3.883; P = 0.049). Contrary to OS, PFS was significantly improved in patients who received consolidation chemotherapy after trimodality therapy. PFS curves are shown in [Figure 2]. On univariate analysis, examined prognostic factors were same as before. pCR (P = 0.062; HR: 1.236 [0.988, 1.615]) and negative lymph node (P = 0.016; HR: 1.735 [1.110, 2.712]) were found to be significantly associated with better PFS. On multivariate analysis, pCR (P = 0.056; HR: 1.273 [0.994, 1.631]) and negative lymph node (P = 0.014; HR: 1.753 [1.121, 2.742]) were also found to be significantly associated with better PFS. PFS curves according to pathologic response and pathologic lymph node status were displayed in [Figure 3] and [Figure 4].
Figure 2: Progression-free survival in two groups by Kaplan–Meier method

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Figure 3: Progression-free survival in patients with pathologic complete response (pCR) and non-pCR after trimodality therapy

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Figure 4: Progression-free survival in patients with pathologically negative lymph nodes or positive lymph nodes after trimodality therapy

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Subgroup analysis showed that risk reduction in TC group was remarkable in the subgroups with non-pCR (P = 0.033; HR: 1.660 [1.041, 2.647]) and males (P = 0.039; HR: 2.122 [1.040, 4.330]). No significant PFS benefit was detected in other subgroups. The outcome is shown in [Figure 5]. In the TC group, the cases who underwent 1, 2, 3, 4 cycles of chemotherapy were 15 (20.8%), 17 (23.6%), 21 (29.2%), and 19 (26.4%), respectively. No significant difference in PFS rates was found among patients who underwent 1, 2, 3, or 4 cycles of chemotherapy postoperatively (χ2= 1.030; P = 0.794).
Figure 5: This forest plot shows hazard ratios (HRs) for disease progression (diamond) and 95% confidence interval (I bars) for 192 patients with locally advanced esophageal squamous cell cancer, according to baseline characteristics. Univariate HRs are shown, as well as HRs adjusted for baseline covariates (gender, tumor length, lymph node status, and pathologic response)

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Disease progression

Disease progression consisted of local regional failure (including anastomotic recurrence and regional lymph nodes recurrence) and distant metastasis. In some cases, two types of disease progression developed simultaneously. The detail of disease progression is enumerated in [Table 2]. Overall, 73 patients (60.8%) experienced disease progression in TT group during follow-up, while 37 patients (51.4%) in TC group. The incidence rate of disease progression did not differ significantly between two groups (χ2= 1.640; P = 0.200).
Table 2: Disease progression in two groups

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Toxicity

Toxicity profiles are shown in [Table 3]. Grade 3 or Grade 4 toxicities were observed in patients who received consolidation chemotherapy, including leukopenia in 3 patients, nausea in 4 patients, and diarrhea in 3 patients. Such severe toxicities developed in only 10% of all patients. Other toxicities, such as renal failure and infection, were observed in 4 patients and 3 patients, respectively. No patient died directly of the toxicity of consolidation chemotherapy. Toxicities were relieved after supportive and symptomatic treatment.
Table 3: Toxicity of the postoperative chemotherapy in TC group

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 > Discussion Top


Multimodality treatment for LAEC developed rapidly in recent years, including preoperative chemoradiotherapy, preoperative chemotherapy, postoperative chemoradiotherapy, postoperative radiotherapy and perioperative chemotherapy, etc.[12],[15],[16],[17],[18],[19] Several clinical trials [5],[6],[7] have revealed that preoperative chemoradiotherapy could improve the 5-year survival rate compared with surgery alone, but other treatment modalities remain controversial. For example, JCOG 9204[17] enrolled 242 patients with squamous cell esophageal cancer, of which 122 patients were randomly assigned to surgery alone group and 120 patients to surgery combined with postoperative chemotherapy group. The 5-year survival rates were 52% and 61% in two groups, with no significant difference detected. However, the 5-year PFS rates were 45% and 55% in two groups and the difference were statistically significant. Though another phase II clinical trial [17] revealed that postoperative chemotherapy could improve 2-year survival rate of esophageal cancer patients, the included pathology was limited to adenocarcinoma and the sample size was small, which needs to be further validated by phase III clinical trial.

Currently, local recurrence and distant metastasis occurred after neoadjuvant chemoradiotherapy combined with surgery still were the primary causes of treatment failure. Although high-dose neoadjuvant chemoradiotherapy was reported to be able to improve the long-term local control rate of LAEC, following problems were the higher incidence of toxicity and no significant improvement in OS.[20] However, if consolidation chemotherapy is additionally administered to patients who have received trimodality therapy, whether the survival rate could be further improved or not? According to our result, the 1-, 3-, and 5-year survival rate was 87.4%, 51.9%, and 43.5% in the TT group, as compared with 93.0%, 58.5% and 48.8% in the TC group (χ2= 1.390; P = 0.238). We speculate that the potential benefit of consolidation chemotherapy could be counteracted by surgical trauma and toxicity of chemotherapy. In addition, trimodality therapy is significantly more effective than surgery alone at increasing OS, and additional consolidation chemotherapy might not be necessary. However, PFS was significantly improved in patients who received consolidation chemotherapy after trimodality therapy (χ2= 3.883; P = 0.049), while the incidence rate of disease progression did not differ significantly between two groups (χ2= 1.640; P = 0.200). It indicates that consolidation chemotherapy after trimodality therapy might prolong the time of disease progression but not the ultimate state of disease progression.

Our results show that both pCR and negative lymph node were associated with higher OS and PFS, which is similar to previous studies.[21],[22] However, subgroup analysis revealed that patients with pCR and negative lymph node did not gain PFS benefit from consolidation chemotherapy. One hypothesis may explain this phenomenon: Preoperative chemoradiotherapy can eliminate tumor cells in subclinical lesions and reduce the opportunity of the implantation metastasis during surgery, so the existence of microscopic metastasis postoperatively is almost impossible. Thus, consolidation chemotherapy after trimodality therapy might not be necessary. In addition, subgroup analysis also revealed that males and patients with non-pCR gained PFS benefit from consolidation chemotherapy. The possible reasons are that tumor burden before treatment was heavy or tumor cells were not much sensitive in patients with non-pCR. Thus, two cycles of preoperative chemotherapy might be not enough to eradicate all tumor cells. Besides, male's body constitution and tolerance to chemotherapy might be better than female's. For these patients, whether it is necessary to add extra cycles of chemotherapy before or after the surgery deserves to be investigated, and the optimal cycles of chemotherapy need exploration further.

In our study, due to the inherent defects of a retrospective study, the heterogeneity of the patient in two groups might induce a potential bias for the analysis. For example, primary tumors with a length ≥5 cm had evidently higher opportunity to receive consolidation chemotherapy. Imbalanced factors might have an impact on the survival difference in two groups.

In summary, compared with trimodality therapy alone, the addition of consolidation chemotherapy demonstrates no OS benefit for locally advanced ESCC, but PFS is significantly improved, especially for males and those who did not achieve pCR after trimodality therapy.

 
 > References Top

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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
 
 
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