Abstract
Background: The prognosis of patients with locally advanced esophageal squamous cell carcinoma (LAESC) is extremely poor. The impact of adverse effects of chemoradiotherapy (CRT), particularly myelosuppression, on postoperative long-term results has remained unclear. Patients and Methods: A total of 44 patients with LAESC who underwent CRT followed by esophagectomy were enrolled. We compared long-term survival by various clinical variables, including myelosuppression (Grade 3 and 4 leukopenia) due to CRT, response to CRT, performance status, postoperative complications, and pathological nodal status. Finally, multivariate analysis of prognostic factors was assessed by the Cox proportional hazards model. Results:The mean age of patients was 62.8 years and the male/female ratio was 32/9. The response rate to CRT was 75% (33/44), which included five cases with complete response and 28 cases with partial response. Grade 3 and 4 leukopenia was 43% (19/44). Mortality and postoperative pneumonia occurred in 3 (7.3%) and 14 cases (31.8%), respectively. Multivariate analysis demonstrated that myelosuppression was a significant negative prognostic factor in overall survival (OS) [hazard ratio (HR)=4.758, p=0.005]. The 5-year OS rate was significantly poorer in the group with myelosuppression than in the group without (15.4% vs. 69.0%, p=0.003). Discontinuation of the preoperative CRT schedule and dose reduction of chemotherapeutic agents was significantly more frequent in the group with myelosuppression than in the group without (p=0.003), and peripheral lymphocyte counts after surgery was significantly lower, which may explain poor prognosis in the group with myelosuppression. Conclusion: Pre-operative CRT-induced myelosuppression has a negative impact on the prognosis of patients with LAESC. Our findings indicate that a careful postoperative follow-up is required for patients who develop myelosuppression after neoadjuvant CRT followed by curative resection for locally advanced esophageal cancer.
Esophageal carcinoma, an aggressive gastroenterological neoplasm, is the sixth leading cause of cancer-related death in the world (1). The esophagus is surrounded by important vital organs such as the heart, trachea and aorta, which are sometimes involved if esophageal cancer spreads. Hence, the prognosis of patients with locally advanced esophageal carcinoma (LAESC) with the potential for involvement of adjacent organs is extremely poor because curative resection for LAESC is difficult. Therefore, chemoradiotherapy (CRT) is conducted prior to the surgical treatment of LAESC (2, 3). Previous reports indicate that the response of patients with LAESC to CRT is closely associated with their long-term survival (4). Traditionally, a 5-fluorouracil (5FU)-based regimen was used for chemotherapy of esophageal cancer (3). Recently, more cytotoxic regimens such as triplet agents using 5FU and cisplatin combined with docetaxel have been used for the treatment for LAESC to increase the response rate (5, 6). However, CRT may cause drug-induced toxic effects, including myelosuppression characterized by leukopenia, neutropenia, anemia, and thrombocytopenia. Once patients have experienced myelosuppression, the discontinuation of the planned CRT schedule or dose reduction of chemotherapeutic agents is often required. Hence, we hypothesized that myelosuppression after CRT has a negative impact on postoperative long-term results because of cancer recurrence after surgery. The aim of the present study was to investigate the prognostic factors, focusing on the impact of myelosuppression on the prognosis of patients with LAESC.
Clinical features of 44 patients with locally advanced esophageal squamous cell carcinoma.
Patients and Methods
A total of 343 patients with esophageal cancer underwent surgical resection at the Department of Surgical Oncology, Osaka City University Hospital between April 2001 and December 2011. Of these, a total of 44 patients with LAESC who underwent CRT followed by esophagectomy were enrolled in this study. LAESC was defined as a tumor that not only had the possibility of involving adjacent organs, such as tracheo-bronchus or aorta, but also had no systemic or distant metastasis.
At our institution, the treatment strategy for LAESC was induction CRT with or without additional surgery. CRT treatment was performed as follows: 250 mg of 5FU and 10 mg cisplatin were administered on days 1-5, 8-12, 15-19, and 22-26. Concurrently, an external beam irradiation with 2.0 mg Gy/fraction for a total dose of 40 Gy was administered. During May 2003 and April 2007, the same CRT protocol was performed but was replaced with nedaplatin. An additional surgery was required if the tumor was still present and likely to be resectable. From March 2007, 700 mg/m2 of 5FU was administered on days 1-4 and 29-32, while 60 mg/m2 of nedaplatin were administered on days 1 and 29. Two Gy/fraction irradiation was given concurrently to a total dose of 50 Gy. After completing CRT, salvage surgery was performed in cases where the tumor remained present and could likely be curatively resected. In cases undergoing additional or salvage surgery, we performed open esophagectomy accompanied by two or three fields of lymph node dissection 1-2 months after the completion of CRT. The details of operative procedures were reported previously (7, 8).
Tumor staging was performed using neck, chest and abdominal computed tomography (CT); esophagoscopy; esophagography; and positron-emission tomography (PET). The pre-treatment tumor status was mainly evaluated by the findings of contrast-enhanced CT. Protrusion into the lumen of the trachea and bronchus or 90° or more angles of tumor contacting against the aorta in three or more slices with a slice thickness of 5 mm on CT was defined as apparent T4 tumor in this study. Large tumor, which had both the possibility of involvement of adjacent organs and no evident findings of apparent T4 tumor, was defined as marginal T4.
Adverse events of CRT were assessed by the National Cancer Institute-Common Toxicity Criteria (NCI-CTC version 3) (9). In this study, grade 3 or 4 leukopenia was defined as myelosuppression.
The CRT response was evaluated according to the Response Evaluation Criteria in Solid Tumor (RECIST) (10) and the Japanese Guidelines for the Clinical and Pathologic Studies on Carcinoma of the Esophagus (11). The response was classified into four categories. Complete regression (CR) was defined as 100% tumor regression of all tumors. Partial response (PR) was characterized by more than 30% reduction in the sum of the longest diameter of measurable lesions. Stable disease (SD) was from 30% reduction and 20% enlargement. Progressive disease (PD) was more than 20% enlargement of the tumor or the occurrence of new lesion. The pathological diagnosis and classifications were made according to the sixth edition of the UICC TNM Classification of Malignant Tumors (12). The Clavien–Dindo classification system was used to evaluate the severity of postoperative complications (13). We evaluated short-term and long-term results of surgery after CRT. The following parameters were evaluated for overall survival (OS) who underwent curative surgery after CRT: age, gender, levels of serum Squamous Cell Carcinoma (SCC) antigen, pre-CRT tumor status, pre-CRT lymph node involvement, tumor response to CRT, CRT-induced leukopenia, pre- and post-CRT Glasgow prognostic score (GPS), surgical complications (pulmonary complication), perioperative transfusions, and chemotherapy regimen. Patients with both CRP ≤10 mg/l and albumin ≥35 g/l were allocated to GPS0; those with only CRP >10 mg/l or albumin <35 g/l were allocated to GPS1, whereas those with CRP >10 mg/l and albumin <35 g/l were allocated to GPS2 (14). Pre-CRT serum CRP and albumin level and lymphocyte counts were investigated immediately before the start of CRT.
Postoperatively, patients were followed-up using blood laboratory tests, CT, and endoscopy every 3-4 months at the Outpatient Department in our hospital.
Postoperative lymphocyte counts were investigated approximately 2 months after surgery. All characteristic data were obtained from medical and nursing records. Informed consent was obtained from all patients prior to their participation in this study.
Univariate and multivariate analysis of prognostic factors of overall survival for 36 patients with locally advanced esophageal squamous cell carcinoma who underwent chemoradiotherapy followed by curative surgery.
Statistical analysis. Comparisons among the data sets were made using analysis of variance, followed by either the t-test or the Chi-square test. The OS periods of various sub-groups were calculated using the Kaplan–Meier method. Prognoses were compared using the log-rank test. Univariate and multivariate analyses of independent prognostic factors were conducted for Cox proportional hazards modeling. Statistical significance was determined as p<0.05. The Statistical Package for the Social Sciences (SPSS) software version 22 (SPSS, Inc., Chicago, IL, USA) was used for all analyses.
Characteristics of 36 patients with locally advanced esophageal squamous cell carcinoma with and without grade 3/4 leukopenia who underwent curative surgery.
Results
The clinicopathological features of 44 patients with LAESC are shown in Table I. The mean patient age and male/female ratio were 62.8 years and 35/9, respectively. Regarding pre-therapy tumor status, an apparent or marginal grade of T4 was observed in 25 and 19 cases, respectively. With respect to adjacent involved organs, trachea-bronchus, aorta, both of these sites, and other sites were involved in 11, 12, 1, and 1 cases, respectively. The total dose of radiation therapy was ≥50 Gy in five and <50 Gy in 39 cases, respectively. Combined chemotherapy regimen of 5FU plus cisplatin was administered in 10 and 5FU-plus-nedaplatin in 34 cases, respectively. The response rate of CRT was 75% (33/44), which included five cases that achieved a CR and 28 with a PR. Grade 3 and 4 leukopenia was confirmed in 43% (19/44) of patients. Postoperative mortality, postoperative pneumonia, and anastomotic leakage occurred in 7.3% (3/44), 31.8% (14/44), and 4.5% (2/44) cases, respectively.
Kaplan–Meier curves of overall survival (OS) for patients with locally advanced esophageal cancer who underwent curative or non-curative surgery. The 5-year OS rate was significantly better in patients with curative resection (R0) than in those without (R1/2) (46.6% vs. 0%, p=0.001).
Curative resection was performed in 36 cases (81.8%), in which the 5-year OS rate was significantly better than for those without curative resection (46.6% vs. 0%, p<0.001) (Figure 1). Univariate and multivariate analysis of OS is shown in Tables II. Univariate analysis revealed that myelosuppression and lymph node metastasis were significant prognostic factors of poorer OS. In addition, multivariate analysis demonstrated that only myelosuppression was a significant negative prognostic factor for OS [hazard ratio (HR)=4.758, p=0.005]. The 5-year OS rate was significantly poorer in the group with myelosuppression than in the group without (15.4% vs. 69.0%, p=0.003) (Figure 2).
Table III shows the clinical features of the groups with and without myelosuppression. Age, gender, pathological nodal status, and response to CRT were comparable between the two groups. However, the discontinuation of radiation, and the dose reduction of chemotherapeutic agents were significantly more frequent in the groups with, than in the group without (p=0.003), while the rate of adjuvant therapy was comparable between the two groups. Postoperative pulmonary complications and severe complications (CD classification IV) were equivalent between the two groups. Peripheral lymphocyte counts prior to CRT were comparable between the two groups, while those after surgery were significantly lower in the groups with myelosuppression than in the group without (p=0.037). However, the neutrophil/lymphocyte ratios were comparable both before CRT and after surgery between the two groups.
Kaplan–Meier curves of overall survival (OS) for patients with locally advanced esophageal cancer with and without myelosuppression after CRT. The 5-year OS rate was significantly poorer in the group with myelosuppression than in that without (15.4% vs. 69.0%, p=0.003).
Discussion
In the present study, patients with LAESC who underwent curative resection after CRT had a relative good long-term survival, which is 46.6% for the 5-year OS rate, whereas the prognosis of patients with no curative resection was extremely poor (0% at 5 years). Hence, curability had the most significant impact on long-term survival for patients with LAESC. At our institution, the treatment strategy for LAESC was induction CRT with or without additional surgery. The impact of additional surgery after CRT for patient with LAESC has remained controversial. Some randomized controlled studies have shown that additional surgery had no impact on long-term prognosis after CRT for patients with LAESC (15, 16), while other reports showed the usefulness of additional surgery for such patients (17-19). In this study, the usefulness of additional surgery after CRT for patients with LAESC remains unclear because we had a selection bias of patients who received additional surgery. On the other hand, the rate of mortality and pneumonia after surgery (7.3% and 31.8%, respectively) was greater than the ones in our previous report of patients who underwent surgery without CRT (1.9 % and 13.8%, respectively) (7). These finding suggested that tumor removal by additional surgery after CRT has a good impact for long-term survival of patients with LAESC, while that had more alert at mortality and pneumonia after surgery than one without CRT.
CRT had adverse events for patients, such as gastrointestinal toxicity, renal toxicity and myelosuppression. However, the impact of CRT-induced adverse effects on long-term results for patients with esophageal cancer has not been fully documented. To the best of our knowledge, only a few articles about the relationship of CRT-induced side-effects and long-term results of patients with esophageal cancer have been published. Hennies et al. reported that esophageal cancer patients with worsening of CRT-induced odynophagia had significantly better survival than patients without odynophagia (20). They indicated that normal and tumoral tissues may behave similarly with respect to treatment response. Hence, they stated that the adverse effect on the oral mucosa was closely associated with a good response of tumor after CRT. On the other hand, Miyoshi et al. reported that myelogenic chemotoxicity was a significant negative factor in patients with T4 esophageal cancer who underwent CRT followed by curative resection (21). They speculated that CRT-related immunosuppression was responsible for decreased tumor immunity and poor prognosis. In this study, similar to the results of Miyoshi et al., CRT-induced myelosuppression was significantly associated with poor prognosis of patients with LAESC.
We suggest two possible explanations for poor prognosis in patients with myelosuppression. Firstly, preoperative CRT-induced myelosuppression leads to early withdrawal from CRT. It is well-known that reduced doses of chemotherapy and discontinuing radiation therapy results in a decrease in the response rate to CRT. This may also explain the early recurrence in the group with myelosuppression; the number of patients who discontinued CRT was significantly higher in this group. Incomplete CRT may lead to poor prognosis in patients with LAESC. Effective and well-tolerated CRT regimens and schedules for LAESC are required. Secondly, CRT-induced leukopenia included decreases of both neutrophil and lymphocyte counts. Lymphocytes have an important role in cancer immune surveillance because they suppress cancer development; many reports have demonstrated that the presence of tumor-infiltrating lymphocytes was significantly correlated to favorable long-term outcomes in many types of cancer (22, 23). Moreover, low circulating lymphocyte counts were reportedly associated with poor prognosis of patients with cancer (24, 25). In the present study, the lymphocyte count was significantly decreased in patients with myelosuppression compared with those without. Other variables, including response to CRT, pre-treatment tumor status and the rate of postoperative complications, did not differ between the two groups of patients. These findings suggest that an impaired cancer immune surveillance system is associated with a poor prognosis in patients with LAESC.
This study suffers some limitations. The study was retrospective and the number of patients was small. Moreover, chemotherapy regimens were different according to study periods. In addition, although nedaplatin is a common platinum agent for esophageal cancer in Japan, it is not widely used throughout the world. Moreover, leukopenia caused a decrease not only in lymphocyte counts but also in neutrophil counts. The prognostic value of low neutrophil counts on the prognosis of patients with esophageal cancer has not been fully addressed.
In conclusion, preoperative CRT-induced myelosuppression has a negative impact on the prognosis of patients with LAESC. Careful monitoring and check-up for cancer recurrence is required for patients with myelosuppression after CRT followed by curative surgery.
- Received April 28, 2015.
- Revision received May 30, 2015.
- Accepted June 3, 2015.
- Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved
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