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  Table of Contents  
ORIGINAL ARTICLE
Year : 2015  |  Volume : 52  |  Issue : 3  |  Page : 454-460
 

Treatment-associated severe thrombocytopenia affects survival rate in esophageal cancer patients undergoing concurrent chemoradiotherapy


1 Department of Internal Medicine, Divisions of Hematology-Oncology, Chang Gung Memorial Hospital, Keelung; Departments of Internal Medicine, Division of Hematology-Oncology, Chang Gung Memorial Hospital, Linkou, Taiwan
2 Department of Internal Medicine, Divisions of Hematology-Oncology, Chang Gung Memorial Hospital, Keelung; College of Medicine, Chang Gung University, Taoyuan, Taiwan
3 Department of Internal Medicine, Divisions of Hematology-Oncology, Chang Gung Memorial Hospital, Keelung, Taiwan
4 College of Medicine, Chang Gung University, Taoyuan; Radiation Oncology, Chang Gung Memorial Hospital, Keelung, Taiwan

Date of Web Publication18-Feb-2016

Correspondence Address:
C H Lai
Department of Internal Medicine, Divisions of Hematology-Oncology, Chang Gung Memorial Hospital, Keelung
Taiwan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0019-509X.176708

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 » Abstract 

Background: Esophageal cancer is commonly treated with surgery, concurrent chemoradiotherapy (CCRT), or a combination of both. The correlation between the hematological parameters during CCRT and early survival of esophageal cancer has not been fully evaluated. Materials And Methods: We analyzed the records of 65 esophageal cancer patients treated by CCRT between 2007 and 2010 retrospectively. The association between CCRT-associated myelosuppression, demographic variables, and survival rates were analyzed by univariate and multivariate analysis. Results: The univariate analysis showed that tumor extent of T3-4, a higher stage of tumor, a lower albumin level, grade 3 or higher anemia and thrombocytopenia, and interruptions in treatment affected survival rates. Further, the multivariate analysis revealed that stage IV (P = 0.030) is an independently negative prognostic factor for a one-year survival rate. Stage IV (P = 0.035), tumor extent of T3-4 (P = 0.002), and grade 3-4 thrombocytopenia (P = 0.015) are independently negative prognostic factors for a two-year survival rate. Conclusions: Severe decrease in platelet count during CCRT independently affects survival of esophageal cancer patients in addition to stage of the tumor.


Keywords: Concurrent chemoradiotherapy, esophageal cancer, myelosuppression, survival, thrombocytopenia


How to cite this article:
Huang Y M, Wang C H, Huang J S, Tsai C S, Yeh K Y, Lan Y J, Wu T H, Chang P H, Chang Y S, Lai C H. Treatment-associated severe thrombocytopenia affects survival rate in esophageal cancer patients undergoing concurrent chemoradiotherapy. Indian J Cancer 2015;52:454-60

How to cite this URL:
Huang Y M, Wang C H, Huang J S, Tsai C S, Yeh K Y, Lan Y J, Wu T H, Chang P H, Chang Y S, Lai C H. Treatment-associated severe thrombocytopenia affects survival rate in esophageal cancer patients undergoing concurrent chemoradiotherapy. Indian J Cancer [serial online] 2015 [cited 2019 Jun 16];52:454-60. Available from: http://www.indianjcancer.com/text.asp?2015/52/3/454/176708



 » Introduction Top


Esophageal cancer is the eighth leading cause of cancer death, with a statistic of 12.97 in men and 0.95 new cases per 100,000 persons per year in Taiwan.[1],[2] Over 90% of the patients in Taiwan are histologically proven to be squamous cell carcinoma patients and in more than 40% of the patients, it occurs in the middle third of the thoracic esophagus.[3]

Esophageal cancer is commonly treated with surgery, concurrent chemoradiotherapy (CCRT), or a combination of both.[4] Surgery is commonly accepted as a standard treatment for resectable cancers but the prognosis remains unsatisfactory, with a five-year survival rate of 5-30%.[5],[6] Cumulative evidence recently obtained with CCRT in clinical trials supports a new standard treatment in the nonsurgical treatment of potentially curable esophageal cancer.[7],[8] The combination of cisplatin and 5-fluorouracil (5-FU) is widely applied to the CCRT schedule because of good clinical results and synergistic effects on radiosensitization.[8] A prospective randomized trial conducted by the Radiation Therapy Oncology Group demonstrated that five-year survival in patients treated by CCRT significantly improved as compared to radiotherapy alone (27 versus 0%).[9] Fiorica et al. reported that neoadjuavnt CCRT followed by surgery improved three-year survival as compared to surgery alone.[10] Further, the treatment efficacy and survival of CCRT for patients with adenocarcinoma appeared comparable to those with squamous cell carcinoma.[11] However, it was reported that there is no survival difference in patients treated by CCRT with and without subsequent surgery.[12],[13],[14]

Chemotherapy often induces myelosuppression. The risk of myelosuppression is increased by chemotherapy combined with radiotherapy.[15] Patients with grade 3 or higher myelosuppression may have a poor quality of life, prolonged stay in hospital, reduced intensity of treatment, and even an interrupted schedule;[16] consequently, this serious adverse effect may shorten survival and increase recurrence of the tumor. Ohtsu et al. found that patients with locally advanced squamous cell carcinoma of the esophagus undergoing definitive CCRT developed grade 3 or higher leukopenia, anemia, and thrombocytopenia occurring in 24, 28, and 17% of the cases, respectively.[17] These patients with grade 3 or higher myelosuppression tend to have a rapid progression course of the tumor or affected quality of life.[18],[19],[20] Further, cumulative evidence showed that the two-year survival rate for esophageal cancer patients treated with a combined modality of chemotherapy (cisplatin and 5-FU) and radiotherapy (40-60 Gy) was around 40%, and over 50% of the patients with inoperable esophageal cancer died within one year of diagnosis.[15] This retrospective study was carried out to investigate the association among the severity of myelosuppression during CCRT, relevant demographic parameters, and early survival rate in patients with esophageal cancer.


 » Materials and Methods Top


We retrospectively reviewed the medical records of 112 patients with esophageal cancer diagnosed and treated at the Chang Gung Memorial Hospital, Keelung, Taiwan from Jan 2007 to Dec 2010. The diagnosis of esophageal cancer was established by biopsy of the tumor, and the clinical TNM stage including extent of tumor, involvement of lymph nodes, and distant metastases were evaluated by panendoscopy, endoscopic ultrasonography, computed tomography of chest, bone scintigraphy, abdominal sonography, and positron emission tomography scans. Tumor locations were classified as cervical esophagus, upper thoracic esophagus, middle thoracic esophagus, and lower thoracic esophagus. The images, pathology reports, and tumor stages of all 112 patients were reviewed and confirmed by the esophageal cancer committee of our institution, which included two medical oncologists, two radiation oncologists, two radiologists, one gastroenterologist, one thoracic surgeon, and two pathologists. We used the sixth edition of the staging system of the American Joint Committee on Cancer (AJCC)[21] in this study.

Among these patients, 69 who were at performance status 0-1 of the Eastern Cooperative Oncology Group (ECOG) underwent primary or neoadjuvant CCRT. Four patients were excluded because of simultaneous occurrence of other cancers, incomplete medical record, unexplained spleen absence, or poor renal function. A total of 65 consecutive patients were ultimately enrolled in the analysis. For each case, we analyzed age, gender, stages of tumor, nodes and AJCC, history of smoking, exposure to alcohol and betel quid, comorbidity, complete blood cell count, and biochemistry data. It was our intent to reach a radiation dose of 50.4 Gy without interruption and dose reduction for induction CCRT or 60-66.6 Gy for primary CCRT. We reduced the chemotherapy dose by 25% if our patients encountered grade 2 neutropenia or thrombocytopenia. All our patients received cisplatin and 5-FU combination chemotherapy of various schedules but similar accumulated doses. In the whole CCRT course, the planned cisplatin dose is around 200-240 mg/m 2 and 5-FU 8,000-8,100 mg/m 2. Dose and interval of the chemotherapeutic agents were chosen at the discretion of the treating physician. Most of the patients received triweekly cisplatin and 5-FU chemotherapy of three sessions or a biweekly schedule of four. For triweekly chemotherapy schedule, cisplatin (75 mg/m2) on day 1 and 5-FU (900 mg/m 2/day) for three days were given intravenously every three weeks. In the biweekly schedule, cisplatin (60 mg/m 2) on day 1 and 5-FU (1,000 mg/m2/day) for two days were given every two weeks. Radiation was delivered at a total dose of 50.4 Gy at 1.8 Gy per fraction five days a week for six consecutive weeks concomitantly with chemotherapy. The target area included the primary tumors and regional lymph nodes plus 3 cm margin craniocaudally from the supraclavicular fossa, mediastinum, and perigastric nodes. There were 10 patients with liver cirrhosis in Child-Pugh A stage treated with the same protocol as others. All the patients were followed up until 31 October, 2012, and the median follow-up duration was 15.4 months (range: 0.8-56.1 months).

We used the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.02 as the grading system of adverse effects. Grade 3-4 leukopenia (<2000/mm 3) was defined as severe leukopenia. Grade 3-4 (<8.0 g/dL) anemia was defined as severe anemia. Grade 3-4 (<50,000/mm 3) thrombocytopenia was defined as severe thrombocytopenia.

Completion of treatment was defined as patients achieving a full radiation dose (50.4 Gy) and receiving at least two-thirds of the planned doses of chemotherapy (cisplatin >150 mg/m 2 and 5-FU >5500 mg/m 2). Interruption of treatment was defined as interruption of radiotherapy more than seven days and was suggested if the following conditions occurred: (i) Severe hematological toxicity (leukopenia grade ≥3 or anemia grade ≥3) or (ii) critical medical morbid status including sepsis, hyperglycemia, and unexplained febrile episodes. Before interruptions, patients were informed of the benefits and disadvantages of delaying treatment schedules.

Statistical methods

We used the Kolmogorov–Smirnov test and Shapiro–Wilk test to determine the probability distribution. The Pearson χ2 test was used to determine the significance of differences between groups for dichotomous variables. All comparisons of clinical characteristics were analyzed with the student's t-test or nonparametric test for continuous variables or the Chi-square test for categorical variables. The Kaplan-Meier method and log rank test were used for surviving calculation. A two-sided probability value of less than 0.05 was considered to be statistically significant. Survival time was measured from the date of tissue proof to the date of death or the last follow-up. Patients alive at the end of the study were considered censored for the purpose of data analysis. All factors that were at least marginally associated with survival rate (P < 0.2) were entered into multivariate analysis. We used logistic regression to estimate the odds ratio and multivariate analysis to adjust potential confounding factors such as age, gender, smoking history, consumption of alcohol, underlying diabetes, and stage of tumor. A P < 0.05 was considered to be statistically significant. The Statistical Package for the Social Sciences (SPSS) version 19 was used.


 » Results Top


Patient characteristics

In the entire group of 65 patients receiving CCRT, the age at diagnosis ranged from 37 to 81 years (median: 55 years) and male gender was dominant (90.8%). Over 85% of the enrolled patients had a history of smoking and consumption of alcohol. Ten patients (15.4%) suffered from diabetes mellitus or liver cirrhosis [Table 1]. Over 90% of the patients had squamous cell carcinoma histology and nearly 50% of the tumor lesions were in the middle third of the thoracic esophagus [Table 1]. There were 28 (43.1%) and 23 (35.4%) patients with stages III and IV disease, respectively [Table 1]. The mean total dose of radiation was 49.2 Gy, the mean cumulative dose of cisplatin was 195.6 mg/m 2, and 5-FU was 6,932 mg/m 2. The pretreatment mean hemoglobin level was 12.5 g/dL, mean white blood cell (WBC) count was 8,184/mm 3, and mean platelet count was 2.2 × 105/mm 3. In all 65 patients, serum markers of hepatitis were checked in 43 patients after 2009; seven patients were positive for hepatitis B surface antigen (16.2%) and three patients were positive for hepatitis C viral antibody (6.9%).
Table 1: Demographic characteristics of 65 patients with esophageal cancer

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After a median follow-up time of 15.4 months (range: from 0.8 to 56.1 months), 24 (39.3%) patients had died, and one-year and two-year overall survival rates were 61.5 and 32.3%, respectively. The median overall survival was 15.4 months.

Association between demographic parameters and myelosuppression during CCRT

We stratified demographic characteristics of the patients according to the severity of myelosuppression during CCRT [Table 2]. CCRT-related grade 3 or higher leukopenia occurred in more than 50% of the patients and was associated with lower pretreatment WBC (P = 0.041) and platelet counts (P = 0.054), but it did not correlate with doses of chemotherapy and radiotherapy, occurrence of interruption of treatment, survival rate, and overall survival [Table 2] and [Figure 1]a. There were 22 out of the 65 patients (33.8%) who developed grade 3 or higher anemia and had a different distribution of tumor location (P = 0.009), more interruptions of treatment (P = 0.001), and had lower one-year (P = 0.005) and two-year (P = 0.007) survival rates, and shorter overall survival [Table 2] and [Figure 1]b. Of the 65 patients, grade 3 or higher thrombocytopenia occurred in 15 patients (23.1%). These patients had a less advanced stage (P = 0.024), more cirrhotic events (P = 0.028), and lower WBC (P = 0.012) and platelet counts (P = 0.003) before CCRT as compared to patients with grade 0-2 thrombocytopenia. Patients with grade 3 or higher thrombocytopenia experienced a smaller dose of chemotherapy, more interruptions in radiotherapy, and had a lower one-year (P = 0.004) and two-year (P = 0.003) survival rate, and shorter overall survival [Table 2] and [Figure 1]c. The interval between the beginning of treatment and the day of lowest cell count ranged from 0 to 84 days. The severity of myelosuppression has no significant correlation with age, gender, cigarette smoking, consumption of alcohol, diabetes, cirrhosis, histologic type, extent of tumor, regional lymph invasion, pretreatment level of hemoglobin, and serum concentrations of albumin, bilirubin, and creatinine [Table 2].
Table 2: Clinical characteristics of 65 patients with esophageal cancer according to the severity of treatment-related myelosuppression

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Figure 1: Kaplan–Meier plot of overall survival; (a) thick line: Patients with grade 3-4 leukopenia during CCRT, thin line: Patients with grade 1-2 leukopenia during CCRT, P = 0.814; (b) thick line: Patients with grade 3-4 anemia during CCRT, thin line: Patients with grade 1-2 anemia during CCRT, P = 0.001; (c) thick line: Patients with grade 3-4 thrombocytopenia during CCRT, thin line: Patients with grade 1-2 thrombocytopenia during CCRT, P = 0.001

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Association between survival and myelosuppression during CCRT

The univariate analysis showed that the demographic variables including age, gender, history of smoking exposure, consumption of alcohol, liver cirrhosis, diabetes mellitus, histologic types, and location of tumor did not have a significant effect on survival rates [Table 3]. In contrast, T3-4 extent of tumor, a higher stage of tumor, lower albumin level, grade 3 or higher anemia and thrombocytopenia, and interruptions of treatment affected survival rates [Table 3]. Further, the multivariate analysis revealed that stage IV (P = 0.030) is an independently negative prognostic factor for the one-year survival rate. Stage IV (P = 0.035), T3-4 extent of tumor (P = 0.002), and grade 3-4 thrombocytopenia (P = 0.015) were independently negative prognostic factors for the two-year survival rate in the current analysis [Table 4]. The patients who had their lowest platelet count recorded after 22 days had a poorer survival rate compared to other patients who had their lowest platelet count recorded before 21 days (one-year survival rate: 52.1:88.2%, P = 0.008; two-year survival: 23.1:70.6%, P = 0.000). There was no difference in survival between a late presence (>22 days) of the lowest hemoglobin or WBC count and early presence (≦21 days).
Table 3: Univariate analysis for survival rate in 65 esophageal cancer patients treated by CCRT

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Table 4: Multivariate analysis for survival rate in 65 esophageal cancer patients treated by CCRT

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 » Discussion Top


The majority of patients with esophageal cancer at diagnosis are inoperable and their cumulative five-year survival rate remains unsatisfactory, despite a significant improvement in CCRT during the previous two decades.[15] To avoid early mortality caused by cancer-induced damage and treatment-related toxicity, a careful treatment plan should consider invasion of the cancer, comorbid status, the efficacy and relevant toxicity from CCRT doses, and the schedule. The current retrospective study analyzed the effect of cancer factors and CCRT factors simultaneously, and demonstrated that an advanced stage of tumor and severe CCRT-related thrombocytopenia are independently negative prognostic factors for early survival rates.

Few reports have addressed the correlation between CCRT-related myelosuppression and treatment outcomes in esophageal cancer patients.[19],[20] A German study analyzed 46 patients with locally advanced esophageal cancer and found that the severity of anemia during CCRT was associated with inferior overall survival.[19] Kogo et al. showed that severe thrombocytopenia induced by CCRT is associated with early death due to bleeding tendency and reduction in both chemotherapeutic and radiation doses.[20] Nonetheless, these two retrospective studies failed to show the independent impact of the severity of CCRT-associated leukopenia, anemia, or thrombocytopenia on survival. The present study demonstrated that severe thrombocytopenia, not leukopenia or anemia, during CCRT was independently associated with survival by multivariate analysis with the adjustment of demographic variables including stage of the tumor. The severity of leukopenia was not found to be a prognostic factor because leukopenia may be used as a pharmcodynamic factor to monitor biologically effective doses in individual patients,[22] and no significant survival difference was reported between patients with grade 3-4 leukopenia and those with grade 0-2 in certain types of cancers.[18] More than half of the patients developed grade 3-4 leukopenia; so, the administration of granulocyte colony–stimulating factor was allowed. There was no significant difference in survival rates and therapeutic dose given for grade 3-4 and grade 0-2; we believe that the average doses of CCRT used for patients in our study were sufficient to produce the antitumor effect. In small-cell lung cancer, the use of growth factors was associated with more thrombocytopenia, but thrombocytopenia did not show its impact on survival.[23] Taken together, the severity of CCRT-related leukopenia may be considered as a dose–decision factor during the course of treatment.

The effect of anemia during CCRT on the survival of esophageal cancer patients has been debated. Taussky's group found that treatment-related anemia had no influence on survival among 41 esophageal cancer patients treated by CCRT or radiotherapy alone,[24] while Hofheinz et al. reported the negative impact of anemia on survival.[19] The present study enrolled a homogenously treated population, and took cancer factor and CCRT factor into consideration by multivariate analyses. We found that the severity of CCRT-related anemia did not affect survival rate at all, even though the univariate analysis supported the correlation between severity of anemia, interruption of treatment, and survival [Table 2]. Treatment-associated anemia may lead to fatigue, exhaustion, and impaired quality of life, but timely management such as transfusion of red blood cells may correct symptoms and help completion of the treatment course with no reduction in the therapeutic dose. Indeed, patients in the present study developed grade 3 or higher anemia during CCRT and received blood transfusion immediately to avoid dose reduction and maintain the CCRT schedule to the extent possible. Hence, the severity of CCRT-related anemia may be considered as an indicator of the quality of life during the course of treatment.

It is estimated that 3-31% of patients with esophageal cancer undergoing CCRT using cisplatin and 5-FU–based regimen developed grade 3 or higher thrombocytopenia.[20],[25],[26],[27] The present analysis found that 23% of the patients developed severe treatment-related thrombocytopenia and the severity of thrombocytopenia was associated with pretreatment WBC and platelet counts and liver cirrhosis events, supporting a notion that a decreasing platelet count during CCRT may indicate poor bone marrow reserve, suboptimal liver function, or bad nutrition and medical status. Additionally, liver cirrhosis is usually accompanied with hypersplenism, portal hypertension, and low production of thrombopoietin.[28] Exposure to alcohol or a comorbid status such as sepsis or metabolic syndrome may precipitate the existing liver dysfunction. Hence, the occurrence of thrombocytopenia during CCRT was usually seen among esophageal cancer patients as viral hepatitis is endemic at Taiwan and a high percentage of patients were exposed to alcohol in the present study and previous reports.[20],[25],[26],[27] When severe thrombocytopenia was noted, interruption of treatment was encountered more frequently than transfusion, resulting in the administration of a lower chemotherapeutic dose [Table 2]. Moreover, platelet count may represent the nutritional condition of patients with esophageal cancer. Intensive enteral feeding for patients with esophageal cancer during neoadjuvant chemotherapy may reduce the risk of thrombocytopenia, not a serum albumin level.[29] The association between a later presence (>22 days) of the lowest platelet count and a poorer outcome might be representative of the changes in the general condition. These changes might occur after the second cycle of chemotherapy, which were not fully studied. The presence of late thrombocytopenia should be noted as a poor prognostic factor. Taken together, the severity of CCRT-related thrombocytopenia is significantly a reasonable prognostic factor for esophageal cancer patients.

This study was limited by its sample size and was not prospectively randomized. The chemotherapy in our study was based on cisplatin and 5-FU, and the findings in this study might not be reproduced under other therapeutic protocols.


 » Conclusion Top


The late presentation of thrombocytopenia should be noted during treatment. The severity of thrombocytopenia during CCRT may be a useful prognostic factor for patients with esophageal cancer in addition to the stage of tumor. Severe thrombocytopenia was associated with a significantly inferior outcome. Further well-designed prospective trials are required to establish an accurate verification of these findings.


 » Acknowledgment Top


The authors thank the Cancer Center Data Bank and all the members of the Cancer Center, Chang Gung Memorial Hospital, Keelung, Taiwan for their invaluable support.

 
 » References Top

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    Tables

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