Jpn J Clin Oncol 2014;44(1)78 – 84 doi:10.1093/jjco/hyt170 Advance Access Publication 11 November 2013
Longitudinal Assessments of Quality of Life and Late Toxicities Before and After Definitive Chemoradiation for Esophageal Cancer Hideomi Yamashita*, Mami Omori, Kae Okuma, Reiko Kobayashi, Hiroshi Igaki and Keiichi Nakagawa Department of Radiation Oncology, University of Tokyo Hospital, Bunkyo-ku, Japan *For reprints and all correspondence: Hideomi Yamashita, Division of Radiation Oncology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: [email protected] Received May 30, 2013; accepted October 15, 2013
Key words: esophageal cancer – chemoradiation – quality of life – combined modality treatment – FACT-E
INTRODUCTION Esophageal cancer is a devastating disease. Many patients who present with dysphagia already have unresectable and/or metastatic disease at the time of diagnosis. As long-term survival increases for patients with esophageal cancer, treatment protocols must consider the long-term effects on patients’ quality of life (QOL). The effects of each mode of therapy on patients’ QOL in acute and long-term settings have not been studied in a methodologically vigorous manner. It has also been documented that oncologists frequently underestimate
the radiation-related long-term morbidities in cancer survivors compared with the patients’ actual experience (1). We performed longitudinal evaluations of QOL and late toxicities in esophageal cancer patients to study the effect of definitive chemoradiotherapy (CRT) with a platinum-based regimen.
PATIENTS AND METHODS The study was performed at a single institution. This study was designed as a prospective descriptive study to measure
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Objective: Definitive chemoradiotherapy is often considered for locally advanced esophageal cancer. We studied the effect of chemoradiotherapy treatment on patients’ quality of life and late toxicities. Methods: Patients undergoing definitive 5-fluorouracil and cis-diammine-glycolatoplatinum (nedaplatin) therapy concurrent with radiotherapy for esophageal cancer without operation adaptation completed standardized quality-of-life questionnaires before and after chemoradiotherapy and at regular times up to 5 years. We analyzed differences in a generic qualityof-life score questionnaire (Functional Assessment of Cancer Therapy-Esophageal scoring) over time by using a linear mixed-effects model. Results: Longitudinal changes before the start of treatment were able to be evaluated in a total of 80 patients. The quality-of-life score before treatment was worse in patients with advanced stages than those with early stages. The quality-of-life score deteriorated once at the time of 2 or 3 months after starting chemoradiotherapy compared with pre-chemoradiotherapy and recovered and rose higher at 4 or 5 months than before starting chemoradiotherapy. After that, the recovery of quality of life was maintained up to the observation end. The score of physical functioning such as fatigue, nausea/vomiting, pain and dyspnea deteriorated at the time of 2 or 3 months after starting chemoradiotherapy compared with before chemoradiotherapy (80, 86, 94 and 89%). Conclusions: The quality-of-life score deteriorates once from before treatment due to acute complications by chemoradiotherapy, but recovers at 4 or 5 months and becomes better than before treatment.
Jpn J Clin Oncol 2014;44(1)
Table 1. Patient characteristics Characteristic
n (%)
Total no. of patients
80
Sex Male Female
After staging by using upper gastrointestinal endoscopy, computed tomography of the chest and upper abdomen, barium contrast X-ray and optional 18F fluorodeoxyglucose-positron emission tomography (FDG-PET), patients with Stages I–IVB who rejected surgery or cannot perform an operation for medical complication were treated with cis-diammine-glycolatoplatinum (nedaplatin), 80 mg/m 2 on Days 1, 29, 57 and 85 and 5-fluorouracil (5-FU), 800 mg/m 2 /day (Days 1 – 4, 29 – 32, 57 – 60 and 85 – 88), with concurrent administration of radiotherapy. For Stage I patients, CRT with two courses of 5-FU/platinum was given; on the other hand, CRT with two courses of 5-FU/platinum followed by boost two courses of 5-FU/platinum was given for Stages II/III. Radiotherapy consisted of a total dose of 50.4 Gy given in 28 fractions of 1.8 Gy with five fractions per week, starting on the first day of the first cycle of chemotherapy. All patients underwent irradiation using external beam radiation with a three-dimensional conformal radiation technique. Gross tumor volume (GTV) was defined by the primary tumor and any enlarged regional lymph nodes or the lesions with the maximum standard uptake value of .2.5 by FDG-PET. The planning target volume provided a 0.5 cm radial margin and a proximal and distal margin of 3 cm around the GTV. We selected the same radiation fields for all stages. QOL MEASURES The QOL was assessed by using the FACT-E, version 4.0. FACT-E is a validated tool to measure the effect of treatment on functional, social, physical and emotional well-being (EWB) that incorporates the esophageal cancer subscale (ECS) and allows for a systematic evaluation of QOL specifically in the context of esophageal cancer (2). The FACT-E reportedly met or exceeded all standards for validity (2). The FACT-E is
9 (11)
Age (years) Median
67
Range
48–79
Karnofsky performance status (%) 90– 100 80 270
59 (74) 8 (9) 13 (17)
Histologic characteristics Squamous-cell carcinoma Adenocarcinoma
TREATMENT
71 (89)
74 (92) 6 (8)
Stage I
17 (21)
II
14 (17)
III
26 (32)
IV
23 (30)
Primary site Cervical
2 (2)
Upper thoracic
9 (11)
Middle thoracic
42 (53)
Lower thoracic
27 (34)
Dysphagia grade at diagnosis (NCI-CTC grading v3.0) 0/1
57 (71)
2
17 (21)
3
6 (8)
4
0 (0)
Body weight loss Severe
20 (25)
Intermediate
12 (15)
None
48 (60)
NCI-CTC, National Cancer Institute-Common Toxicity Criteria.
the ECS and used as a supplement to the FACT-G instrument. The FACT-G consists of 27 generic items, which was divided into four QOL domains [physical well-being (PWB), social/ family well-being, EWB and functional well-being (FWB)]. The ECS consists of 18 esophageal cancer QOL-specific items. The total FACT-E score is the sum of the ECS and the FACT-G scores. A trial outcome index (TOI) score was computed by adding the PWB and FWB scores to the ECS score. Within the ECS, swallowing index consists of five items (hn7, e1, e2, e4 and e5), and the eating index consists of three items (hn1, hn5
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the QOL and to define its determinants in patients with esophageal cancer undergoing radiotherapy. The sample of the study consisted of 84 consecutive esophageal cancer patients who had been admitted to the Department of Radiation Oncology at University of Tokyo Hospital in Japan. All patients received radiation therapy (RT) with chemotherapy. The period of registration was from August 2008 to July 2010. The last follow-up date was August 2013. Once informed consent was obtained, the baseline patient demographics were collected, including age, presenting symptoms, Karnofsky performance status as well as concurrent significant medical and psychiatric comorbidities at the initial consultation visit. The characteristics of the tumor including histologic characteristics, clinical stage and primary site were subsequently recorded (Table 1). The QOL was measured using the Functional Assessment of Cancer Therapy-Esophageal scoring (FACT-E, version 4.0) at the baseline assessment and every 3 months for a maximum of 5 years. This study had ethics/Institutional Review Board approval (#2287).
79
80
QOL changes after CCRT for esophageal cancer
and e6). Higher numbers on the FACT-G and ECS always represent better QOL and fewer symptoms. TIMING OF ASSESSMENTS Baseline QOL assessments were performed before starting CRT. Follow-up data were collected 2 – 3, 4 – 5, 6 – 8, 9 – 12, 13 – 18, 19 – 24, 25 – 36 and 37 months after starting CRT. The patients filled in the questionnaires themselves. STATISTICS
QOL SCORES AT THE BASELINE
RESULTS QUESTIONNAIRE COMPLIANCE AND MISSING DATA During a 24-month period, 84 patients were approached for participation and 80 patients agreed to participate. Only four patients declined. Fifty-three patients (66%) presented with dysphagia as their main presenting symptom. Most patients (73 of 80, 91%) had no concurrent significant other comorbidities, with the rest having their medical conditions well controlled by oral medication. Table 1 lists the distribution of clinical presentations and pathologic features of the study cohort. The mean age was 67 years (range 48 – 79), and 89% were men (Table 1). Only two tumors were located at the cervical esophagus. Histology was adenocarcinoma in six (8%) patients and squamous-cell carcinoma in 74 (92%) patients (Table 1). The clinical stage at enrollment was Stage I in 17 (21%) patients, Stage II in 14 (17%), Stage III in 26 (32%) and Stage IV in 23 (30%) patients (Table 1). Forty-five disease recurrences after complete response with protocol treatment and/or newly detected metastases during or after protocol treatment developed in the study cohort during the study period. The median follow-up for the whole cohort was 34 months. Of the 80 patients, 36 had follow-up of .24 months. None of the patients withdrew from the study. The number of patients who died at each time point was 10 at 6 – 8 months, 16 at 9 – 12 months, 22 at 13– 18 months, 32 at 19– 24 months, 37 at 25– 36 months and 39 at over 37 months. Regarding the compliance with CRT, 79 patients excluding one who died during CRT accomplished RT and additional
The pre-treatment E-TOI score of Stages I and II was significantly better than that of Stages III and IV (72.0/119 vs. 59.5/ 119, P ¼ 0.023), and the pre-treatment E-total score of Stages I and II was better than that of Stages III and IV (55.6/134 vs. 48.8/134, P ¼ 0.068). There was no difference in the pre-treatment QOL scores between patients who had recurrent disease after completing CRT and who was disease-free at the time of analysis (E-TOI score: 83.2/134 vs. 96.2/134, P ¼ 0.060, G-total score: 46.6/ 71 vs. 50.0/71, P ¼ 0.38 and E-total score: 86.8/134 vs. 94.5/ 134, P ¼ 0.17). The QOL average scores before treatment of four patients who suffered from any severe Grade 3 – 4 complication were 97.9/119 of E-TOI, 57.9/71 of G-total and 109.6/134 of E-total. These values were not inferior to the other patients. SURVIVAL DATA The progression-free survival rate at 3 years was 76.2 + 12.2% in Stage I, 38.1 + 7.9% in Stages II and III and 12.1 + 7.4% in Stage IV (P ¼ 0.024 by univariate log-rank test), 47.9 + 8.5% in the better E-TOI score before CRT and 27.4 + 7.3% in the worse (P ¼ 0.0063) and 48.7 + 8.7% in the better E-total score before CRT and 26.7 + 7.2% in the worse (P ¼ 0.0023). There was no difference in progression-free survival rates between the better (80– 100%) and worse (270%) Karnofsky Performance Status (K-PS) (P ¼ 0.92) and among tumor locations (P ¼ 0.67). The patient number including our study was too small to perform multivariate analysis.
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Descriptive statistics were used to summarize the patient demographics. Student’s t-tests were used to compare the mean QOL domain scores to established population norms at baseline. Almost half of the patients died during the evaluation period and there were some informative missing of QOL measurements due to death. No more than 50% of the items were missing from any subscale. Progression-free and overall survival rates were calculated by the Kaplan – Meier method. Univariate analysis was performed by log-rank test. The Statistical Package for Social Sciences, version 15 (SPSS for Windows, SPSS, Chicago, IL, USA) was used for all data manipulation and analysis. All P values ,0.05 were considered statistically significant.
three patients were given only one cycle of chemotherapy. Fifty-two out of 63 patients with Stages II – IV completed full four cycles of chemotherapy. No questionnaire but rejection was missed because of administrative errors (patients accidentally not handed the questionnaires or patients did not complete questionnaires). Numbers of questionnaires available for analysis are listed in Table 2. The numbers decreased over time because of random administrative problems and the death of 39 of 80 patients (49%). The number of available questionnaires at each point was 65 patients (81%) at 2 – 3 months, 62 (78%) at 4 – 5 months, 50 (63%) at 6 – 8 months, 41 (51%) at 9 – 12 months, 34 (43%) at 13 – 18 months, 33 (41%) at 19 – 24 months, 32 (40%) at 25 – 36 months and 28 (35%) at over 37 months. One patient died during CRT, two patients died of complications of CRT and 36 patients died of recurrent disease between 5 and 22 months of follow-up. Overall, 347 questionnaires were completed. Analyses were performed using the available data. In other words, the data of the patients who rejected to participate in the questionnaires before starting CRT or could not answer because of the death were excluded from this analysis. However, the data of the patients with progression of the general condition or disease halfway through the observation period were not excluded.
Table 2. Mean and SD values of Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores for all patients who completed the treatment FACT-E
Baseline
2– 3 months
4 –5 months
6 –8 months
9– 12 months
13– 18 months
19–24 months
25– 36 months
37 months
Subject number
80
65
62
50
41
34
33
32
28
Functional scales
Mean
SD
Mean
SD
81.9
23.7
78.4
23.9
*
G-total
73.2
17.0
69.7
15.9
E-total
116.9
27.4
113.6
27.8
Physical functioning
20.9
6.0
18.2
6.5
Social functioning
18.3
6.8
17.3
6.1
E-TOI
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
91.1
20.5
**
96.7
20.2
98.7
13.9
107.2
15.3
104.6
18.6
102.0
16.7
98.4
18.6
*
73.0
15.6
*
125.8
77.8
14.0
79.8
11.8
85.8
13.7
85.2
12.8
79.5
14.5
78.5
15.0
25.8
**
131.5
23.0
135.0
17.4
145.3
20.5
143.2
22.1
137.0
21.4
134.6
21.8
*
21.6
5.7
**
22.5
5.3
23.0
5.1
24.9
4.1
24.9
4.3
25.2
4.5
24.2
4.3
16.4
7.4
17.6
6.0
17.0
6.7
18.6
6.6
18.3
6.6
15.6
6.6
17.1
7.0
Emotional functioning
16.7
4.7
17.8
4.8
18.4
4.1
17.2
5.0
19.2
2.7
19.5
3.7
20.3
3.3
19.4
3.0
19.2
2.9
Cognitive functioning
17.3
7.2
16.3
6.3
16.6
5.8
20.5
5.6
20.5
4.4
22.8
4.9
21.7
5.2
19.2
6.5
18.1
7.6
ECS
43.7
14.2
43.9
14.4
52.9
13.0
53.7
13.0
55.2
7.1
59.5
8.4
57.9
12.7
57.5
8.2
56.1
11.7
Fatigue
3.0
1.3
2.4
1.2
*
2.7
1.3
2.9
1.0
3.1
1.0
3.4
1.0
3.6
0.8
3.3
1.0
3.3
1.2
Nausea/vomiting
3.6
0.9
3.1
1.2
*
3.8
0.8
**
3.8
0.6
4.0
0.2
3.9
0.3
3.9
0.2
3.9
0.3
3.9
0.4
Pain
3.3
1.0
3.1
1.2
*
3.4
1.0
**
3.1
1.4
3.4
1.1
3.7
0.7
3.6
1.1
3.7
0.6
3.5
0.7
Dyspnea
3.6
0.9
3.2
1.0
*
3.6
1.0
**
3.6
0.7
3.6
0.7
3.8
0.5
3.6
1.0
3.6
1.0
3.3
1.2
**
**
Symptom items **
2.4
1.3
2.6
1.2
2.4
1.2
2.9
1.1
2.9
1.2
3.3
0.9
3.2
1.0
2.7
1.1
2.8
1.0
Appetite loss
2.0
1.5
2.1
1.5
2.6
1.2
**
2.7
1.5
2.7
1.2
3.3
1.1
3.4
0.7
3.2
0.8
3.1
1.1
Dysphagia
2.3
1.6
2.5
1.5
3.1
1.3
**
3.2
1.4
3.3
1.1
3.5
0.9
3.4
1.2
3.6
0.8
3.3
1.1
Eating
1.8
1.6
2.0
1.5
3.0
1.2
**
2.9
1.4
3.1
0.9
3.2
1.1
3.3
1.0
3.2
1.0
3.4
1.1
Reflux
3.8
0.6
3.6
0.8
*
3.7
0.8
3.5
1.2
3.7
0.6
3.9
0.2
3.8
0.6
3.9
0.3
3.8
0.5
Choking
3.1
1.3
3.1
1.3
*
3.4
1.1
**
3.4
1.1
3.5
0.8
3.6
0.9
3.5
1.3
3.7
0.6
3.7
0.8
**
**
Dry mouth
2.8
1.4
2.8
1.1
3.1
1.1
3.2
1.2
3.0
1.0
3.5
0.8
3.4
1.3
3.2
0.9
3.3
1.2
Cough
3.3
1.2
3.2
1.2
3.4
1.1
3.5
1.1
3.7
0.7
3.9
0.2
3.8
0.7
3.2
1.3
3.3
1.1
Speech
3.1
1.0
3.3
0.9
3.4
1.1
3.5
0.7
3.5
0.8
3.6
0.7
3.4
0.8
3.3
0.9
3.2
0.8
E-TOI, E-trial outcome index; ECS, esophageal cancer subscale. *P , 0.05 compared with baseline by a paired t-test. **P , 0.05 compared with nadir.
Jpn J Clin Oncol 2014;44(1)
Insomnia
81
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QOL changes after CCRT for esophageal cancer
The overall survival rate was 58.1 + 8.0% in the better E-total score before CRT and the worse (P ¼ 0.0042) and 56.8 + 8.0% in the better E-TOI score before CRT and 24.9 + 7.3% in the worse (P ¼ 0.014). There was no difference in overall survival rates among stages (P ¼ 0.12), between the better and worse K-PS (P ¼ 0.93) and among tumor locations (P ¼ 0.84). The response rate was 16/17 patients (94%) in Stage I, 24/ 40 (60%) in Stages II and III and 17/23 (74%) in Stage IV (P ¼ 0.14 by x 2 test).
Importantly, dysphagia was improved or relieved with CRT in all patients in whom it was a presenting complaint (41 patients with the slightest symptom of dysphagia). Similarly, both eating and swallowing indices increased significantly with CRT by 4 – 5 months (Fig. 4). The average QOL score (E-TOI, G-total, and E-total) at 2 – 3 months was 79 (+16), 71 (+7) and 116 (+14) in Stage I and 79 (+26), 69 (+18) and 113 (+31) in Stages II – IV. The score at 4 – 5 months was 100 (+17), 76 (+14) and 133 (+20) in Stage I and 89 (+21), 72 (+16) and 124 (+27) in Stages II – IV.
CHANGE OF QOL LATE TOXICITIES Severe side effects (Grade 3) of the lung and heart were seen in two patients (radiation pneumonitis) at 2 and 3 months and in one patient (cardiac tamponade) at 6 months, respectively. Two out of these three patients recovered from those side effects and recovered in the QOL score after the recovery
Figure 2. Longitudinal changes in the physical functioning score (high score ¼ less symptoms).
Figure 1. Longitudinal changes in the E-trial outcome index, G-total and E-total scores (high score ¼ less symptoms).
Figure 3. Longitudinal changes in the esophageal cancer subscale (high score ¼ less symptoms).
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The mean and SD values of FACT-E scores for all patients who completed the treatment are listed in Table 2 (all available data are reported). The average (+SD) E-total score was 117 (+27) at pre-treatment, 114 (+28) at 2–3 months, 126 (+26) at 4–5 months, 132 (+23) at 6–8 months, 135 (+17) at 9–12 months, 145 (+21) at 13–18 months, 143 (+22) at 19–24 months, 137 (+21) at 25–36 months and 134 (+22) at over 37 months. FACT-E scores (E-total) decreased significantly after starting CRT at 2 – 3 months (83.3/134 at 2 – 3 months vs. 90.3/134 at baseline, P ¼ 0.020). Changes in FACT-E scores are shown in Fig. 1. At 4 – 5 months, there was a statistically significant improvement in scores compared with those seen at baseline (90.3/134 vs. 100/134, P ¼ 0.038). FACT-E scores continued to increase over time until at least 13 – 18 months after definitive CRT. In analyzing the subscales of the FACT-E, there was a significant decrease in scores for physical and FWB after CRT (Fig. 2), whereas emotional and social well-being scores remained fairly stable. The esophageal cancer-specific concerns reflected in the ECS improved with CRT by 2 – 3 months (Fig. 3).
Jpn J Clin Oncol 2014;44(1)
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from toxicity. Additionally, one patient died of sepsis shock without cancer recurrence at 3 months after CRT. No late side effect involving the esophagus, skin or spinal cord was seen.
DISCUSSION This study described longitudinal QOL in patients with esophageal cancer who undergo definitive CRT. Few studies (3) have examined the long-term QOL effects on patients of CRT for this disease. Definitive CRT has a significant effect on QOL because FACT-E scores decrease significantly at 2 – 3 months after starting CRT but again return over baseline levels within 4 – 5 months of CRT, and after that, the score will get even better. Significantly greater increases in FACT-E scores were observed in patients who were still alive 1 year after CRT with or without disease but were observed to decrease in those who died within 1 year of CRT. In our study, 92% of the patients presented with squamouscell carcinoma despite only 2 of 80 patients having a proximal third (cervical) esophageal carcinoma. The percentage of patients with adenocarcinoma appears to be very low, but this is not a rare thing in Japan. Squamous-cell carcinoma accounts for 95% of all esophageal carcinomas and other histologic types, including adenocarcinoma, account for the remaining 5% (4). In addition, it appears that 30% of the patients were Stage IV at presentation and appeared to proceed to receive radical CRT. We performed radical CRT for patients with supra-clavicular or abdominal para-aortic lymph node metastasis even if it is Stage IV. Since the number of the total cycles of chemotherapy was different between Stage I and the other stages in this study, we
analyzed the data depending on the stage. However, it did not largely affect the QOL at 2 – 5 months. We selected nedaplatin, 80 mg/m2 on Days 1, 29, 57 and 85 and 5-FU, 800 mg/m2 /day (Days 1 – 4, 29 – 32, 57 – 60 and 85 – 88), with concurrent administration of radiotherapy. This is not the standard regimen for esophageal cancer. However, we have given nedaplatin in place of cisplatin since 2000 because in a clinical study, combination chemotherapy using nedaplatin and 5-FU has been reported to be a safe and effective method for treating advanced esophageal cancer (5 – 7). Nedaplatin may be considered to be helpful in reducing toxicity from a previous study. Nedaplatin instead of cisplatin contributes to decrease toxicities, especially renal and heart toxicities, because there is no need for a lot of hydration fluid. We selected the same radiation fields for all stages like INT 0123 study (8) and Cancer Research UK (9), in which the radiation field was not different depending on the stage. Brooks et al. (10) and Safieddine et al. (11) also used the FACT-E to determine the effect of surgical intervention on the health-related QOL in patients with esophageal cancer. On analyzing the FACT-E subscales, it is an interesting observation that the physical and FWB scales decrease after CRT, whereas the emotional and social well-being scales remain stable. This reflects the resilience of the patient’s perception of social and emotional support, despite physical and functional debility. In a randomized study of CRT vs. CRT plus surgical intervention, QOL scores were significantly worse at the first follow-up visit (3 months) in the surgical patients, but this difference resolved by the second visit at 6 months, and over time, QOL scores remained similar in both arms (12). This supports our finding that the adverse effect of CRT on the
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Figure 4. Longitudinal changes in fatigue, nausea/vomiting, pain, dyspnea, reflux, choking and dysphagia (high score ¼ less symptoms).
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QOL changes after CCRT for esophageal cancer
CONCLUSION Our longitudinal assessments of QOL in esophageal cancer patients showed that no significant adverse long-term effect on patients’ overall QOL resulted from definitive CRT. The acute worsening of QOL during the treatment phase had significantly improved with longer term follow-up.
Conflict of interest statement None declared.
References 1. Vistad I, Cvancarova M, Fossa SD, et al. Postradiotherapy morbidity in long-term survivors after locally advanced cervical cancer: how well do physicians’ assessments agree with those of their patients? Int J Radiat Oncol Biol Phys 2008;71:1335– 42. 2. Darling G, Eton D, Sulman J, Casson A, Cella D. Validation of the functional assessment of cancer therapy esophageal cancer subscale. Cancer 2006;107:854– 63. 3. Kachnic LA, Winter K, Wasserman T, et al. Longitudinal quality-of-life analysis of RTOG 94 – 05 (Int 0123): a phase III trial of definitive chemoradiotherapy for esophageal cancer. Gastrointest Cancer Res 2011;4:45–52. 4. The Japanese Society for Esophageal Diseases. Comprehensive Registry of Esophageal Cancer in Japan (1998, 1999) & Long-Term Result of Esophagectomy in Japan (1988 – 1997). Tokyo: The Japanese Society of Esophageal Diseases 2002. 5. Yamashita H, Nakagawa K, Tago M, et al. Radiation therapy combined with cis-diammine-glycolatoplatinum (nedaplatin) and 5-fluorouracil for Japanese stage II – IV esophageal cancer compared with cisplatin plus 5-fluorouracil regimen: a retrospective study. Dis Esophagus 2006;19:15–9. 6. Yamashita H, Okuma K, Wakui R, et al. Details of recurrence sites after elective nodal irradiation (ENI) using 3D-conformal radiotherapy (3D-CRT) combined with chemotherapy for thoracic esophageal squamous cell carcinoma—a retrospective analysis. Radiother Oncol 2011;98:255–60. 7. Yoshioka T, Gamoh M, Shineha R, et al. A new combination chemotherapy with cis-diammine-glycolatoplatinum (Nedaplatin) and 5-fluorouracil for advanced esophageal cancers. Intern Med 1999;38:844–8. 8. Minsky BD, Pajak TF, Ginsberg RJ, et al. INT 0123 (Radiation Therapy Oncology Group 94 – 05) phase III trial of combined-modality therapy for esophageal cancer: high-dose versus standard-dose radiation therapy. J Clin Oncol 2002;20:1167–74. 9. Crosby T, Hurt CN, Falk S, et al. Chemoradiotherapy with or without cetuximab in patients with oesophageal cancer (SCOPE1): a multicentre, phase 2/3 randomised trial. Lancet Oncol 2013;14:627– 37. 10. Brooks JA, Kesler KA, Johnson CS, Ciatta D, Brown JW. Prospective analysis of quality of life after surgical resection for esophageal cancer: preliminary results. J Surg Oncol 2002;81:185–94. 11. Safieddine N, Xu W, Quadri SM, et al. Health-related quality of life in esophageal cancer: effect of neoadjuvant chemoradiotherapy followed by surgical intervention. J Thorac Cardiovasc Surg 2009;137:36–42. 12. Bonnetain F, Bouche O, Michel P, et al. A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Ann Oncol 2006;17:827– 34. 13. Blazeby JM, Farndon JR, Donovan J, Alderson D. A prospective longitudinal study examining the quality of life of patients with esophageal carcinoma. Cancer 2000;88:1781–7. 14. Fang FM, Tsai WL, Chiu HC, Kuo WR, Hsiung CY. Quality of life as a survival predictor for esophageal squamous cell carcinoma treated with radiotherapy. Int J Radiat Oncol 2004;58:1394 –404. 15. Bedenne L, Michel P, Bouche´ O, et al. Chemoradiation followed by surgery compared with chemoradiation alone in squamous cancer of the esophagus: FFCD 9102. J Clin Oncol 2007;25:1160– 8. 16. Chiu PW, Chan AC, Leung SF, et al. Multicenter prospective randomized trial comparing standard esophagectomy with chemoradiotherapy for treatment of squamous esophageal cancer: early results from the Chinese University Research Group for Esophageal Cancer (CURE). J Gastrointest Surg 2005;9:794–802. 17. Bonnetain F, Bouche´ O, Michel P, et al. A comparative longitudinal quality of life study using the Spitzer quality of life index in a randomized multicenter phase III trial (FFCD 9102): chemoradiation followed by surgery compared with chemoradiation alone in locally advanced squamous resectable thoracic esophageal cancer. Ann Oncol 2006;17:827– 34.
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QOL score is transient, and this strategy should be pursued in an effort to improve survival. Several groups have suggested that the baseline QOL scores are predictive of survival. Blazeby et al. (13) reported that the baseline QOL scores were not associated with postoperative morbidity, but were significantly associated with survival at 6 months postoperatively after adjusting for known risk factors. A similar finding has been reported for patients treated with primary radiotherapy, and in particular, the physical functioning role at baseline was predictive of survival (12,14). We did not find any association between the pre-treatment baseline QOL score and disease-free survival after CRT (62% with recurrence vs. 72% without disease in E-TOI score). There are three randomized clinical trials (8,15,16) comparing CRT with surgery or CRT (two have QOL (3,17)). The FFCD 9102 trial (17) reported that the mean QOL score decreased between baseline and the first follow-up and between the first and the second follow-ups. According to the INT 0123 trial (3), the total mean QOL was significantly lower in the high-dose arm of 64.8 Gy (P ¼ 0.02) and remained lower at 8 and 12 months after the start of CRT, but these values did not reach statistical significance and change in the mean QOL from baseline to each of the three subsequent assessment time points did not differ significantly between the two treatment arms (50.4 vs. 64.8 Gy). In this study, the average QOL scores before CRT of four patients with severe complication were not inferior to the other patients. The pre-treatment QOL score was not a predictive factor of late severe toxicities. Two patients recovered from severe side effects and recovered also in the QOL score after the recovery from toxicity. Late severe toxicities had not much influence on long-term QOL in this study. Our study had some limitations. The first is that the small number of patients resulted from a convenient sample recruited during a 24-month period and limited our ability to perform multiple adjustments for potential confounders and the power of our analysis to detect small differences. Second, the non-randomized nature of the assignment of CRT could have introduced some selection bias. Third, this is not a prospective study in the strict sense to compare the previous historical data in the change of QOL score after CRT. Consequently, there were no statistical considerations including endpoints or sample size estimation. We had only obtained questionnaires at fixed intervals prospectively for consecutive patients with esophageal cancer who undergo a certain protocol of definitive CRT in our department.
Longitudinal Assessments of Quality of Life and Late Toxicities Before and After Definitive Chemoradiation for Esophageal Cancer Hideomi Yamashita*, Mami Omori, Kae Okuma, Reiko Kobayashi, Hiroshi Igaki and Keiichi Nakagawa Department of Radiation Oncology, University of Tokyo Hospital, Bunkyo-ku, Japan *For reprints and all correspondence: Hideomi Yamashita, Division of Radiation Oncology, University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan. E-mail: [email protected] Received May 30, 2013; accepted October 15, 2013
Key words: esophageal cancer – chemoradiation – quality of life – combined modality treatment – FACT-E
INTRODUCTION Esophageal cancer is a devastating disease. Many patients who present with dysphagia already have unresectable and/or metastatic disease at the time of diagnosis. As long-term survival increases for patients with esophageal cancer, treatment protocols must consider the long-term effects on patients’ quality of life (QOL). The effects of each mode of therapy on patients’ QOL in acute and long-term settings have not been studied in a methodologically vigorous manner. It has also been documented that oncologists frequently underestimate
the radiation-related long-term morbidities in cancer survivors compared with the patients’ actual experience (1). We performed longitudinal evaluations of QOL and late toxicities in esophageal cancer patients to study the effect of definitive chemoradiotherapy (CRT) with a platinum-based regimen.
PATIENTS AND METHODS The study was performed at a single institution. This study was designed as a prospective descriptive study to measure
# The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]
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Objective: Definitive chemoradiotherapy is often considered for locally advanced esophageal cancer. We studied the effect of chemoradiotherapy treatment on patients’ quality of life and late toxicities. Methods: Patients undergoing definitive 5-fluorouracil and cis-diammine-glycolatoplatinum (nedaplatin) therapy concurrent with radiotherapy for esophageal cancer without operation adaptation completed standardized quality-of-life questionnaires before and after chemoradiotherapy and at regular times up to 5 years. We analyzed differences in a generic qualityof-life score questionnaire (Functional Assessment of Cancer Therapy-Esophageal scoring) over time by using a linear mixed-effects model. Results: Longitudinal changes before the start of treatment were able to be evaluated in a total of 80 patients. The quality-of-life score before treatment was worse in patients with advanced stages than those with early stages. The quality-of-life score deteriorated once at the time of 2 or 3 months after starting chemoradiotherapy compared with pre-chemoradiotherapy and recovered and rose higher at 4 or 5 months than before starting chemoradiotherapy. After that, the recovery of quality of life was maintained up to the observation end. The score of physical functioning such as fatigue, nausea/vomiting, pain and dyspnea deteriorated at the time of 2 or 3 months after starting chemoradiotherapy compared with before chemoradiotherapy (80, 86, 94 and 89%). Conclusions: The quality-of-life score deteriorates once from before treatment due to acute complications by chemoradiotherapy, but recovers at 4 or 5 months and becomes better than before treatment.
Jpn J Clin Oncol 2014;44(1)
Table 1. Patient characteristics Characteristic
n (%)
Total no. of patients
80
Sex Male Female
After staging by using upper gastrointestinal endoscopy, computed tomography of the chest and upper abdomen, barium contrast X-ray and optional 18F fluorodeoxyglucose-positron emission tomography (FDG-PET), patients with Stages I–IVB who rejected surgery or cannot perform an operation for medical complication were treated with cis-diammine-glycolatoplatinum (nedaplatin), 80 mg/m 2 on Days 1, 29, 57 and 85 and 5-fluorouracil (5-FU), 800 mg/m 2 /day (Days 1 – 4, 29 – 32, 57 – 60 and 85 – 88), with concurrent administration of radiotherapy. For Stage I patients, CRT with two courses of 5-FU/platinum was given; on the other hand, CRT with two courses of 5-FU/platinum followed by boost two courses of 5-FU/platinum was given for Stages II/III. Radiotherapy consisted of a total dose of 50.4 Gy given in 28 fractions of 1.8 Gy with five fractions per week, starting on the first day of the first cycle of chemotherapy. All patients underwent irradiation using external beam radiation with a three-dimensional conformal radiation technique. Gross tumor volume (GTV) was defined by the primary tumor and any enlarged regional lymph nodes or the lesions with the maximum standard uptake value of .2.5 by FDG-PET. The planning target volume provided a 0.5 cm radial margin and a proximal and distal margin of 3 cm around the GTV. We selected the same radiation fields for all stages. QOL MEASURES The QOL was assessed by using the FACT-E, version 4.0. FACT-E is a validated tool to measure the effect of treatment on functional, social, physical and emotional well-being (EWB) that incorporates the esophageal cancer subscale (ECS) and allows for a systematic evaluation of QOL specifically in the context of esophageal cancer (2). The FACT-E reportedly met or exceeded all standards for validity (2). The FACT-E is
9 (11)
Age (years) Median
67
Range
48–79
Karnofsky performance status (%) 90– 100 80 270
59 (74) 8 (9) 13 (17)
Histologic characteristics Squamous-cell carcinoma Adenocarcinoma
TREATMENT
71 (89)
74 (92) 6 (8)
Stage I
17 (21)
II
14 (17)
III
26 (32)
IV
23 (30)
Primary site Cervical
2 (2)
Upper thoracic
9 (11)
Middle thoracic
42 (53)
Lower thoracic
27 (34)
Dysphagia grade at diagnosis (NCI-CTC grading v3.0) 0/1
57 (71)
2
17 (21)
3
6 (8)
4
0 (0)
Body weight loss Severe
20 (25)
Intermediate
12 (15)
None
48 (60)
NCI-CTC, National Cancer Institute-Common Toxicity Criteria.
the ECS and used as a supplement to the FACT-G instrument. The FACT-G consists of 27 generic items, which was divided into four QOL domains [physical well-being (PWB), social/ family well-being, EWB and functional well-being (FWB)]. The ECS consists of 18 esophageal cancer QOL-specific items. The total FACT-E score is the sum of the ECS and the FACT-G scores. A trial outcome index (TOI) score was computed by adding the PWB and FWB scores to the ECS score. Within the ECS, swallowing index consists of five items (hn7, e1, e2, e4 and e5), and the eating index consists of three items (hn1, hn5
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the QOL and to define its determinants in patients with esophageal cancer undergoing radiotherapy. The sample of the study consisted of 84 consecutive esophageal cancer patients who had been admitted to the Department of Radiation Oncology at University of Tokyo Hospital in Japan. All patients received radiation therapy (RT) with chemotherapy. The period of registration was from August 2008 to July 2010. The last follow-up date was August 2013. Once informed consent was obtained, the baseline patient demographics were collected, including age, presenting symptoms, Karnofsky performance status as well as concurrent significant medical and psychiatric comorbidities at the initial consultation visit. The characteristics of the tumor including histologic characteristics, clinical stage and primary site were subsequently recorded (Table 1). The QOL was measured using the Functional Assessment of Cancer Therapy-Esophageal scoring (FACT-E, version 4.0) at the baseline assessment and every 3 months for a maximum of 5 years. This study had ethics/Institutional Review Board approval (#2287).
79
80
QOL changes after CCRT for esophageal cancer
and e6). Higher numbers on the FACT-G and ECS always represent better QOL and fewer symptoms. TIMING OF ASSESSMENTS Baseline QOL assessments were performed before starting CRT. Follow-up data were collected 2 – 3, 4 – 5, 6 – 8, 9 – 12, 13 – 18, 19 – 24, 25 – 36 and 37 months after starting CRT. The patients filled in the questionnaires themselves. STATISTICS
QOL SCORES AT THE BASELINE
RESULTS QUESTIONNAIRE COMPLIANCE AND MISSING DATA During a 24-month period, 84 patients were approached for participation and 80 patients agreed to participate. Only four patients declined. Fifty-three patients (66%) presented with dysphagia as their main presenting symptom. Most patients (73 of 80, 91%) had no concurrent significant other comorbidities, with the rest having their medical conditions well controlled by oral medication. Table 1 lists the distribution of clinical presentations and pathologic features of the study cohort. The mean age was 67 years (range 48 – 79), and 89% were men (Table 1). Only two tumors were located at the cervical esophagus. Histology was adenocarcinoma in six (8%) patients and squamous-cell carcinoma in 74 (92%) patients (Table 1). The clinical stage at enrollment was Stage I in 17 (21%) patients, Stage II in 14 (17%), Stage III in 26 (32%) and Stage IV in 23 (30%) patients (Table 1). Forty-five disease recurrences after complete response with protocol treatment and/or newly detected metastases during or after protocol treatment developed in the study cohort during the study period. The median follow-up for the whole cohort was 34 months. Of the 80 patients, 36 had follow-up of .24 months. None of the patients withdrew from the study. The number of patients who died at each time point was 10 at 6 – 8 months, 16 at 9 – 12 months, 22 at 13– 18 months, 32 at 19– 24 months, 37 at 25– 36 months and 39 at over 37 months. Regarding the compliance with CRT, 79 patients excluding one who died during CRT accomplished RT and additional
The pre-treatment E-TOI score of Stages I and II was significantly better than that of Stages III and IV (72.0/119 vs. 59.5/ 119, P ¼ 0.023), and the pre-treatment E-total score of Stages I and II was better than that of Stages III and IV (55.6/134 vs. 48.8/134, P ¼ 0.068). There was no difference in the pre-treatment QOL scores between patients who had recurrent disease after completing CRT and who was disease-free at the time of analysis (E-TOI score: 83.2/134 vs. 96.2/134, P ¼ 0.060, G-total score: 46.6/ 71 vs. 50.0/71, P ¼ 0.38 and E-total score: 86.8/134 vs. 94.5/ 134, P ¼ 0.17). The QOL average scores before treatment of four patients who suffered from any severe Grade 3 – 4 complication were 97.9/119 of E-TOI, 57.9/71 of G-total and 109.6/134 of E-total. These values were not inferior to the other patients. SURVIVAL DATA The progression-free survival rate at 3 years was 76.2 + 12.2% in Stage I, 38.1 + 7.9% in Stages II and III and 12.1 + 7.4% in Stage IV (P ¼ 0.024 by univariate log-rank test), 47.9 + 8.5% in the better E-TOI score before CRT and 27.4 + 7.3% in the worse (P ¼ 0.0063) and 48.7 + 8.7% in the better E-total score before CRT and 26.7 + 7.2% in the worse (P ¼ 0.0023). There was no difference in progression-free survival rates between the better (80– 100%) and worse (270%) Karnofsky Performance Status (K-PS) (P ¼ 0.92) and among tumor locations (P ¼ 0.67). The patient number including our study was too small to perform multivariate analysis.
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Descriptive statistics were used to summarize the patient demographics. Student’s t-tests were used to compare the mean QOL domain scores to established population norms at baseline. Almost half of the patients died during the evaluation period and there were some informative missing of QOL measurements due to death. No more than 50% of the items were missing from any subscale. Progression-free and overall survival rates were calculated by the Kaplan – Meier method. Univariate analysis was performed by log-rank test. The Statistical Package for Social Sciences, version 15 (SPSS for Windows, SPSS, Chicago, IL, USA) was used for all data manipulation and analysis. All P values ,0.05 were considered statistically significant.
three patients were given only one cycle of chemotherapy. Fifty-two out of 63 patients with Stages II – IV completed full four cycles of chemotherapy. No questionnaire but rejection was missed because of administrative errors (patients accidentally not handed the questionnaires or patients did not complete questionnaires). Numbers of questionnaires available for analysis are listed in Table 2. The numbers decreased over time because of random administrative problems and the death of 39 of 80 patients (49%). The number of available questionnaires at each point was 65 patients (81%) at 2 – 3 months, 62 (78%) at 4 – 5 months, 50 (63%) at 6 – 8 months, 41 (51%) at 9 – 12 months, 34 (43%) at 13 – 18 months, 33 (41%) at 19 – 24 months, 32 (40%) at 25 – 36 months and 28 (35%) at over 37 months. One patient died during CRT, two patients died of complications of CRT and 36 patients died of recurrent disease between 5 and 22 months of follow-up. Overall, 347 questionnaires were completed. Analyses were performed using the available data. In other words, the data of the patients who rejected to participate in the questionnaires before starting CRT or could not answer because of the death were excluded from this analysis. However, the data of the patients with progression of the general condition or disease halfway through the observation period were not excluded.
Table 2. Mean and SD values of Functional Assessment of Cancer Therapy-Esophageal (FACT-E) scores for all patients who completed the treatment FACT-E
Baseline
2– 3 months
4 –5 months
6 –8 months
9– 12 months
13– 18 months
19–24 months
25– 36 months
37 months
Subject number
80
65
62
50
41
34
33
32
28
Functional scales
Mean
SD
Mean
SD
81.9
23.7
78.4
23.9
*
G-total
73.2
17.0
69.7
15.9
E-total
116.9
27.4
113.6
27.8
Physical functioning
20.9
6.0
18.2
6.5
Social functioning
18.3
6.8
17.3
6.1
E-TOI
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
Mean
SD
91.1
20.5
**
96.7
20.2
98.7
13.9
107.2
15.3
104.6
18.6
102.0
16.7
98.4
18.6
*
73.0
15.6
*
125.8
77.8
14.0
79.8
11.8
85.8
13.7
85.2
12.8
79.5
14.5
78.5
15.0
25.8
**
131.5
23.0
135.0
17.4
145.3
20.5
143.2
22.1
137.0
21.4
134.6
21.8
*
21.6
5.7
**
22.5
5.3
23.0
5.1
24.9
4.1
24.9
4.3
25.2
4.5
24.2
4.3
16.4
7.4
17.6
6.0
17.0
6.7
18.6
6.6
18.3
6.6
15.6
6.6
17.1
7.0
Emotional functioning
16.7
4.7
17.8
4.8
18.4
4.1
17.2
5.0
19.2
2.7
19.5
3.7
20.3
3.3
19.4
3.0
19.2
2.9
Cognitive functioning
17.3
7.2
16.3
6.3
16.6
5.8
20.5
5.6
20.5
4.4
22.8
4.9
21.7
5.2
19.2
6.5
18.1
7.6
ECS
43.7
14.2
43.9
14.4
52.9
13.0
53.7
13.0
55.2
7.1
59.5
8.4
57.9
12.7
57.5
8.2
56.1
11.7
Fatigue
3.0
1.3
2.4
1.2
*
2.7
1.3
2.9
1.0
3.1
1.0
3.4
1.0
3.6
0.8
3.3
1.0
3.3
1.2
Nausea/vomiting
3.6
0.9
3.1
1.2
*
3.8
0.8
**
3.8
0.6
4.0
0.2
3.9
0.3
3.9
0.2
3.9
0.3
3.9
0.4
Pain
3.3
1.0
3.1
1.2
*
3.4
1.0
**
3.1
1.4
3.4
1.1
3.7
0.7
3.6
1.1
3.7
0.6
3.5
0.7
Dyspnea
3.6
0.9
3.2
1.0
*
3.6
1.0
**
3.6
0.7
3.6
0.7
3.8
0.5
3.6
1.0
3.6
1.0
3.3
1.2
**
**
Symptom items **
2.4
1.3
2.6
1.2
2.4
1.2
2.9
1.1
2.9
1.2
3.3
0.9
3.2
1.0
2.7
1.1
2.8
1.0
Appetite loss
2.0
1.5
2.1
1.5
2.6
1.2
**
2.7
1.5
2.7
1.2
3.3
1.1
3.4
0.7
3.2
0.8
3.1
1.1
Dysphagia
2.3
1.6
2.5
1.5
3.1
1.3
**
3.2
1.4
3.3
1.1
3.5
0.9
3.4
1.2
3.6
0.8
3.3
1.1
Eating
1.8
1.6
2.0
1.5
3.0
1.2
**
2.9
1.4
3.1
0.9
3.2
1.1
3.3
1.0
3.2
1.0
3.4
1.1
Reflux
3.8
0.6
3.6
0.8
*
3.7
0.8
3.5
1.2
3.7
0.6
3.9
0.2
3.8
0.6
3.9
0.3
3.8
0.5
Choking
3.1
1.3
3.1
1.3
*
3.4
1.1
**
3.4
1.1
3.5
0.8
3.6
0.9
3.5
1.3
3.7
0.6
3.7
0.8
**
**
Dry mouth
2.8
1.4
2.8
1.1
3.1
1.1
3.2
1.2
3.0
1.0
3.5
0.8
3.4
1.3
3.2
0.9
3.3
1.2
Cough
3.3
1.2
3.2
1.2
3.4
1.1
3.5
1.1
3.7
0.7
3.9
0.2
3.8
0.7
3.2
1.3
3.3
1.1
Speech
3.1
1.0
3.3
0.9
3.4
1.1
3.5
0.7
3.5
0.8
3.6
0.7
3.4
0.8
3.3
0.9
3.2
0.8
E-TOI, E-trial outcome index; ECS, esophageal cancer subscale. *P , 0.05 compared with baseline by a paired t-test. **P , 0.05 compared with nadir.
Jpn J Clin Oncol 2014;44(1)
Insomnia
81
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82
QOL changes after CCRT for esophageal cancer
The overall survival rate was 58.1 + 8.0% in the better E-total score before CRT and the worse (P ¼ 0.0042) and 56.8 + 8.0% in the better E-TOI score before CRT and 24.9 + 7.3% in the worse (P ¼ 0.014). There was no difference in overall survival rates among stages (P ¼ 0.12), between the better and worse K-PS (P ¼ 0.93) and among tumor locations (P ¼ 0.84). The response rate was 16/17 patients (94%) in Stage I, 24/ 40 (60%) in Stages II and III and 17/23 (74%) in Stage IV (P ¼ 0.14 by x 2 test).
Importantly, dysphagia was improved or relieved with CRT in all patients in whom it was a presenting complaint (41 patients with the slightest symptom of dysphagia). Similarly, both eating and swallowing indices increased significantly with CRT by 4 – 5 months (Fig. 4). The average QOL score (E-TOI, G-total, and E-total) at 2 – 3 months was 79 (+16), 71 (+7) and 116 (+14) in Stage I and 79 (+26), 69 (+18) and 113 (+31) in Stages II – IV. The score at 4 – 5 months was 100 (+17), 76 (+14) and 133 (+20) in Stage I and 89 (+21), 72 (+16) and 124 (+27) in Stages II – IV.
CHANGE OF QOL LATE TOXICITIES Severe side effects (Grade 3) of the lung and heart were seen in two patients (radiation pneumonitis) at 2 and 3 months and in one patient (cardiac tamponade) at 6 months, respectively. Two out of these three patients recovered from those side effects and recovered in the QOL score after the recovery
Figure 2. Longitudinal changes in the physical functioning score (high score ¼ less symptoms).
Figure 1. Longitudinal changes in the E-trial outcome index, G-total and E-total scores (high score ¼ less symptoms).
Figure 3. Longitudinal changes in the esophageal cancer subscale (high score ¼ less symptoms).
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The mean and SD values of FACT-E scores for all patients who completed the treatment are listed in Table 2 (all available data are reported). The average (+SD) E-total score was 117 (+27) at pre-treatment, 114 (+28) at 2–3 months, 126 (+26) at 4–5 months, 132 (+23) at 6–8 months, 135 (+17) at 9–12 months, 145 (+21) at 13–18 months, 143 (+22) at 19–24 months, 137 (+21) at 25–36 months and 134 (+22) at over 37 months. FACT-E scores (E-total) decreased significantly after starting CRT at 2 – 3 months (83.3/134 at 2 – 3 months vs. 90.3/134 at baseline, P ¼ 0.020). Changes in FACT-E scores are shown in Fig. 1. At 4 – 5 months, there was a statistically significant improvement in scores compared with those seen at baseline (90.3/134 vs. 100/134, P ¼ 0.038). FACT-E scores continued to increase over time until at least 13 – 18 months after definitive CRT. In analyzing the subscales of the FACT-E, there was a significant decrease in scores for physical and FWB after CRT (Fig. 2), whereas emotional and social well-being scores remained fairly stable. The esophageal cancer-specific concerns reflected in the ECS improved with CRT by 2 – 3 months (Fig. 3).
Jpn J Clin Oncol 2014;44(1)
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from toxicity. Additionally, one patient died of sepsis shock without cancer recurrence at 3 months after CRT. No late side effect involving the esophagus, skin or spinal cord was seen.
DISCUSSION This study described longitudinal QOL in patients with esophageal cancer who undergo definitive CRT. Few studies (3) have examined the long-term QOL effects on patients of CRT for this disease. Definitive CRT has a significant effect on QOL because FACT-E scores decrease significantly at 2 – 3 months after starting CRT but again return over baseline levels within 4 – 5 months of CRT, and after that, the score will get even better. Significantly greater increases in FACT-E scores were observed in patients who were still alive 1 year after CRT with or without disease but were observed to decrease in those who died within 1 year of CRT. In our study, 92% of the patients presented with squamouscell carcinoma despite only 2 of 80 patients having a proximal third (cervical) esophageal carcinoma. The percentage of patients with adenocarcinoma appears to be very low, but this is not a rare thing in Japan. Squamous-cell carcinoma accounts for 95% of all esophageal carcinomas and other histologic types, including adenocarcinoma, account for the remaining 5% (4). In addition, it appears that 30% of the patients were Stage IV at presentation and appeared to proceed to receive radical CRT. We performed radical CRT for patients with supra-clavicular or abdominal para-aortic lymph node metastasis even if it is Stage IV. Since the number of the total cycles of chemotherapy was different between Stage I and the other stages in this study, we
analyzed the data depending on the stage. However, it did not largely affect the QOL at 2 – 5 months. We selected nedaplatin, 80 mg/m2 on Days 1, 29, 57 and 85 and 5-FU, 800 mg/m2 /day (Days 1 – 4, 29 – 32, 57 – 60 and 85 – 88), with concurrent administration of radiotherapy. This is not the standard regimen for esophageal cancer. However, we have given nedaplatin in place of cisplatin since 2000 because in a clinical study, combination chemotherapy using nedaplatin and 5-FU has been reported to be a safe and effective method for treating advanced esophageal cancer (5 – 7). Nedaplatin may be considered to be helpful in reducing toxicity from a previous study. Nedaplatin instead of cisplatin contributes to decrease toxicities, especially renal and heart toxicities, because there is no need for a lot of hydration fluid. We selected the same radiation fields for all stages like INT 0123 study (8) and Cancer Research UK (9), in which the radiation field was not different depending on the stage. Brooks et al. (10) and Safieddine et al. (11) also used the FACT-E to determine the effect of surgical intervention on the health-related QOL in patients with esophageal cancer. On analyzing the FACT-E subscales, it is an interesting observation that the physical and FWB scales decrease after CRT, whereas the emotional and social well-being scales remain stable. This reflects the resilience of the patient’s perception of social and emotional support, despite physical and functional debility. In a randomized study of CRT vs. CRT plus surgical intervention, QOL scores were significantly worse at the first follow-up visit (3 months) in the surgical patients, but this difference resolved by the second visit at 6 months, and over time, QOL scores remained similar in both arms (12). This supports our finding that the adverse effect of CRT on the
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Figure 4. Longitudinal changes in fatigue, nausea/vomiting, pain, dyspnea, reflux, choking and dysphagia (high score ¼ less symptoms).
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QOL changes after CCRT for esophageal cancer
CONCLUSION Our longitudinal assessments of QOL in esophageal cancer patients showed that no significant adverse long-term effect on patients’ overall QOL resulted from definitive CRT. The acute worsening of QOL during the treatment phase had significantly improved with longer term follow-up.
Conflict of interest statement None declared.
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QOL score is transient, and this strategy should be pursued in an effort to improve survival. Several groups have suggested that the baseline QOL scores are predictive of survival. Blazeby et al. (13) reported that the baseline QOL scores were not associated with postoperative morbidity, but were significantly associated with survival at 6 months postoperatively after adjusting for known risk factors. A similar finding has been reported for patients treated with primary radiotherapy, and in particular, the physical functioning role at baseline was predictive of survival (12,14). We did not find any association between the pre-treatment baseline QOL score and disease-free survival after CRT (62% with recurrence vs. 72% without disease in E-TOI score). There are three randomized clinical trials (8,15,16) comparing CRT with surgery or CRT (two have QOL (3,17)). The FFCD 9102 trial (17) reported that the mean QOL score decreased between baseline and the first follow-up and between the first and the second follow-ups. According to the INT 0123 trial (3), the total mean QOL was significantly lower in the high-dose arm of 64.8 Gy (P ¼ 0.02) and remained lower at 8 and 12 months after the start of CRT, but these values did not reach statistical significance and change in the mean QOL from baseline to each of the three subsequent assessment time points did not differ significantly between the two treatment arms (50.4 vs. 64.8 Gy). In this study, the average QOL scores before CRT of four patients with severe complication were not inferior to the other patients. The pre-treatment QOL score was not a predictive factor of late severe toxicities. Two patients recovered from severe side effects and recovered also in the QOL score after the recovery from toxicity. Late severe toxicities had not much influence on long-term QOL in this study. Our study had some limitations. The first is that the small number of patients resulted from a convenient sample recruited during a 24-month period and limited our ability to perform multiple adjustments for potential confounders and the power of our analysis to detect small differences. Second, the non-randomized nature of the assignment of CRT could have introduced some selection bias. Third, this is not a prospective study in the strict sense to compare the previous historical data in the change of QOL score after CRT. Consequently, there were no statistical considerations including endpoints or sample size estimation. We had only obtained questionnaires at fixed intervals prospectively for consecutive patients with esophageal cancer who undergo a certain protocol of definitive CRT in our department.
