Health-related Quality of Life in Patients with ...

Jpn J Clin Oncol 2010;40(5)412 – 419 doi:10.1093/jjco/hyp185 Advance Access Publication 18 January 2010

Health-related Quality of Life in Patients with Colorectal Cancer Who Receive Oral Uracil and Tegafur plus Leucovorin Akira Tsunoda1,2,*, Kentaro Nakao2, Makoto Watanabe2, Nobuaki Matsui2 and Yuko Tsunoda1 1

Department of Surgery, Kameda Medical Center, Chiba and 2Department of Gastroenterological and General Surgery, Showa University School of Medicine, Tokyo, Japan *For reprints and all correspondence: Akira Tsunoda, Department of Surgery, Kameda Medical Center, 929 Higashi-cho, Kamogawa City, Chiba, 296-8602, Japan. E-mail: [email protected] Received October 6, 2009; accepted November 25, 2009

Key words: health-related quality of life – adjuvant chemotherapy – colorectal cancer – UFT – leucovorin

INTRODUCTION 5-Fluorouracil (5-FU) has been widely used since the 1960s as the first-line chemotherapy for colorectal cancer in both adjuvant and palliative settings and remains the backbone of many combination chemotherapy regimens (1 – 3). Uracil/ tegafur (UFT) combines 1-(tetrahydrofuryl)-5-fluorouracil (tegafur [FT]) and uracil in a molar ratio of 1:4. The co-administration of uracil enhances both the concentration of 5-FU in tumors and the resulting antitumor activity of FT (4). The results of the National Surgical Adjuvant Breast and Bowel (NSABP) Trial C-06 demonstrated that oral UFT plus

leucovorin (LV) achieved similar disease-free survival and overall survival as did intravenous 5-FU plus LV (Roswell Park regimen) (5). These two regimens did not differ with regard to their impact on health-related quality of life (HRQOL) (6). However, HRQOL during the treatment phase was evaluated only once, which may not lead to accurate results. We have recently assessed whether polymorphisms in nine genes related to 5-FU metabolism could be used to predict toxicity in patients treated with oral UFT plus LV (7). This report focuses on the HRQOL results of that study. The primary assessments were designed to estimate the nature and magnitude of changes in HRQOL during the

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Objective: Adjuvant chemotherapy with oral uracil/tegafur plus leucovorin has been acknowledged to be a standard treatment for Stage II or III cancer of the colon. The objective of the study was to examine the health-related quality of life during treatment in patients with colorectal cancer who receive oral uracil/tegafur plus leucovorin. Methods: Health-related quality of life was assessed at baseline ( pre-treatment) and at 5-week intervals during treatment, using the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaires. Health-related quality of life data for five courses of treatment were then analyzed longitudinally. Results: Ninety-four patients completed the baseline and post-treatment health-related quality of life assessments. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all the scales except cognitive function, dyspnea, insomnia, constipation and diarrhea. Role function and social function changed by 10 or more points considered clinically significant. Most of the scales in patients with Grade 0 – 1 toxicities were better than those with Grade 2 –3 toxicities, but Grade 2– 3 toxicities were not associated with post-treatment deteriorations in health-related quality of life. The development of Grade 3 toxicities negatively affected on the four scales at the next assessment, compared with Grade 1 – 2 toxicities. Conclusions: Overall health-related quality of life did not deteriorate during adjuvant chemotherapy with oral uracil/tegafur plus leucovorin in patients with colorectal cancer, despite the effect from surgical damage, whereas the development of Grade 3 toxicities negatively affected on short-term health-related quality of life. Further comparative studies are needed.

Jpn J Clin Oncol 2010;40(5)

course of treatment and to examine the relationship between such changes and toxicity.

PATIENTS AND METHODS PATIENTS

TREATMENT AND TOXICITY ASSESSMENT Chemotherapy was started between 21 and 42 days after surgery in all eligible patients. UFT (Taiho Pharmaceutical Co., Ltd, Tokyo, Japan) was administered at an oral dose of 300 mg/m 2/day, and LV (Taiho Pharmaceutical Co., Ltd) was administered at an oral dose of 75 mg/day on days 1 – 28, followed by a 7-day rest. This cycle was repeated every 35 days for up to five cycles. Both UFT and LV were divided into three equivalent doses and administered together 8 h apart, along with water. Patients were instructed to avoid eating between 1 h before and 1 h after each dose. To prevent gastrointestinal mucositis, patients received lafutidine, an H2-receptor blocker, at standard doses when UFT was given. Toxicity was evaluated and recorded according to the National Cancer Institute Common Toxicity Criteria, version 2.0. Physical examination, a full blood count and serum chemical analyses were done before every treatment cycle. If the absolute neutrophil count was ,1000/mm3 or the platelet count was under ,7.5 10 4/mm3 , treatment was delayed until the recovery of bone marrow function. Treatment was discontinued in the event of unacceptable toxicity, a delay of .42 days in starting the next cycle of treatment or at the patient’s request. Protocol-specified dose reductions and delays were based on toxicity in the previous cycle, evaluated on the basis of both hematological nadirs and hematological/biochemical values on the day after treatment. In this study, the dose of UFT was reduced by 100 mg/day if Grade 3 toxicity occurred in the previous treatment cycle, but the dose of LV remained at 75 mg/day.

ASSESSMENT OF HRQOL HRQOL was assessed using QLQ-C30 questionnaires designed by the European Organization for the Research and Treatment of Cancer (EORTC) (8). The reliability and validity of the Japanese versions of QLQ-C30 (9) has been confirmed. QLQ-C30 consists of 30 questions grouped in five functional scales ( physical, role, emotional, cognitive and social functioning), a global QOL measure and symptom assessment, including fatigue, pain, diarrhea and constipation. Each patient’s scores are evaluated on a scale of 0 – 100, where 0 denotes the worst score and 100 the best score on functioning scales, and 0 denotes the best score and 100 the worst score on symptom scales. If any responses were missing, multi-item scores were derived by calculating the means for non-missing items if at least half of the items of the corresponding scale had been completed (EORTC scoring manual) (10). Participants completed QLQ-C30 for seven times; at baseline ( pre-treatment) and 1 week before the second to fifth cycle of treatment and 4 weeks after the completion of the treatment. STATISTICAL ANALYSES Longitudinal analyses were conducted using mixed-effect models to estimate the changes in the scores over time. In these models, time was defined as the time of HRQOL assessment and was regarded as a continuous variable. Time and intercepts were treated as random effects. A binary predictor variable, ‘post-treatment,’ was created so that 0 represents baseline and 1 represents all post-treatment observations. The model included time, toxicity (Grades 0 – 1 vs. 2 – 3), baseline and ‘post-treatment’ as predictors, and an individual’s series of baseline and post-treatment scores as outcomes (dependent variables). Finally, the interaction term ‘toxicity over time’ was entered into the model to determine whether the grade of toxicities correlated with the changes in HRQOL over time. P values were calculated using two-tailed tests. Longitudinal mixed-effect models, which utilize likelihood-based methods, utilize all available data, account for an individual’s correlated toxicity over time, and result in unbiased estimates when missing data are ignored (11). ANOVA with Bonferroni’s post hoc test for multiple comparisons was used to compare the mean HRQOL score differences between the measurements. P values of ,0.05 were considered to indicate statistical significance. Statistical analysis was performed using JMP 8 (SAS Institute Inc., Cary, NC, USA).

RESULTS PATIENT CHARACTERISTICS The study group comprised 58 men and 41 women, with a mean age of 65 years (range, 30 – 80). Performance status


From June 2005 through October 2008, a total of 103 consecutive patients were prospectively enrolled. Four patients refused to participate in the study after providing consent. The other 99 patients underwent curative resection and received oral UFT plus LV as adjuvant chemotherapy in the Department of Gastroenterological and General Surgery, Showa University School of Medicine. Data from these latter patients were included in analysis. Eligible patients had to have histologically proved adenocarcinoma of the colon or rectum, with Stage II or III tumors, an Eastern Cooperative Oncology Group performance status of 1 and adequate bone marrow, renal and hepatic functions. Patients who had received any prior or concurrent radiation therapy or chemotherapy were excluded. Written informed consent, including permission to use blood and tissue samples for research purposes, was obtained from all patients. The study was approved by the hospital’s ethical committee and was conducted in accordance with the Declaration of Helsinki.

413

414

HRQOL in patients with colorectal cancer

Table 2. Toxicity 1

4

Grade 3 (%)

Leucopenia Anemia

5

2

0

0

0 (0)

11

5

1

0

0 (0)

1

0

0

0

0 (0)

Thrombocytopenia Non-hematological toxicities Stomatitis

8

14

1

0

1 (1)

Appetite loss

12

4

6

0

6 (6)

Nausea

16

4

3

0

3 (3)

Vomiting

2

2

0

0

0 (0)

Diarrhea

18

9

6

0

6 (6)

6

7

1

0

1 (1)

Pigmentation

12

1

Fatigue

42

8

3

0

3 (3)

Taste

11

0

Rash

Sense of smell

9

0

Muscle pain

1

0

1

Hyperbilirubinemia

22

12

1

0

1 (0)

AST

20

4

0

0

0 (0)

ALT

17

8

3

0

3 (3)

1

1

0

0

0 (0)

1 (1)

AST, aspartate aminotransferase; ALT, alanine aminotransferase.

Table 1. Patient characteristics Number

99

Age (years) (mean + SD)

65 + 10 (30–80)

Sex Male

58

Female

41

Location Colon

59

Rectum

40

Stage II

49

III

50

Performance status 0

72

1

27

Differentiation Well

33

Mod

64 2

Stoma Yes

7

No

92

SD, standard deviation.

3

Hematological toxicities

Creatinine

Others

2

MIXED-EFFECT MODELS HRQOL was not evaluated either before or after treatment in 5 of the 99 enrolled patients; both baseline and posttreatment evaluations were available for the other 94 patients. Of 94 patients, the numbers of patients who completed the HRQOL questionnaires were 90 (96%) at baseline, and 87 (93%), 85 (90%), 88 (94%), 84 (89%) and 81 (86%), consecutively. The mean number of evaluations per patient was 6.2 (range, 3 – 7). Table 3 shows the mean modeled baseline values, post-treatment values and differences between the post-treatment and baseline values for each of the QLQ-C30 transformed scores. The post-treatment assessments changed significantly from the baseline values and favored post-treatment for all the scales except cognitive function, dyspnea, insomnia, constipation and diarrhea. Role function and social function changed by 10 or more points considered clinically significant. Table 4 shows the number of the patients in the treatment cycle when those developed the worst grade toxicities. Seventy-three percent of the patients with Grade 1 toxicities and 61% of the patients with Grade 2 – 3 toxicities showed the worst grade toxicity until the second treatment cycle. The HRQOL characteristics of the 42 patients with Grade 0 – 1 toxicities and the 52 patients with Grade 2 – 3 toxicities are shown in Table 5. Scores for all scales changed significantly and were better in patients


was 0 in 72 patients and 1 in 27. The primary tumor was located in the colon in 59 patients and in the rectum in 40. The depths of invasion according to the tumor – node – metastasis classification were T1 or T2 for 7 tumors, T3 for 84 tumors and T4 for 8 tumors. The disease stage was Stage II in 51 patients and Stage III in 48. Seven patients had a stoma (Table 1). The 99 patients had received a total of 444 treatment cycles (median, 5 cycles; range, 0.1 – 5 cycles). Toxicity is summarized according to the worst grade per patient during all treatment cycles in Table 2. There were no treatment-related deaths. The most common type of toxicity was fatigue. However, the incidence of Grade 3 or 4 fatigue was very low. The most common type of hematological toxicity was anemia, which was generally mild. Six patients had Grade 3 diarrhea and six had Grade 3 anorexia. Treatment was discontinued in 18 of the 99 patients, because of toxicity in 14, developing pneumonia in 1, tumor recurrence in 1 and patient’s claim in 2. The main type of toxicity in the 14 patients was Grade 3 diarrhea with Grade 2 – 3 anorexia in 5, Grade 2 – 3 anorexia in 2, Grade 2 – 3 liver injury in 2, Grade 3 jaundice in 2, Grade 2 rash in 1, Grade 2 diarrhea in 1 and Grade 3 muscle pain in 1. Nine of these 14 patients received UFT alone after the toxicities had resolved. The other five patients refused further chemotherapy.


Table 3. Mean baseline scores, post-treatment scores and score differences (mixed model with transformed scores) on the QLQ-C30 Scale

Baseline (SE)

Post-treatment (SE)

QL

61.7 (2.3)

71.4 (0.9)

Post-treatment minus baseline (SE)

P value ,0.0001

9.6 (2.2)

Functional scales PF

80.7 (1.6)

87.3 (0.7)

6.7 (1.8)

,0.0001

RF

72.8 (2.7)

82.8 (1.0)

10.0 (2.6)

,0.0001

EF

81.6 (1.8)

87.8 (0.8)

6.2 (1.9)

0.0003

CF

81.5 (2.3)

83.2 (0.9)

1.8 (2.3)

0.37

SF

76.8 (2.8)

87.3 (0.9)

10.3 (2.4)

,0.0001

22.9 (0.9)

29.5 (2.1)

,0.0001

Symptom scales FA

32.6 (2.0) 2.3 (0.7)

2.1 (0.4)

20.2 (0.9)

0.027

20.3 (2.3)

10.7 (0.9)

29.4 (2.2)

,0.0001

DY

13.8 (2.1)

12.2 (0.9)

21.5 (2.1)

0.174

SL

17.8 (2.5)

12.8 (1.0)

24.8 (2.4)

0.056

AP

15.4 (2.2)

8.7 (0.9)

26.6 (2.1)

,0.0001

CO

11.1 (2.1)

16.1 (1.3)

5.0 (3.0)

0.128

DI

11.8 (2.3)

13.0 (0.9)

1.3 (2.4)

0.654

FI

25.6 (3.1)

17.9 (1.1)

27.7 (2.8)

,0.0001

For the functional and global quality of life scales, higher scores indicate better functioning; for the symptom scales, higher scores indicate severer symptoms. SE, standard error; QL, global quality of life; PF, physical function; RF, role function; EF, emotional function; CF, cognitive function; SF, social function; FA, fatigue; NV, nausea and vomiting; PA, pain; DY, dyspnea; SL, insomnia; AP, appetite loss; CO, constipation; DI, diarrhea; FI, financial difficulties.

Table 4. Number of the patients in the treatment cycle when those developed the worst grade toxicities Treatment cycle

Worst grade toxicity Grade 1

Grades 2– 3

1

18

22

2

6

14

3

2

9

4

4

12

5

3

2

33

59

Total

with Grade 0 – 1 toxicities, except for the pain and diarrhea scales. However, there were no significant post-treatment deteriorations for any scale in patients with Grade 2 – 3 toxicities. This also applied to the 13 patients with Grade 3 toxicities (data not shown). Figure 1 shows the time courses of the changes in the mean scores for all of the scales according to the grade of toxicity (Grade 0 – 1 vs. 2 – 3). Table 6 shows the mean score differences in the

QLQ-C30 according to the type of toxicity immediately before and after the worst grade toxicity occurred. There were significant differences in the scores on the physical function, emotional function, nausea and vomiting, and pain scale, among Grade 1, 2 and 3 toxicities, respectively. The mean changes of the scores in the patients with Grade 3 toxicities were significantly greater than those with Grade 1 or 2 toxicities in these four scales.

DISCUSSION To our knowledge, this is the first study to precisely examine changes in HRQOL during adjuvant treatment with oral UFT plus LV in patients with colorectal cancer. The posttreatment scores did not significantly deteriorate for any scale and improved for about two-thirds of the scales. HRQOL results are important because they influence patients’ and clinicians’ treatment choices. Patients and clinicians consider HRQOL results an important component of informed decision-making in oncology settings (12,13). NSABP C-06 was a randomized trial comparing FU plus LV with oral UFT plus LV in patients with Stage II and III carcinoma of the colon (5). The impact of these two regimens on HRQOL, measured three times (at baseline, 15 or 16 weeks, and 1 year), was found not to differ (6). In the present study, HRQOL was assessed every treatment cycle up to five times, permitting a more accurate analysis of timecourse changes. Previous investigations have suggested that changes in HRQOL scales of 10 or more points are perceived to be moderate by patients (14,15), suggesting that most of the functional and symptomatic changes in our study were not clinically meaningful to the study group as a whole. Two exceptions were the role function and social function scales, which both improved by 10 or more points after treatment. Our results agree with those of previous studies showing that chemotherapy with UFT plus LV is generally well tolerated and provides a safer, more convenient alternative to standard bolus intravenous regimens of FU plus LV in patients with metastatic colorectal cancer (16,17). The incidence and severity of toxicity in the previous Japanese studies (18) were similar to those in our study, whereas differences in toxicity profiles have been noted between Japanese patients and patients in the USA. In particular, the incidence of diarrhea is higher in the latter (18). Patients’ scores for most of the scales on QLQ-C30 improved with time in this study. This improvement in scores may be attributed to the fact that HRQOL at baseline was probably suboptimal because the patients were in the convalescent phase after surgery. We previously reported that the scores of five QOL scales ( physical function, role function, fatigue, pain and dyspnea) dropped significantly below the pre-operative values 1 month after surgery and returned to the pre-operative values within 3 months after surgery (19).


NV PA

415

416


Table 5. Mean baseline scores, post-treatment scores and score differences (mixed model with transformed scores) on the QLQ-C30 for patients with Grade 0–1 toxicities and those with Grade 2– 4 toxicities Scale

QL

Grade 0– 1 toxicities Baseline (SE)

Post-treatment (SE)

68.8 (3.5)

79.5 (1.1)

Grade 2– 3 toxicities Post-treatment minus baseline (SE)

P value

Baseline (SE)

Post-treatment (SE)

Post-treatment minus baseline (SE)

10.8 (3.0)

55.7 (2.7)

64.4 (1.3)

8.9 (3.3)

,0.0001


82.1 (2.5)

91.3 (0.8)

9.3 (2.1)

79.6 (2.1)

83.8 (1.2)

4.6 (2.7)

,0.0001

RF

74.8 (4.2)

86.5 (1.2)

11.6 (3.4)

71.1 (3.6)

79.5 (1.6)

8.7 (3.9)

0.0008

EF

84.7 (2.7)

92.5 (0.8)

7.9 (2.2)

79.0 (2.3)

83.7 (1.2)

4.9 (2.9)

,0.0001

CF

84.1 (3.3)

88.3 (1.1)

4.3 (2.8)

79.4 (3.1)

78.8 (1.4)

20.1 (3.5)

,0.0001

SF

80.5 (3.7)

91.2 (1.0)

10.8 (2.9)

73.9 (4.0)

83.8 (1.4)

10.1 (3.7)

,0.0001

213.8 (2.9)

35.0 (2.6)

29.0 (1.2)

26.0 (3.0)

3.6 (1.2)

3.3 (0.6)

Symptom scales 29.6 (3.1)

15.8 (1.1)

0.8 (0.6)

0.7 (0.2)

20.07 (0.6)

0.0004 (0.2)

PA

19.4 (3.8)

6.9 (1.0)

212.5 (2.8)

20.9 (2.9)

14.1 (1.4)

26.8 (3.4)

DY

10.3 (3.3)

6.6 (0.9)

23.7 (2.6)

16.7 (2.7)

17.1 (1.3)

0.4 (3.3)

,0.0001 ,0.0001

,0.0001

SL

13.8 (3.7)

7.7 (1.1)

26.2 (3.1)

20.9 (3.4)

17.2 (1.4)

24.3 (3.7)

,0.0001

AP

11.9 (2.7)

3.1 (0.6)

28.8 (1.9)

18.3 (3.3)

13.6 (1.4)

24.7 (3.5)

,0.0001

CO

6.3 (2.3)

11.6 (1.2)

5.1 (2.9)

15.0 (3.1)

19.9 (2.1)

5.8 (5.2)

0.0002

DI

9.5 (3.6)

11.9 (1.2)

2.4 (3.2)

13.7 (2.8)

14.0 (1.4)

0.4 (3.4)

0.146

FI

24.6 (5.0)

13.1 (1.4)

211.5 (3.9)

26.5 (3.9)

22.0 (1.6)

25.6 (4.4)

0.0001

For the functional and global quality of life scales, higher scores indicate better functioning; for the symptom scales, higher scores indicate severer symptoms.

When the HRQOL scores were compared according to the type of toxicity, the scores changed significantly for most of scales and were better in patients with Grade 0 – 1 toxicities. However, even Grade 2 – 3 toxicities were not associated with post-treatment deteriorations of HRQOL. UFT plus LV was associated with increased scores for some symptoms, whereas overall HRQOL did not deteriorate. This also applied to the patients with Grade 3 toxicities. However, when the HRQOL score differences immediately before and after the worst grade toxicity occurred were compared according to the type of toxicity, grade 3 toxicities negatively affected on the four scales at the next assessment, compared with Grade 1 or 2 toxicities. Especially, the emotional function and the nausea and vomiting scales, both deteriorated by 10 or more points, considered clinically significant. A previous prospective study investigated the impact of adjuvant chemotherapy on HRQOL in patients with colorectal cancer when compared with patients who received surgery alone (20). Zaniboni et al. (20) reported the GIVIO-SITTAC-01 (Gruppo Italiano Volutazione Interventi in Oncologia-Studio Italino Terapia Adiuvante Colon) study in which patients with Dukes’ B2 or C colon cancers were randomly assigned to receive six cycles of 5-FU plus folic acid or to be observed. Adjuvant therapy had no apparent effect on HRQOL. However, HRQOL was assessed 0, 6 and

24 months after randomization and was not evaluated during the treatment phase. Changes in HRQOL during chemotherapy may therefore have been overlooked. Several studies have previously investigated the impact of adjuvant chemotherapy on HRQOL in patients with colorectal cancer. However, the use of various regimens for adjuvant chemotherapy (21) or a cross-sectional study design (22) may have led to difficulty in interpreting the results. In this study, no patient received pre-operative chemoradiotherapy for rectal cancer. Pre-operative adjuvant radiochemotherapy is the standard of care for patients with locally advanced rectal cancer in Western countries. In Japan, however, autonomic nerve-preserving pelvic sidewall dissection without adjuvant chemoradiotherapy is one standard procedure for patients with T3 – T4 lower rectal cancer, because of the greater risk of positive lateral lymph nodes (23). A recent meta-analysis demonstrated that adjuvant chemotherapy with oral UFT significantly improves survival in patients with curatively resected rectal cancer (24). This study had several limitations. Most importantly, it was a single-arm, open-label study performed in a small number of patients. Because of subject attrition, we performed statistical analyses that could account for missing data and incorporate all available data. We conclude that overall HRQOL did not deteriorate during adjuvant chemotherapy with oral UFT plus LV in


FA NV


417

Downloaded from http://jjco.oxfordjournals.org/ by guest on December 30, 2015 Figure 1. Longitudinal assessment of each scale according to the type of toxicity. For the functional and global quality of life scales, higher scores indicate better functioning; for the symptom scales, higher scores indicate severer symptoms. Bars are standard error; grade, toxicity grade.

418


patients with colorectal cancer, despite the effect from surgical damage, whereas the development of Grade 3 toxicities negatively affected on short-term HRQOL. Further comparative studies are needed to better understand how adjuvant therapy influences HRQOL in patients with colorectal cancer.

Conflict of interest statement None declared.

References

Scale

QL

Grade 1 toxicities (n ¼ 29) 1.4 (2.6)

Grade 2 toxicities (n ¼ 34) 0.7 (3.3)

Grade 3 toxicities (n ¼ 11)

P valuea

212.1 (8.1)

0.103


4.8 (1.7)*

RF

2.3 (2.4)

29.7 (8.7)

0.013

22.0 (3.1)

210.6 (9.9)

0.166

2.8 (1.5)*

EF

0.4 (2.6)

4.2 (2.2)

210.6 (8.2)

0.034

CF

0.6 (1.8)

1.5 (3.1)

24.5 (7.5)

0.573

SF

6.3 (2.7)

22.6 (3.7)

1.5 (12.2)

0.320

Symptom scales FA NV

22.3 (2.7) 1.1 (1.4)**

24.9 (2.2)

3.0 (8.5)

0.381

0.0 (1.0)**

15.2 (9.1)

0.004

PA

25.2 (2.2)*

25.4 (2.7)**

22.3 (2.4)

0.007

DY

2.3 (1.6)

22.0 (3.2)

23.0 (10.5)

0.597

SL

21.1 (3.1)

0.0 (2.5)

9.1 (6.5)

0.204

AP

21.1 (2.0)

0.0 (3.2)

15.2 (13.8)

0.107

CO

0.0 (2.3)

21.0 (3.1)

DI

2.3 (3.3)

23.0 (3.9)

FI

23.4 (2.5)

27.8 (3.5)

10.0 (7.1) 9.1 (10.1) 26.1 (4.1)

0.178 0.292 0.594

Parentheses, standard error; figures, QOL scores immediately after the worst grade toxicity occurred minus those after the last measurement. For the functional and global quality of life scales, higher scores indicate better functioning; for the symptom scales, higher scores indicate severer symptoms. a ANOVA with Bonferroni’s post hoc test for multiple comparisons. *P , 0.05 vs. Grade 3 toxicities. **P , 0.01 vs. Grade 3 toxicities.


Table 6. Mean score differences on the QLQ-C30 immediately before and after the worst grade toxicity occurred, according to the type of toxicity

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