Evaluation of Quality of Life in Patients with Metastatic Colorectal Cancer Treated with Capecitabine

Original

Contribution

Evaluation of Quality of Life in Patients with Metastatic Colorectal Cancer Treated with Capecitabine José G.M. Segalla,1 Brigitte Van Eyll,2 Mirian Hatsue Honda Federico,3 Nills G. Skare,4 Fábio A. Franke,5 Martha R. Perdicaris,6 Urias de Paula Filho,7 Otávio Gampel,8 Sebastião Cabral,9 Ronaldo de Albuquerque Ribeiro10 Abstract Purpose:This study evaluated the effects of oral capecitabine on the quality of life (QOL) of Brazilian patients with metastatic colorectal cancer who received capecitabine (1000 or 1250 mg/m2 twice a day on days 1-14, every 3 weeks) in a prospective, multicenter, open-label, noncomparative study. Patients and Methods: Patients completed the European Organization for Research and Treatment of Cancer QLQ-C30 and QLQ-CR38 questionnaires before cycle 1, at weeks 7 and 13, and at the end of treatment. In total, 1437 patients (mean age, 59.6 years [± 13.5 years]) were enrolled. Results: In women, statistically significant improvements were observed in 6 QLQ-C30 and 6 QLQ-CR38 domains (QLQ-C30: emotional function, nausea/ vomiting, pain, constipation, financial problems, and body image; QLQ-CR38: future perspective, micturition problems, defecation problems, stoma-related problems, weight loss and global health status). In men, statistically significant improvements were observed in 8 QLQ-C30 and 5 QLQ-CR38 domains (QLQ-C30: emotional function, social function, pain, insomnia, appetite loss, constipation, financial problems, and future perspective; QLQ-CR38: micturition problems, defecation problems, stomarelated problems, weight loss, and global health status). Statistically significant worsening of sexual function/enjoyment occurred in both sexes. Conclusion: Overall, 59%-86% of patients maintained or improved QOL during capecitabine therapy. Clinical Colorectal Cancer, Vol. 7, No. 2, 126-133, 2008 Key words: 5-Fluorouracil, Least square mean value, Leucovorin, Uracil-tegafur

Introduction The drug 5-fluorouracil (5-FU) has been the main agent for the treatment of metastatic colorectal cancer (mCRC) for over 1Hospital Amaral 2Instituto

Carvalho, Jaú, São Paulo, Brazil do Câncer Arnaldo Vieira de Carvalho (ICAVC), São Paulo,

Brazil 3Hospital das Clínicas de São Paulo, São Paulo, Brazil 4Hospital Erasto Gaertner, Curitiba, Paraná, Brazil 5Associação Hospital de Caridade de Ijuí, Ijuí, Rio Grande du Sul, Brazil 6Hospital Beneficência Portuguesa de Santos, Santo, São Paulo, Brazil 7Hospital São Joaquim - Real e Benemérita Sociedade Portuguesa de Beneficiência de São Paulo, SP, Brazil 8Instituto de Assistência Médica ao Servidor Público Estadual, São Paulo, Brazil 9Centro de Quimioterapia e Imunoterapia Ltda., Belo Horizonte, Minas Gerais, Brazil 10Instituto do Câncer do Ceará, Fortaleza, Ceará, Brazil Submitted: Aug 20, 2007; Revised: Jan 3, 2008; Accepted: Jan 17, 2008 Address for correspondence: José G.M Segalla, MD, Rua das Palmeiras, 122 Jaú, São Paulo, Brazil, CEP: 17210-120 Fax: 55-14-3624-9422; e-mail: [email protected]

40 years. Conventional bolus schedules of 5-FU are associated with gastrointestinal toxicity (eg, diarrhea, stomatitis) and myelosuppression.1 Although infused 5-FU–based regimens offer some efficacy benefits and a better tolerability profile to bolus regimens,2,3 they carry the added cost of the unwanted complications, discomforts, and inconveniences associated with central venous access.4 Capecitabine is an oral fluoropyrimidine that is replacing 5-FU as single-agent therapy for mCRC because of its good efficacy, favorable tolerability profile, and convenience in this patient group.1,5 Pooled results from 2 pivotal randomized phase III clinical trials in which capecitabine (1250 mg/m2 twice daily on days 1-14 every 3 weeks) was compared with 5-FU/leucovorin (LV; Mayo Clinic regimen) in > 1200 patients showed that capecitabine achieved a higher overall response rate (26% vs. 17%, P < .0002), while the median time to disease progression (4.5 months) and overall survival (13 months; OS) were similar in both groups.5 In addition, efficacy data from the X-ACT adjuvant trial in stage III colon cancer shows that capecitabine single-agent therapy results in at least equivalent disease-free survival, superior

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126 • Clinical Colorectal Cancer

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Patients and Methods Patient Selection This prospective, multicenter, open-label, noncomparative trial was conducted to evaluate the effects of oral capecitabine on the QOL of patients with mCRC. Patients receiving capecitabine alone as first- or second-line therapy for mCRC were eligible for the trial. Patients receiving capecitabine in combination with other chemotherapeutic agents were not included. All patients gave written informed consent to participate in the trial. Local ethical committees were informed of the study (observational study).

Treatment Schedule Patients received oral capecitabine 1000 mg/m2 or 1250 mg/m2 twice daily on days 1-14 every 3 weeks. Treatment was interrupted in the event of toxicities classified as grade 2 or higher. Dose modifications were applied after resolution to grade 1 or 0 as outlined previously by Cassidy et al.1 Treatment interruption or dose reduction was not indicated for adverse reactions unlikely to become serious or life threatening, for example alopecia.

Evaluation of Quality of Life Quality of life was assessed using the EORTC questionnaires QLQ-C30 (version 3.0) together with the CRC-specific module QLQ-CR38.10,11 The QLQ-C30 questionnaire comprises 5 functional scales (physical, role, emotional, cognitive, and social), 9 symptom scales (fatigue, nausea/vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, and financial difficulties) and a global health scale. The QLQ-CR38 questionnaire consists of 4 functional scales (body image, sexual function, sexual enjoyment, and future

Figure 1

Global Health Status Scores for Female and Male Patients

100 Women (P = .0032) Men (P < .0001) 80

Least Square Mean

relapse-free survival (RFS), and a strong trend toward superior OS compared with bolus 5-FU/LV.6 This has led to the recent approval of capecitabine for adjuvant therapy of stage III colon and rectal cancer. The efficacy benefits offered by capecitabine in terms of secondary endpoints (RFS, OS, multivariate and subgroup analyses) are supported by improved safety and pharmacoeconomic benefits versus 5-FU/LV in the adjuvant setting as well.7-9 Although outcomes such as objective response, time to disease progression, and OS are well-established measures of clinical efficacy, other measures, such as tolerability and quality of life (QOL), are likely to be just as important to patients with more advanced disease. The objective of the present study was to evaluate the QOL of a large population of Brazilian patients with mCRC undergoing treatment with oral capecitabine. Quality of life was assessed using the European Organization for Research and Treatment of Cancer (EORTC) questionnaire QLQ-C30 together with the CRC-specific module QLQ-CR38.10,11 The CRC module is intended for use among a wide range of patients with CRC at different stages and receiving different treatment modalities. We selected these questionnaires because they are validated, specific for patients with CRC, and widely used in patients with mCRC.10,11

60

40

20

0

0

7

13

End of Treatment

Week

perspective) and 7 symptom scales (micturition problems, chemotherapy side effects, gastrointestinal symptoms, male/ female sexual problems, defecation problems, stoma-related problems, and weight loss). Each domain is measured on a scale ranging from 0-100. A high score on the global health or functional scales represents a high or healthy level of function, whereas a high score on the symptom scales indicates a high level of problems/symptoms. Questionnaires were administered by a nurse, nurse assistant, social assistant, psychologist, or a volunteer member of the group during the patient’s visit to the clinic. It was recommended that questionnaires be administered before the patients’ consultation with a doctor. Patients completed the questionnaires on 4 occasions: before cycle 1 (baseline), at week 7, at week 13, and the at end of treatment. Demographic and clinical data were also collected before cycle 1.

Statistical Analysis and Data Interpretation Least square mean values (and standard errors) were calculated for each QOL domain and for each assessment period. The analysis included all patients who completed the questionnaire at each timepoint, excluding those who dropped out over time. Linear models for repeated measures were used to analyze the QOL data over time. When a statistical significance of time effect was detected, multiple comparisons were developed to verify which periods differed significantly. To guarantee a global significance level (P value), the Tukey-Kramer adjusting method was used. Although the questionnaires were the same for all patients, we analyzed data for each sex separately because men and women have different viewpoints. The clinical significance of the QOL data was interpreted according to the findings of Osoba et al.12 For all domains, changes in least square mean scores between baseline and end of treatment were taken to indicate the following: a change of 5-10 points indicated that the patient experienced a small Clinical Colorectal Cancer March 2008 • 127

Evaluation of Quality of Life with Capecitabine Table 1

Baseline Patient Characteristics (n = 1437) Characteristic

Mean Age ± SD, Years

(Range)*

No. of Patients

Percent

59.6 ± 13.5 (20-93 Years)

Sex

Female Patients

Male

728

51

Female

701

49

8

<1

White

1155

80

Black

122

9

Asian

29

2

Other

88

6

Data missing

43

3

0

635

44

1

546

38

2

157

11

3

31

2

4

2

<1

Data missing

66

5

Data missing

The mean dose of capecitabine used during the study was 1000 mg/m2 twice daily. During the study period patients received an average of 6.6 cycles (range, 1-12 cycles) of capecitabine and the capecitabine dose was reduced in 12% of patients.

Ethnicity

ECOG Performance Status

Percentages subject to rounding error. *Information missing for 8 patients. Abbreviations: ECOG = Eastern Cooperative Oncology Group; SD = standard deviation

improvement/worsening in their QOL; a change of 10-20 points indicated a moderate improvement/worsening; a change of > 20 points indicated great improvement/worsening. The proportion of patients who showed improvement or maintenance of their QOL for each domain was also analyzed from week 7 onward. Improvement was defined as an increase in functional scores or a decrease in symptom scores of ≥ 10 points between baseline and ≥ 1 period scores. Worsening was defined as a decrease in functional scores or an increase in symptom scores of ≥ 10 points between baseline and ≥ 1 period scores. Quality of life was judged to be maintained if no improvement or worsening occurred. Proportions were analyzed with generalized linear models for repeated measures with binomial response, using a generalized estimating questions technique. Data were analyzed using an SAS® program (system version 9.1).

Global health status scores for both genders were similar (Figure 1). While there were only small fluctuations in scores for most domains in the least square mean values for QLQC30 and QLQ-CR38 questionnaires over the 4 assessment periods of the study, statistically significant improvements were observed in female patients’ perception of emotional function (P < .0001), nausea/vomiting (P = .0258), pain (P < .0001), constipation (P = .0068), financial problems (P = .0010, body image (P = .0050), future perspective (P < .0001), micturition problems (P = .0080), defecation problems (P = .0299), stoma-related problems (P < .0001), weight loss (P < .0001), and global health status (P = .0032; Table 2). Statistically significant worsening of females’ perception of sexual enjoyment (P = .0041; Table 3) was also reported. Using the findings of Osoba et al12 to interpret these data, there were small improvements in females’ perception of pain (5.9-point change), constipation (6-point change), financial problems (8-point change), future perspective (8.5-point change), stoma-related problems (5.2-point change), and emotional functioning (6-point change), together with a moderate improvement in weight loss (12.6-point change) between baseline and end of treatment. There was also a small worsening in females’ perception of sexual enjoyment (7.6-change). Figures 2A and 2B show the proportion of female patients who experienced improvement or maintenance of QLQ-C30 and QLQ-BR38 domains, respectively, between baseline and ≥ 1 subsequent visits. Between 13% and 49% of women reported improvement and 15%-66% reported maintenance during capecitabine therapy for the domains on the 2 questionnaires. More than 40% of women reported improvement in the perception of pain (46%), micturition problems (49%), emotional functioning (43%), fatigue (47%), and chemotherapy side effects (42%). With the exception of chemotherapy side effects (59%), > 60% of women showed improved or maintained QOL according to each of the questionnaire domains during capecitabine therapy (range, 62%-86%).

Male Patients

Results The baseline characteristics of the 1437 patients who participated in the study are presented in Table 1. There were 728 men (51%) and 701 women (49%) with a mean age of 59.6 years (± 13.5 years). Most patients (82%) had an Eastern Cooperative Oncology Group performance status of 0 or 1. Before cycle 1, 1429 patients (99%) completed the QOL questionnaire, 1231 (86%) at week 7, 888 (62%) at week 13, and 668 (46%) at treatment end. At all visits, nurses were most often responsible for administering the QOL questionnaires (59%-65% of patients).

128 • Clinical Colorectal Cancer

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Global health status scores for both genders were similar (Figure 1). While there were only small fluctuations in scores for most domains in the least square mean values for QLQC30 and QLQ-CR38 questionnaires over the 4 assessment periods of the study, statistically significant improvements were observed in male patients’ perception of emotional functioning (P = .0006), social function (P = .0072), pain (P = .0046), insomnia (P = .0120), appetite loss (P = .0091), constipation (P = .0004), financial problems (P < .0001), future perspective (P < .0001), micturition problems (P = .0004), defecation problems (P = .0344), stoma-related problems

José G.M. Segalla et al Figure 2

Figure 3

QLQ-C30 and QLQ-C38: Female Patients

A QLQ-C30

QLQ-C30 and QLQ-C38: Male Patients

A QLQ-C30

100

100 Maintained Improved

Maintained Improved

Patients (%)

80

60

40

60

40

20

0

0

B QLQ-C38

Gl ob al He Ph alth ys ica Stat l F us R unc Em ole F tion u oti on ncti on al F So un c c Co ial F tion gn un itiv ct e F ion un cti on Na us Fatig ea /Vo ue m itin g Pa i n Dy sp n Ins ea Ap omn pe i tite a Co Los ns s tip ati Fin o an Dia n cia rrh l P ea ro ble m s

20

Gl ob al He Ph alth ys ica Stat l F us Ro unct Em le F ion u oti on ncti on al F So un cia ctio Co gn l Fun n itiv ct e F ion un cti on Na us Fatig ea /Vo ue m itin g Pa Dy in sp n Ins ea Ap omn pe i tite a Co Los ns s tip ati Fin on D an cia iarrh l P ea ro ble m s

Patients (%)

80

B QLQ-C38

100

100 Maintained Improved

Maintained Improved

Patients (%)

80

60

40

60

40

20

0

0 Bo dy

Bo dy

(P = .0064), weight loss (P < .0001), and global health status (P < .0001; Table 4). Statistically significant worsening of their perception of sexual functioning (P = .0380) and sexual enjoyment (P = .0255) was also observed (Table 5). According to the interpretation of Osoba et al,12 these findings equate to small improvements in men’s perception of pain (5.1-point change), appetite loss (6.1-point change), constipation (6.2-point change), future perspective (8.6-point change), stoma-related problems (5.3-point change), weight loss (7.4point change) and global health status (5.9-point change). Figure 3A and 3B show the proportion of male patients who reported an improved or maintained QOL for QLQ-C30 and QLQ-BR38 domains, respectively, between baseline and subsequent assessments. Between 12% and 47% of men

Fu Im tur ag eP e er sp ec Se t ive xu al Fu Se nc xu tio al n En Mi joy ctu m Ch r e i t nt em ion oth Pr ob er ap lem Sy yS s m ide pto Eff m s e cts Fe of m the ale GI Se T ra xu ct al De Pr ob fec l em ati St on s om Pr aob Re lem lat ed s Pr ob lem s We igh tL os s

20

Fu Im tur ag eP e er sp ec Se tiv xu e al Fu Se n cti xu o al n En Mi joy ctu m Ch r e i tio nt em nP oth ro er ble ap m Sy yS s m ide pto Eff m s ec Fe of ts m the ale GI Se Tra xu ct al De Pr ob fec lem ati St on s om Pr aob Re lem lat ed s Pr ob lem s We igh tL os s

Patients (%)

80

reported improvement and a further 21%-69% of patients reported maintained QOL during capecitabine treatment. More than 40% of men reported improvement in their perception of fatigue (41%), micturition problems (47%), and global health status (42%). Over 60% of patients experienced an improved or maintained QOL according to each of the questionnaire domains during capecitabine therapy (range, 60%-84%).

Discussion The results of this study performed in a large population of Brazilian patients show that, in addition to the welldocumented efficacy and safety profile of oral capecitabine in patients with mCRC,1,5 QOL is generally maintained or improved during therapy. Over the course of our study, Clinical Colorectal Cancer March 2008 • 129

Evaluation of Quality of Life with Capecitabine Table 2

QLQ-C30: Least Square Mean Values (Standard Errors) in Female Patients Before Cycle 1

Week 7

Week 13

End of Treatment P Value

Domain

N

Mean

SE

N

Mean

SE

N

Mean

SE

N

Mean

SE

700

65.1

0.9

615

67.8

0.9

436

68.3

1.1

335

69.2

1.2

.0032

Physical function

699

66.7

1.1

614

65.2

1.1

436

65.2

1.2

337

64.2

1.3

.1256

Role function

701

61.9

1.4

615

62

1.4

435

64.5

1.6

335

64.3

1.8

.2879

Emotional function

700

58.5

1.1

615

63.7

1.2

435

65.4

1.3

338

64.5

1.5

< .0001

Social function

700

72.8

1.2

615

74.5

1.2

435

75.7

1.3

338

76.4

1.5

.1293

Cognitive function

700

72.4

1.1

615

71.5

1.1

435

73.1

1.3

338

72.6

1.4

.3578

Fatigue

701

37.9

1.1

615

36.7

1.2

436

35.3

1.3

337

35.2

1.5

.2932

Nausea/vomiting

701

17

0.9

615

18.7

1

436

16

1.1

338

15.1

1.3

.0258

Pain

701

39

1.3

615

33.8

1.3

436

33.5

1.5

338

33.1

1.7

< .0001

Dyspnea

701

12.1

0.9

612

13

1

434

12.6

1.1

337

13.8

1.2

.4451

Insomnia

698

35.4

1.4

614

33

1.5

434

30.9

1.7

335

30.7

1.9

.0861

Appetite loss

700

34.9

1.4

613

33.8

1.5

434

29.8

1.7

336

30.9

2

.0519

Constipation

690

22.1

1.2

608

19.5

1.3

432

17.2

1.5

335

16.1

1.7

.0068

Diarrhea

699

14

1

613

13.4

1

434

13.7

1.2

337

12.2

1.4

.6658

Financial problems

700

37.3

1.4

614

34.2

1.5

434

32.6

1.7

337

29.4

1.9

.001

Global Health Status Functional Scales

Symptom Scales

Score increase indicates improvement for the functional scales and score decrease indicates improvement for the symptom scales. Abbreviation: SE = standard error

Table 3

QLQ-CR38: Least Square Mean Values (Standard Errors) in Female Patients Before Cycle 1

Domain

Week 7

Week 13

End of Treatment P Value

N

Mean

SE

N

Mean

SE

N

Mean

SE

N

Mean

SE

Body image

696

69.3

1.2

605

69.9

1.3

429

73.7

1.4

335

71.6

1.6

.0050

Future perspective

696

37.2

1.5

611

45.5

1.5

429

48.4

1.8

335

45.6

2

< .0001

Sexual function

651

12.4

0.8

572

11.4

0.9

390

11.4

1

300

12.2

1.1

.4474

Sexual enjoyment

222

38.3

2.2

193

30.9

2.3

144

30.3

2.6

118

30.7

2.9

.0041

Micturition problems

699

36.4

0.8

606

35.3

0.8

430

33.4

1

336

32.3

1.1

.0080

Chemotherapy side effects

690

29.5

0.9

601

30.1

1

424

28.2

1.1

334

26.9

1.3

.0985

Symptoms in the GI tract

681

27.5

0.8

603

27.7

0.8

431

28.1

0.9

335

27.9

1.1

.9551

Female sexual problems

192

17.5

1.9

157

18.2

2

120

16.6

2.2

85

18.3

2.7

.7745

Defecation problems

414

17.1

0.7

369

16.9

0.7

272

15.3

0.8

220

14.6

0.9

.0299

Stoma-related problems

274

37.8

1.5

238

32.8

1.6

155

31.7

1.8

109

32.6

2

< .0001

Weight loss

695

29.6

1.2

604

21.7

1.3

428

18.3

1.5

333

17

1.7

< .0001

Functional Scales

Symptom Scales

Score increase indicates improvement for the functional scales and score decrease indicates improvement for the symptom scales. Abbreviations: GI = gastrointestinal; SE = standard error

statistically significant improvements were evident in approximately half the domains of the EORTC QLQ-C30 and QLQCR38 questionnaires in both women (12 of 26 domains) and men (13 of 26 domains). A statistically significant change in QOL outcome, however, does not necessarily translate into a

130 • Clinical Colorectal Cancer

March 2008

clinically meaningful change for the patient. To enable us to interpret the results of our study from the perspective of our patients, the findings of Osoba et al were applied to the data and showed that both women and men experienced small or moderate improvements in 7 QOL domains; women also

José G.M. Segalla et al Table 4

QLQ-C30: Least Square Mean Values (Standard Errors) in Male Patients Before Cycle 1

Week 7

Week 13

End of Treatment P Value

Domain

N

Mean

SE

N

Mean

SE

N

Mean

SE

N

Mean

SE

726

63

0.8

614

67

0.9

451

67.2

1

330

68.8

1.1

< .0001

Physical function

727

69.4

1

615

68.1

1.1

451

67.6

1.2

328

66.3

1.3

.1148

Role function

727

65.8

1.3

615

68.1

1.4

452

67.9

1.5

330

67.7

1.8

.2713

Emotional function

728

64.1

1.1

615

67.7

1.1

452

66.7

1.2

330

67.6

1.4

.0006

Social function

727

73.7

1.1

614

76.9

1.2

452

76

1.3

330

75.4

1.5

.0072

Cognitive function

728

79.5

0.9

615

79.3

1

452

77.2

1.1

330

78.2

1.3

.1285

Fatigue

727

34.7

1.1

616

33.9

1.2

452

33.3

1.3

330

33.7

1.5

.7731

Nausea/vomiting

727

12.6

0.8

616

13.6

0.8

452

12.4

0.9

330

10.6

1.1

.0816

Pain

727

35.2

1.3

616

31.6

1.3

452

31.3

1.5

330

30.1

1.7

.0046

Dyspnea

726

11.8

0.9

615

12.2

1

451

12.9

1.1

330

13.6

1.2

.5875

Insomnia

726

33.5

1.4

614

29.6

1.4

450

28.5

1.6

329

29.1

1.9

.0120

Appetite loss

725

31.3

1.3

614

28.2

1.4

451

25.8

1.6

330

25.2

1.9

.0091

Constipation

723

19.1

1.1

613

15.4

1.1

452

13.7

1.3

327

12.9

1.5

.0004

Diarrhea

725

12.3

1

610

14.7

1.1

450

13.9

1.2

329

14.9

1.4

.1102

Financial problems

727

36.3

1.4

614

31.1

1.5

451

30.6

1.6

330

32.9

1.9

< .0001

Global Health Status Functional Scales

Symptom Scales

Score increase indicates improvement for the functional scales and score decrease indicates improvement for the symptom scales. Abbreviation: SE = standard error

Table 5

QLQ-CR38: Least Square Mean Values (Standard Errors) in Male Patients Before Cycle 1

Domain

Week 7

Week 13

End of Treatment P Value

N

Mean

SE

N

Mean

SE

N

Mean

SE

N

Mean

SE

Functional Scales Body image

720

74

1.1

603

75.8

1.1

445

76.8

1.3

324

75

1.4

.0767

Future perspective

721

43.7

1.5

611

49.8

1.5

448

51.8

1.7

328

52.3

2

< .0001

Sexual function

696

27.7

1

588

25.2

1.1

432

25.4

1.2

313

25

1.4

.0380

Sexual enjoyment

330

51.7

1.8

272

47.1

1.9

199

50.9

2.2

162

48.7

2.4

.0255

Micturition problems

718

37.4

0.8

609

34.2

0.9

448

35.2

1

324

35.5

1.1

.0004

Chemotherapy side effects

718

21.9

0.8

599

21.4

0.8

443

21.7

1

326

20.7

1.1

.6271

Symptoms in the GI tract

717

25

0.7

598

25.2

0.8

445

25.7

0.9

326

24.7

1

.5714

Male sexual problems

471

30

1.6

382

28.3

1.7

279

27.8

1.9

204

25.9

2.2

.3569

Defecation problems

444

18.8

0.7

378

17.3

0.7

279

16.8

0.8

208

16.2

0.9

.0344

Stoma-related problems

268

31.8

1.4

224

29

1.4

167

27.4

1.6

118

26.5

1.8

.0064

Weight loss

725

27.4

1.2

610

19.3

1.3

450

19.2

1.5

327

19.9

1.7

< .0001

Symptom Scales

Score increase indicates improvement for the functional scales and score decrease indicates improvement for the symptom scales. Abbreviations: GI = gastrointestinal; SE = standard error

experienced a small degree of worsening in their perception of 1 domain (sexual enjoyment).12 Expressed another way, approximately 60%-85% of patients reported improved or maintained QOL during treatment with capecitabine. These findings are highly relevant for a patient group with meta-

static disease in whom it is important to balance the benefits of therapy against potential treatment-related toxicity. Domains for which improvements were observed appeared to differ between men and women, suggesting that there might be gender-related differences in the sensitivities of Clinical Colorectal Cancer March 2008 • 131

Evaluation of Quality of Life with Capecitabine various questionnaire items. However, to our knowledge, there are no gender-related studies of QOL data to aid the interpretation of these observations. Consistent findings of improvements in weight loss in both sexes, possibly linked to the improvements in appetite loss also noted in both sexes, are particularly encouraging given that an oral formulation was used. The improvements in perception of future perspective, again reported by both men and women, are possibly a function of the ‘do something’ rule described by Cella, that is, patients feel better/have a better outlook because something is being done to treat their cancer, rather than any direct effect of the drug.13 Small improvements in pain, again noted in both sexes, are also of interest and are consistent with reports of pain relief with capecitabine in other types of cancer.14,15 Although it is difficult to pinpoint with any accuracy the properties of capecitabine that might have contributed to the positive QOL changes observed in the present study, it is possible that the manageable and predictable tolerability profile of the agent played a role. Capecitabine also offers practical and economic advantages because it can be administered orally, thereby removing the need for regular visits to the clinic for intravenous (I.V.) drug administration and central venous catheterization if an infusional regimen is selected. These benefits are important because, if asked, most patients with cancer (89%) will state a preference for oral over I.V. chemotherapy provided that efficacy is not compromised.16 The main reasons given for preferring oral treatment are convenience (57%), avoidance of problems associated with I.V. lines (55%), and better control over the environment in which they receive chemotherapy (33%).16 However, it is interesting to note that no differences in QOL were reported in a comparative trial of an oral fluoropyrimidine (uracil-tegafur [UFT]) with parenteral 5-FU/LV,17 regardless of the obvious conveniences offered by the oral regimen. Several other large studies have investigated QOL during chemotherapy using the QLQ-C30 in patients with mCRC.17-21 Although details regarding QOL data in these trials were generally sparse, it is possible to make some observations. Improvements in global health status observed with capecitabine in the present study appeared at least as great as those reported with 5-FU21 or oral eniluracil/5FU20 when administered as first-line therapy. Capecitabine also showed a similar or better profile of QOL outcomes compared with eniluracil/5-FU for other functional or symptomatic QLQ-C30 scales.20 Although we acknowledge the limitations of cross-study comparisons, these observations are encouraging and suggest that capecitabine might provide even better QOL outcomes when used at earlier stages of the disease. Recently, Kopec et al compared health-related QOL, symptoms, and convenience of care in patients with stage II/III carcinoma of the colon who received oral UFT plus LV or standard I.V. 5-FU/LV as adjuvant chemotherapy. The study accrued 1,608 patients and showed that patients perceived adjuvant treatment with UFT plus LV as more convenient than standard I.V. treatment with FU plus LV. Both regimens are well tolerated and do not differ in their affect

132 • Clinical Colorectal Cancer

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on health-related QOL, perhaps because of the required I.V. administration of LV.22 In performing a pharmacoeconomic analysis of adjuvant oral capecitabine versus I.V. 5-FU/LV using data collected during the X-ACT trial, Cassidy et al predicted that the use of capecitabine for adjuvant treatment of colon cancer would not only save direct medical costs, but also improve health outcomes compared with 5-FU/LV.23 The projected 3.7% absolute improvement in the patient survival outcome observed during the trial period should yield an equivalent of > 9 months of additional survival over a lifetime, after discounting for the time value of money and adjusting for possible QOL changes because of later relapse. The findings of the present study need to be balanced against the limitations of its design. Without a control group against which to compare the results, it is difficult to ascertain whether the QOL changes documented were actually a function of treatment, progressive metastatic disease, or some other factor. The slight worsening in patients’ perception of physical functioning observed in both men and women suggest that disease progression might have occurred, at least in some patients, during the study. Possible biases were also introduced into the study by the reduced number of patients completing questionnaires at later timepoints. Consequently, the analysis included all patients who completed the questionnaire at each timepoint, excluding those who dropped out over time. However, the dropoff in patient numbers is consistent with other QOL studies performed in patients with mCRC.19,20 It should also be noted that Osoba et al, whose findings were used to interpret our data, investigated only 4 items on the QLQ-C30 questionnaire.12 We have, in effect, extrapolated their findings to interpret all of the QLQ-C30 and QLQ-CR38 questionnaire domains, which might limit the validity of these analyses. When analyzing the results of this study, one should take into account that, in countries where biologic agents are currently approved, this setting of single-agent capecitabine would not be common. Combination therapies will further affect a QOL analysis because it will be difficult to ascertain what exactly is improving the QOL. However, although approved in many countries, biologic therapies are not available for a large number of patients because of reimbursement issues, and monotherapy with capecitabine is a reality in more countries than one would prefer, which reinforces the importance of the study.

Conclusion In conclusion, our findings indicate that most patients with mCRC experience improved or maintained QOL during treatment with oral capecitabine. These data provide further support for the increasing use of capecitabine in the first- and second-line settings.

Acknowledgements This is an observational study without any intervention by the physician regarding the choice of treatment. Roche Brazil provided financial support for the workers (nurses, social workers, psychologists) who assisted patients in completing the questionnaires.

José G.M. Segalla et al We would like to thank the following centres for their involvement in this study: Hospital Amaral Carvalho, Jaú; Instituto do Câncer Arnaldo Vieira de Carvalho, São Paulo; Hospital das Clinicas de São Paulo; Hospital Ernesto Gaertner, Curitiba; Associação Hospital de Caridade de Ijuí, Ijuí; Hospital Beneficência Portuguesa de Santos, Santos; Hospital São Joaquim - Real Benemérita Sociedade Portuguesa de São Paulo, São Paulo; Instituto de Assistência ao Servidor Publico Estadual, São Paulo; Centro de Quimioterapia A. Imunoterapia, Belo Horizonte; Instituto do Câncer do Ceará, Fortaleza; Hospital Santa Rita da Irm. da Santa Casa de Misericordia de Porto Alegre; Instituto Brasileiro do Controle do Câncer, São Paulo; Fundação de Apoio Universitário FAU, Pelotas; Instituto do Câncer do Ceará, Fortaleza; Hosp. São Paulo, UNIFESP; Fundação de Apoio HEMOSC/Cepon (Fahecen); Centro de Referência à Saúde da Mulher, São Paulo; Fundação Benjamin Guimarães; Policlínica de Referência de Blumenau; Hospital Municipal do Andaraí; Soc Piauiense Combate Câncer; Centro de Terapia Oncológica, Petrópolis; Liga NorteRiograndense Combate o Câncer; Santa Casa de Misericórdia de São Paulo; IPSEMG H Gov Israel Pinheiro; Núcleo de Oncologia da Bahia; Instituto Nacional do Câncer – INCA; Centro Regional Integrado de Oncologia; Irmandade Sta Casa Misericórdia Santos; Hospital Israelita Albert Einstein; Clínica Médica Nuclear e Oncol Sul Fluminense (Radiclin); Hospital das Clínicas UFMG; CEHON, CTO Hemat. Oncol da Bahia; Clinica Santa Maria SC Ltda, Campos; Oncotech; Instituto Oncológico do Vale S/C Ltda; Fundação Universidade de Caxias do Sul (Hosp. Geral); Instituto de Câncer de Londrina – ICL; Hospital Anchieta; Ass Amigos Mario Penna; Centro Logístico de Saúde da Marinha (H. N. Marcílio Dias); Clinicon Prev, Caxias do Sul; Centro de Oncologia de Cascavel; Instituto de Assistência Médica do Servidor Público Estadual Fundação Felice Rosso; Cto. de Tratamento do Cancer S/C Ltda; Soc. Camp. C Pierro – PUCC; Hospital Sta Izabel-Salvador; Clinica Oncológica de Ilhéus; Clínica Especializada em Oncologia S/C Ltda. Ceon; Santa Casa de Misericórdia, Maceió; Clínica de Oncologia e Quimioterapia Paraná Bigorrilho (Inter-Rad); Inst. De Oncol. Clínica Erechim; Hospital do Câncer de Barretos-Pio XII; Centro Privado de Oncologia (Nove de Julho); Centro de Diag. e Tratam. de Neoplasias Ltda, Ponta Grossa; Instituto Oncológico, Juiz de Fora; Centro Médico Hospitalar Oncológico, Itabuna; União Oeste Paranaense de Estudos e Combate ao Câncer; Santa Casa Misericórdia de Franca-Hosp. do Câncer; Inst. Halsted S/C Ltda; Hosp São Lucas; Hospital da Cidade de Passo Fundo; Vitória da Conquista; Hosp. Fêmina, Porto Alegre; Hospital e Maternidade Frei Galvão, Guarulhos.

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