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Quality of Life in Operable Colon Cancer Patients Receiving Oral Compared With Intravenous Chemotherapy: Results From National Surgical Adjuvant Breast and Bowel Project Trial C-06

Jacek A. Kopec, Greg Yothers, Patricia A. Ganz, Stephanie R. Land, Reena S. Cecchini, H. Samuel Wieand, Barry C. Lembersky, Norman Wolmark

From the National Surgical Adjuvant Breast and Bowel Project Operations and Biostatistical Centers, Pittsburgh, PA; University of British Columbia, Vancouver, BC, Canada; Schools of Medicine and Public Health and the Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA; University of Pittsburgh Medical Center Cancer Center at Magee-Women's Hospital, Pittsburgh, PA; and Allegheny General Hospital, Pittsburgh, PA
Deceased.

Address reprint requests to Jacek Kopec, ARC, 895 West 10th Ave, Vancouver, BC, Canada V5Z 1L7; e-mail: jkopec{at}arthritisresearch.ca

	ABSTRACT

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Purpose: We compared health-related quality of life (HRQL), symptoms, and convenience of care (COC) in patients with stage II/III carcinoma of the colon who received either oral uracil/ftorafur (UFT) plus leucovorin (LV) or standard intravenous (IV) fluorouracil (FU) plus LV as adjuvant chemotherapy.

Patients and Methods: We measured HRQL with the Functional Assessment of Cancer Therapy–Colorectal (FACT-C) questionnaire, Short Form-36 Vitality Scale (SF-36), and a Quality of Life Rating Scale (QLRS) at baseline, once during chemotherapy, and at 1 year. We used the Symptom Distress Scale (SDS) and treatment-specific Symptom Checklist (SCL) to assess symptoms and a modified Burden of Care form to assess COC at baseline, on day 1 of each treatment cycle, and at 1 year. Repeated measures analyses controlling for demographic variables and baseline scores were used for statistical comparisons.

Results: The study accrued 1,608 patients, 803 to the FU arm and 805 to the UFT arm. There were no differences between the arms in overall FACT-C scores, FACT-C scores within the subscales of colon-specific, physical, emotional, social, and functional health, or QLRS scores. Patients taking UFT reported substantially higher COC. Statistically significant but small differences were observed for SF-36, favoring FU, and for SDS and SCL, both favoring UFT.

Conclusion: Patients perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL.

	INTRODUCTION

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In patients with operable colon cancer, adjuvant chemotherapy with intravenous (IV) fluorouracil (FU) and leucovorin (LV) prolongs disease-free survival and overall survival.¹ However, approximately one third of such patients will develop a recurrence within 5 years after surgery.¹ National Surgical Adjuvant Breast and Bowel (NSABP) Protocol C-06 was a randomized equivalence trial to compare FU plus LV with oral uracil/ftorafur (UFT) plus LV in the treatment of patients with stages II and III carcinoma of the colon. Efficacy results from this trial have recently been reported.² The study demonstrated that the two regimens are equivalent in terms of disease-free survival and overall survival.² These results are consistent with previous reports showing similar efficacy of these two treatments in patients with advanced cancer.^3,4

Adverse reactions associated with FU + LV have been well documented.^5,6 The most common adverse reactions are GI toxicity (diarrhea, nausea, stomatitis) and granulocytopenia. Randomized comparisons in metastatic colon cancer^3,4 reported safety benefits for oral UFT + LV over FU + LV in terms of myelosuppression, but no difference in overall quality of life. In two studies, patients with metastatic cancer preferred oral treatment with UFT,^7,8 the main reasons being lower toxicity and greater convenience of home treatment. The only study comparing the two regimens in the adjuvant setting was a small, nonrandomized trial in Japan.⁹ No differences in efficacy, toxicities, or quality of life were found.

The primary objective of the health-related quality of life (HRQL) component of NSABP C-06 was to compare HRQL reported by patients receiving adjuvant FU + LV versus UFT + LV following surgery for stage II or III colon cancer. Secondary objectives were to compare symptoms and convenience of care (COC). We hypothesized that the oral regimen would be associated with higher HRQL and that it would be perceived as more convenient.

	PATIENTS AND METHODS

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NSABP C-06 Design
Patients with resected stage II or III carcinoma of the colon were randomly assigned to FU + high-dose LV versus UFT + LV. Patients were stratified using a biased coin minimization algorithm¹⁰ according to the number of positive nodes (none, one to three, four or more) and participating institution. Those assigned to FU + LV received LV 500 mg/m² by IV infusion over 2 hours and FU 500 mg/m² by IV bolus 1 hour after LV infusion weekly for 6 weeks (on days 1, 8, 15, 22, 29, and 36), followed by a rest period. Treatment was restarted 21 days after the date of administration of the sixth dose of the previous cycle (one cycle = 8 weeks). A total of three cycles were administered. Patients assigned to UFT + LV received UFT 300 mg/m²/d plus LV 90 mg/d for 28 days followed by a 7-day rest period. Patients in this group took both drugs orally, the total daily dose divided into three doses to be taken 8 hours apart. A total of five cycles were administered. Chemotherapy in both arms began within 1 week from random assignment and 7 weeks from surgery.

Measurement of HRQL
HRQL was measured with the Functional Assessment of Cancer Therapy–Colorectal (FACT-C),¹¹ the Short Form-36 Vitality Scale¹² and a Quality of Life Rating Scale (QLRS). The FACT-C is a multidimensional, 44-item, cancer-oriented measure developed by Cella et al. Six subscales provide scores for physical well-being, social/family well-being, relationship with physician, emotional well-being, functional well-being, and problems commonly experienced by patients with colorectal cancer. The questionnaire has been extensively validated.^11,13 The four-item Vitality Scale is part of the MOS SF-36.¹² It includes questions about fatigue and lack of energy. A higher score on both FACT-C and Vitality Scale indicates better health. The QLRS evaluates the patient's overall perception of quality of life on a 0 to 10 scale, where 0 indicates the lowest and 10 indicates the highest possible quality of life. Validity and reliability of a similar scale in cancer patients has been reported.¹⁴ These instruments were administered at the following time points: before random assignment (baseline); approximately two thirds of the way through chemotherapy (ie, on day 1 of cycle 3 for the FU + LV regimen [week 16] and day 1 of cycle 4 for the UFT + LV regimen [week 15]); and at 1 year. A single assessment during chemotherapy was considered sufficient, as we did not expect large fluctuations in overall HRQL from cycle to cycle.

Measurement of Symptoms
We used the Symptom Distress Scale (SDS)¹⁵ and a treatment-specific Symptom Checklist (SCL) to assess patient-reported symptoms. The SDS contains 13 items asking about frequency or severity of nausea (two items), appetite, insomnia, pain (two items), fatigue, bowel, concentration, appearance, breathing, outlook, and cough. Each item is evaluated on a five-point Likert scale. An overall score is calculated by averaging the nonmissing item scores. Previous studies documented both validity and reliability of the SDS in cancer patients receiving chemotherapy.^15,16 The SCL covers a wide range of symptoms, including six items developed for Southwest Oncology Group (SWOG) colorectal cancer studies and 11 items specific to fluoropyrimidine. The questions ask how much the patient has been bothered by each symptom within the last week on a five-point scale from "not at all" to "very much." Higher scores on the SDC and SLC indicated worse symptoms. The scales were administered at baseline, on day 1 of each treatment cycle except cycle 1 (weeks 8 and 16 for UFT and weeks 5, 10, 15, and 20 for FU), and at 1 year. At the time of scale administration, 8 days had elapsed since the last treatment on the UFT arm, whereas 21 days had elapsed since the last treatment on the FU arm. For the SCL, which has not been previously validated, we calculated the Cronbach's alpha coefficient and found that the scale was internally consistent (Cronbach's alpha = .73).

COC
COC was measured with a modified Eastern Cooperative Oncology Group (ECOG) Burden of Care Form (unpublished instrument) consisting of the following two items: (1) "Receiving treatment is convenient for me" and (2) "I am satisfied with my current treatment." A third item, "My treatment has disrupted my life" was deleted after preliminary analyses revealed highly skewed responses and low internal consistency of the three-item scale (Cronbach's alpha = 0.45). Internal consistency of the two-item scale in our sample was good (Cronbach's alpha = 0.71), justifying the calculation of a total COC score. COC questions were administered at baseline, on day 1 of each treatment cycle except cycle 1, and at 1 year, but only the responses during chemotherapy treatment were considered in the analysis.

Statistical Analysis
The primary end point for this study was the FACT-C total score. Statistical comparisons of HRQL used linear repeated measures mixed models¹⁷ with visit (during chemotherapy, 1 year) as the repeated variable, and a compound symmetric covariance structure. Statistical comparisons of symptoms and COC during chemotherapy used linear repeated measures mixed models with the nominal time in weeks to each visit (5, 8, 10, 15, 16, 20) as the repeated variable. Odds ratios for specific symptoms were computed after dichotomizing the five-level responses by collapsing the two mildest levels and the three most severe levels. A logistic model was fitted using data obtained on day 1 of cycle 4 for UFT (week 15) and day 1 of cycle 3 for FU (week 16). All statistical comparisons controlled for the demographic factors of age (0 to 59 years, 60+ years), sex (female, male), and race (white, nonwhite). Other than COC, all comparisons controlled for the patient's baseline score. Treatment-by-time interactions were investigated by including the interaction term in the model and then dropping the term if the interaction was nonsignificant at the 0.05 alpha level.

Since there were significant differences in response rates between the two treatment arms, we could not assume that the data were missing completely at random. We performed a sensitivity analysis to determine whether the observed treatment differences in scores could be caused by reporting bias. Specifically, for some of the missing values on the treatment arm with the poorer reporting, we substituted extreme values (either minimum or maximum possible scale score), which would tend to reduce the observed treatment differences. The number of substitutions was calculated so that both treatment arms would have reporting rates equivalent to the arm with superior reporting.

All patients in the C-06 efficacy study were allowed to participate in the HRQL study. Since power exceeds 95% to detect a difference equivalent to 0.2 standard deviations with alpha of .01, we performed all statistical testing at the two-sided .01 alpha level.

	RESULTS

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Accrual and Participation Rates
The trial opened on February 14, 1997, and closed on March 31, 1999, after accruing 1,608 patients. Of those, 803 were randomly assigned to FU + LV and 805 to UFT + LV. Patients who contributed to HRQL analysis were similar to the full study population. Almost 60% were 60 years old or older, slightly over 50% were male, and 87% were white (Table 1). Close to half of the patients had tumors classified as stage II (Dukes' B) and the rest were stage III (Dukes' C). The distribution of patient and tumor characteristics was similar in both arms of the trial.

View larger version (11K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Functional Assessment of Cancer Therapy–Colorectal (FACT-C) total scores, change from baseline (BL) by treatment arm in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 ( is better). Bars represent 95% CIs. UFT, uracil/ftorafur; FU, fluorouracil.

View larger version (10K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Short Form-36 (SF-36) Vitality Scale change from baseline (BL) scores by treatment arm in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 ( is better). Bars represent 95% CIs. UFT, uracil/ftorafur; FU, fluorouracil.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Symptom Distress Scale change from baseline (BL) scores by treatment arm in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 ( is better). Bars represent 95% CIs. UFT, uracil/ftorafur; FU, fluorouracil.

View larger version (12K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 4. Symptom Checklist change from baseline (BL) scores by treatment arm in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 ( is better). Bars represent 95% CIs. UFT, uracil/ftorafur; FU, fluorouracil.

View larger version (9K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 5. Convenience of care scores by treatment arm in National Surgical Adjuvant Breast and Bowel Project (NSABP) C-06 ( is better). Bars represent 95% CIs. UFT, uracil/ftorafur; FU, fluorouracil.

	DISCUSSION

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The primary end point for this study was HRQL as measured by the FACT-C. We did not find any differences between patients receiving UFT versus FU, either for the total score or any of the subscales. Overall ratings of quality of life were also similar. Our study demonstrated a statistically significant but very small difference favoring FU in the SF-36 Vitality Scale. The difference was only 3.3 points on a 0 to 100 scale (effect size < 0.15 standard deviations) and, therefore, unlikely to be clinically important. Small but significant differences in the pattern of change for SDS and SCL overall scores during chemotherapy were also detected. All of the differences in mean scores and change scores during chemotherapy were less than 2.4 points on a 0 to 100 scale. The treatment differences at week 15/16 were 1.1 points for SDS (effect size < 0.15 standard deviations) and 1.3 points for SCL (effect size < 0.25 standard deviations). Several symptoms, including gas pain and diarrhea, were more commonly reported as bothersome in the UFT arm, whereas other symptoms, such as vomiting, skin and eye problems, were more common in the FU arm. Patients in the UFT arm were generally less worried and more satisfied with their appearance. There was a substantial difference of roughly nine points on a 0-to-100 scale between the regimens, favoring UFT, in COC scores (effect size > 0.3 standard deviations).

The results of our study agree with previous reports indicating that chemotherapy with UFT + LV is generally well tolerated.^3,4,9,18 Douillard et al³ and Carmichael et al⁴ reported lower rates of hematologic toxicity in patients with metastatic colon cancer receiving UFT, compared with FU. In the latter study, UFT was associated with higher rates of patient-reported diarrhea; however, this could be due to differences in the timing of assessment.⁴ Neither Carmichael et al⁴ in metastatic cancer nor Kim et al⁹ in operable cancer found any differences in overall quality of life. With respect to patient preferences, our findings are consistent with previous reports in demonstrating a clear and substantial advantage of the oral regimen.

Mean FACT-C scores and vitality scores did not change appreciably from baseline to week 15/16 despite an increase in the symptoms associated with chemotherapy, whereas overall quality of life actually improved. This result was unexpected. The most likely explanation is that adverse effects of therapy did not have a strong impact on HRQL. Although many patients reported being "a little bothered" by the symptoms, severe symptoms were relatively rare. In addition, HRQL at baseline was likely suboptimal, because some patients may have suffered from the physical consequences of surgery and psychological effects of cancer diagnosis. Follow-up scores at 1 year clearly showed an improvement in HRQL. It seems unlikely that more frequent assessments of HRQL during chemotherapy would have revealed important changes in quality of life between the cycles or differences between the treatment arms.

During chemotherapy, the outcomes were assessed at the time of scheduled clinic visits, which occurred at the end of a rest period. It is possible that the reported symptoms would have been more severe had these assessments been carried out before the rest period. The proportion of patients with any diarrhea according to the Common Toxicity Criteria (CTC) was higher than the proportion reporting being at least "a little bothered" by diarrhea on the SCL. Furthermore, CTC-based reports of diarrhea slightly favored UFT, whereas self-reports favored FU. Several factors could account for this apparent discrepancy. We would expect differences between the patient's and the clinician's perspectives in reporting symptoms. The SCL asked how bothersome the symptoms were to the patient, not whether or not they were experienced. In addition, patient responses may have been influenced by differences between the two assessment methods in the recall period relative to treatment schedule. The rest period was 21 days for the FU patients versus 8 days for the UFT patients, and the questions referred to symptoms experienced in the last week. Patients in the FU arm may have experienced diarrhea slightly more often while receiving chemotherapy but recovered better between the cycles.

A limitation of the study is that compliance with the HRQL study was not optimal. Although more than 70% of patients in both arms completed the HRQL questionnaire while receiving chemotherapy, only approximately 50% completed all required forms at all time points. Furthermore, compliance rates differed between the arms. We addressed this issue by conducting a sensitivity analysis. Differences in compliance rates may explain the observed small difference in vitality, but not the difference in treatment convenience.

Our data do not allow us to compare the total costs of therapy with FU versus UFT in the adjuvant setting. A study by Maroun et al¹⁹ in Canada, based on data from two randomized trials in advanced colon cancer, found that patients on the UFT regimen visited outpatient oncology clinics less often, and this resulted in savings of more than $3,000 Canadian per patient per treatment. The costs of drugs were not considered.

In conclusion, patients with colon cancer perceive adjuvant treatment with UFT + LV as more convenient than standard IV treatment with FU + LV. Both regimens are well tolerated and do not differ in their impact on HRQL. We hope these results will help clinicians in preparing patients for chemotherapy after colon cancer surgery and in selecting the best therapy for each patient.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: H. Samuel Wieand, Taiho Pharmaceuticals Stock: N/A Honoraria: N/A Research Funds: N/A Testimony: N/A Other: N/A

	AUTHOR CONTRIBUTIONS

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Conception and design: Jacek A. Kopec, Greg Yothers, Patricia A. Ganz, Norman Wolmark

Administrative support: Norman Wolmark

Provision of study materials or patients: Barry C. Lembersky

Collection and assembly of data: Greg Yothers

Data analysis and interpretation: Greg Yothers, Patricia A. Ganz, Stephanie R. Land, Reena S. Cecchini, H. Samuel Wieand, Barry C. Lembersky

Manuscript writing: Jacek A. Kopec, Greg Yothers, Patricia A. Ganz, Stephanie R. Land, H. Samuel Wieand, Norman Wolmark

Final approval of manuscript: Jacek A. Kopec, Greg Yothers, Patricia A. Ganz, Stephanie R. Land, Reena S. Cecchini, H. Samuel Wieand, Barry C. Lembersky, Norman Wolmark

	NOTES

 
Supported by Public Health Service Grants No. U10CA-12027, P-U10CA-37377, U10CA-69651, U10CA-69974 from the National Cancer Institute, Department of Health and Human Services; Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT; and Taiho Pharmaceutical Co, Lts, Tokyo, Japan.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

	REFERENCES

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1. Wolmark N, Rockette H, Fisher B, et al: The benefit of leucovorin-modulated fluorouracil as postoperative adjuvant therapy for primary colon cancer: Results from National Surgical Adjuvant Breast and Bowel Project protocol C-03. J Clin Oncol 11:1879-1887, 1993[Abstract/Free Full Text]

2. Lembersky BC, Wieand HS, Petrelli NJ, et al: Oral uracil and tegafur plus leucovorin compared with intravenous fluorouracil and leucovorin in stage II and III carcinoma of the colon: Results from National Surgical Adjuvant Breast and Bowel Project Protocol C-06. J Clin Oncol 24:2059-2064, 2006[Abstract/Free Full Text]

3. Douillard JY, Hoff PM, Skillings JR, et al: Multicenter phase III study of uracil/tegafur and oral leucovorin versus fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3605-3616, 2002[Abstract/Free Full Text]

4. Carmichael J, Popiela T, Radstone D, et al: Randomized comparative study of tegafur/uracil and oral leucovorin versus parenteral fluorouracil and leucovorin in patients with previously untreated metastatic colorectal cancer. J Clin Oncol 20:3617-3627, 2002[Abstract/Free Full Text]

5. Wolmark N, Bryant J, Smith R, et al: Adjuvant 5-fluorouracil and leucovorin with or without interferon alfa-2a in colon carcinoma: National Surgical Adjuvant Breast and Bowel Project protocol C-05. J Natl Cancer Inst 90:1810-1816, 1998[Abstract/Free Full Text]

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Submitted January 12, 2006; accepted November 9, 2006.

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Alert me to new issues of the journal Save to my personal folders Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kopec, J. A. Articles by Wolmark, N. Search for Related Content PubMed Articles by Kopec, J. A. Articles by Wolmark, N.