Current Medical Research & Opinion 0300-7995 doi:10.1185/03007995.2015.1014030
Vol. 31, No. 4, 2015, 731–741
Article ST-0414.R1/1014030 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Original article Observational study of adjuvant therapy with capecitabine in colon cancer Claus-Christoph Steffens MVZ Ha¨matologie/Onkologie Klinik Dr. Hancken, Stade, Germany
Barbara Tschechne Klinikum Neustadt am Ru¨benberge, Neustadt am Ru¨benberge, Germany
Christof Schardt Onkologische Praxis, Gelsenkirchen, Germany
Georg Jacobs Praxis fu¨r Ha¨matologie und Onkologie, Saarbru¨cken, Germany
Annette-Rosel Valdix Onkologische Schwerpunktpraxis, Schwerin, Germany
Peter Schmidt Onkologische Gemeinschaftspraxis Dr. Schmidt & Dr. Klaproth, Neunkirchen, Germany
Richard Hansen Praxis fu¨r Onkologie Kaiserslautern, Kaiserslautern, Germany
Hendrik Kro¨ning Schwerpunktpraxis fu¨r Ha¨matologie und Onkologie, Magdeburg, Germany
Tim Wohlfarth Roche Pharma AG, Grenzach-Wyhlen, Germany
Dorothee Guggenberger Onkologische Schwerpunktpraxis, Aachen, Germany Address for correspondence: Dr. Claus-Christoph Steffens MVZ, Ha¨matologie/ Onkologie Klinik Dr. Hancken, Harsefelder Strasse 8, 21680 Stade, Germany. Tel.: +49 4141-604-147; [email protected] Keywords: Adjuvant chemotherapy – Administration and dosage – Capecitabine – Colonic neoplasms – Oxaliplatin – Patient satisfaction – Safety Accepted: 27 January 2015; published online: 12 February 2015 Citation: Curr Med Res Opin 2015; 31:731–41
Abstract Objective: This observational study was conducted to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. Research and design methods: ML20431 was a prospective, multicenter, non-interventional, observational study. It was designed to answer five research questions relating to safety, dosage and administration, and discontinuation from capecitabine-based adjuvant therapy. Patients were required to have R0 resected stage III colon cancer and have started treatment with capecitabine-based adjuvant therapy based on a decision by the investigator. Patients were followed over an observation period of 6 months after initiation of therapy. Investigators were required to complete the study case report form at study entry, each treatment cycle, and at the final examination. Main outcome measures: A total of 1485 patients were included in the study, and 1481 patients were treated with capecitabine and formed the analysis population. Most patients had colon cancer (78.3%), followed by rectal cancer (16.4%). Most patients had stage III disease (69.3%); the remaining patients had stage II disease (30.7%). The most common all-grade adverse reactions were hand–foot syndrome (46.9%), diarrhea (34.4%), and hemoglobin decreases (31.5%). Grade 3/4 adverse reactions were infrequent (54%). Serious adverse events were reported in 96 patients (6.5%). Six or more cycles of treatment were completed by 77.9% of patients. Approximately two-thirds of patients (67.3%) received capecitabine monotherapy and the remainder (32.7%) received capecitabine in combination with 1 drugs, most commonly oxaliplatin (460 cases). Discontinuation of capecitabine was documented in 344 patients (23.2%). Study limitations: no efficacy data were collected; the questionnaires for patients’ expectations and satisfaction were not formally validated; and a few patients (51.5%) had some retrospective data. Conclusions: The safety profile of capecitabine-based adjuvant therapy in a broad patient population with colon cancer is similar to that previously documented in phase III clinical trials.
Introduction Capecitabine (Xeloda*), an oral fluoropyrimidine, is widely approved for adjuvant therapy in early-stage colon cancer. This is based on the findings from two randomized phase III clinical trials – X-ACT (Xeloda in Adjuvant Colon Cancer Therapy; M66001)1 and XELOXA (XELOX Adjuvant; NO16968)2. The X-ACT trial demonstrated that capecitabine was at least equivalent to intravenous 5-fluorouracil/leucovorin (5-FU/LV) in patients with resected stage III colon cancer1. In this study, capecitabine (1250 mg/m2 twice daily on *
! 2015 Informa UK Ltd www.cmrojournal.com
Xeloda is a registered trade name of F. Hoffmann La Roche
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
731
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
April 2015
days 1–14 every 21 days for 24 weeks) was compared with a bolus schedule of 5-FU/LV (Mayo Clinic regimen). The intention-to-treat population comprised 1987 patients (capecitabine, n ¼ 1004; 5-FU/LV, n ¼ 983). After 3 years, disease-free survival was equivalent in patients receiving capecitabine versus 5-FU/LV (hazard ratio 0.87, 95% confidence interval 0.75–1.00); the upper limit of the confidence interval was significantly below both predefined margins (1.25 and 1.20) for at least equivalence (p50.001). Capecitabine had an improved safety profile compared with bolus 5-FU/LV, and was associated with significantly less diarrhea, nausea or vomiting, stomatitis, alopecia, and neutropenia, but more hand–foot syndrome and hyperbilirubinemia3. The XELOXA study compared oxaliplatin (130 mg/m2 on day 1) plus capecitabine (1000 mg/m2 twice daily on days 1–14 plus every 21 days for 24 weeks) with a bolus schedule of 5-FU/LV (Mayo Clinic or Roswell Park regimens) in patients with resected stage III colon cancer2. The intention-to-treat population comprised 1886 patients (capecitabine plus oxaliplatin, n ¼ 944; 5-FU/ LV, n ¼ 942). The addition of oxaliplatin to capecitabine improved 3 year disease-free survival compared with 5-FU/ LV (hazard ratio 0.80; 95% confidence interval 0.69–0.93; p ¼ 0.0045). Most treatment-related adverse events occurred at similar rates in the study treatment arms; however, patients receiving capecitabine plus oxaliplatin experienced less diarrhea and alopecia, but more neurosensory toxicity, vomiting, and hand–foot syndrome than those receiving 5-FU/LV4. Historical data suggest that most patients prefer oral chemotherapy, provided that efficacy is not compromised5. This preference is based on the convenience of receiving chemotherapy at home and avoidance of intravenous access. However, chemotherapy at home also poses several challenges for the oncology care team. Education of patients is important so that they can recognize and report adverse events promptly. Ongoing support for patients from the practice is also necessary to assist with any concerns regarding treatment. This non-interventional, observational study (ML20431) was conducted to determine the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical practice conditions in Germany. As well as monitoring adverse events, details of capecitabine treatment (i.e. dose, duration, combination agents, etc.) were documented during the study observation period. Patient expectations and patient contact were also evaluated. The study was initiated in 2006, when only single-agent capecitabine was approved for adjuvant therapy, and finished in 2012, by which time capecitabine plus oxaliplatin had also been approved for use as adjuvant therapy in Europe. The study therefore covers a period when capecitabine monotherapy and, later, combination 732
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
therapy were possible choices available to participating investigators.
Patients and methods Study design ML20431 was a prospective, multicenter, non-interventional, observational study designed to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. The study was conducted in hospital departments, outpatient clinics and oncology practices in Germany. The conduct of the study did not influence the treatment procedure of individual patients, and had no influence on medical decisions and procedures. Study investigators were completely free to decide which patients to treat with the study drug, which dosage to choose, which diagnostic measures to take, how to monitor the course of treatment, and which accompanying or additional medication(s) to prescribe. The appointments for each patient with their physician were determined individually. The study complied with the German Medicinal Products Act (‘Arzneimittelgesetz’; section 67, subsection 6). Although a formal review of the study observation plan by an ethics committee was not performed, it was permissible for study investigators to obtain advice from their local ethics committee regarding the observation plan.
Study questions The study was conducted to address the following questions: Are the reported adverse reaction rates consistent with the previously described adverse reaction profile? Is the safety profile identified in clinical research reproducible in routine clinical practice? Do any previously undocumented adverse drug reactions occur with the treatment regimens used in practice? What dosages, regimens (mono- and combination therapies) and administration schedules are used in routine practice? What are the reasons for discontinuing treatment?
Patients Patients who were enrolled had Union Internationale Contre le Cancer (UICC) stage III (Dukes’ C) colon cancer and required adjuvant drug treatment following successful (R0) surgery and for whom the investigator had made an individual decision, outside the study, to www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
start treatment with capecitabine. Treatment was to be based on daily medical requirements and the current prescribing information for relevant drugs. Patients were followed over an observation period of up to 6 months after the initial dose of adjuvant therapy.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Documentation and investigation variables The observation period was divided into study entry (or baseline), each treatment cycle and a final examination. Investigators were asked to complete the study case report form (CRF) at each of these time-points. The CRF was designed to reflect the normal course of treatment as closely as possible. Treatment Variables concerning treatment and administration included the duration of treatment, number of cycles, capecitabine dose, use of monotherapy or combination therapy, combination drugs given with capecitabine, treatment interruptions, duration of treatment interruptions, dose adjustments, reasons for dose adjustments, and treatment discontinuations. The details of treatment were recorded at study entry and at each treatment cycle. If treatment was discontinued early (i.e. before completion of eight cycles), the reason for premature withdrawal was documented. Safety In this study, adverse reactions were defined as toxicities whose cause was given as ‘Xeloda’, ‘not assessable’, or ‘unknown’. All adverse reactions were recorded on the CRF. The CRF contained a list of predefined toxicities (i.e. decreased hemoglobin, decreased leucocytes, decreased granulocytes, decreased thrombocytes, increased bilirubin, nausea, vomiting, diarrhea, mucocitis/stomatitis, motor function, alopecia, hand–foot syndrome, fever, pain). Any other toxicities could also be documented by the investigator using free text. The intensity of adverse reactions was graded according to the toxicity categories of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Serious adverse events were also reported separately on a dedicated form.
April 2015
more time at home, more time for personal things, more time flexibility at work. At the end of the observation period, patients were asked if their expectations regarding lifestyle, the treatment diary and patient support had been met. Patients were also asked to rate their overall satisfaction with the conduct of treatment and their ability to cope with side effects on a 6-point scale (1 ¼ very good, 2 ¼ good, 3 ¼ satisfactory, 4 ¼ fair, 5 ¼ poor, 6 ¼ unsatisfactory). At study entry, patients were asked if they planned to have any telephone contact with the center. In addition, patients were asked to clarify whether the contact was to be with the investigator or the nursing staff. Patients were also asked whether calls were to be made by the center, by themselves or both. Investigators also documented whether or not patients were given a treatment diary. At each treatment cycle and the final examination, the questions regarding telephone contact were repeated and patients were also asked if they had completed the treatment diary carefully and completely.
Statistical analysis The analysis population was defined as all prospectively documented patients who were treated with capecitabine. The sample size was based on the analysis of safety. The original planned sample size was 850 patients. This was amended to 1000 patients in September 2010 to allow for the revised labeling of capecitabine, i.e. use of capecitabine in combination with oxaliplatin. In a sample of 1000 patients, adverse reactions with an incidence of between 1/100 and 1/1000 were expected to occur with over 99.9% probability. This sample size was sufficient to observe such an adverse reaction or interaction at least four times with a probability of 99.0%; 95% confidence intervals for adverse reaction incidence rates would have a maximum width of 3.1%. It was anticipated that 320 patients would receive combination therapy with capecitabine and oxaliplatin; for this subgroup, events with an incidence of 1/100 were expected to occur at least once with a probability of 95%. The data were analyzed in a descriptive manner. Analyses were performed using SAS software, version 8.2.
Results Patient expectations and contact At study entry, each patient was asked specific questions about their expectations regarding oral treatment, i.e. freedom from port, fewer side effects, ability to manage daily routine better, and conduct of treatment made easier by use of a treatment diary. Patients indicating that they expected improved management of their daily routine were further asked about the possible advantages, i.e. ! 2015 Informa UK Ltd www.cmrojournal.com
Patient population A total of 1485 patients were included in the study at 203 centers in Germany between February 2006 and November 2012. Of these, 1481 patients were treated with capecitabine and formed the analysis population. The following protocol violations were documented in the analysis population: no successful surgery (n ¼ 119); Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
733
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 1. Baseline patient demographics and characteristics.
Table 2. Chemotherapeutic and targeted agents given in combination with capecitabine.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Analysis population (N ¼ 1481) Age, years Median (range) Gender, n (%) Male Female Body surface area, m2 Median (range) ECOG performance status, n (%) 0 1 2 3 Cancer diagnosis, n (%)* Colon cancer Rectal cancer Rectosigmoid cancer Colorectal cancer UICC stage, n (%) II III Time from surgical resection, n (%) 8 weeks 48 weeks Carcinoembryonic antigen, ng/mL Mean (SD) Employed, n (%) No Yes
71 (20–93) 820 (55.5) 657 (44.5) 1.8 (1.0–2.8) 594 (41.7) 710 (49.9) 110 (7.7) 9 (0.6) 1159 (78.3) 243 (16.4) 53 (3.6) 15 (1.0) 434 (30.7) 979 (69.3) 1012 (74.5) 346 (25.5) 2.6 (4.2) 1228 (86.9) 185 (13.1)
*Most common diagnoses listed only. ECOG ¼ Eastern Cooperative Oncology Group; SD ¼ standard deviation; UICC ¼ Union Internationale Contre le Cancer.
retrospective documentation (n ¼ 22); other diagnosis (n ¼ 8); no information on diagnosis (n ¼ 7); and no post-baseline value (n ¼ 1). The median duration of observation was 180 (range 4 to 583) days. In the analysis population, a total of 588 (39.7%) patients withdrew early from the study. Reasons for early withdrawal (multiple responses permitted) were: severe adverse reactions (n ¼ 178, 12.0%); refusal of treatment (n ¼ 125, 8.4%); end of treatment regimen (i.e. shorter than eight cycles, n ¼ 111, 7.5%); adverse event (n ¼ 57, 3.8%); no further contact with patient/patient did not attend (n ¼ 37, 2.5%); recurrence (n ¼ 27, 1.8%); death (n ¼ 18, 1.2%); progression (n ¼ 13, 0.9%); and other reasons (n ¼ 88; 5.9%). A summary of baseline patient demographics and disease characteristics is shown in Table 1. The median age of the patient population was 71 (range 20 to 93) years; approximately two-thirds of patients (n ¼ 1000; 67.8%) were over 65 years. The most common tumor diagnosis was colon cancer (78.3%) followed by rectal cancer (16.4%). While most patients (69.3%) had stage III disease, almost one-third (30.7%) had stage II disease. Most patients (86.9%) were no longer working. At least one coexisting condition was documented in 15.3% (n ¼ 227) of 734
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
Analysis population (N ¼ 1481) No combination therapy Combination therapy Oxaliplatin Bevacizumab, oxaliplatin Bevacizumab Irinotecan Bevacizumab, irinotecan Cetuximab, oxaliplatin Epirubicin, oxaliplatin 5-Fluorouracil Cisplatin, epirubicin Dexamethasone, oxaliplatin Folinic acid, oxaliplatin Melphalan Monoclonal antibodies, oxaliplatin Oxaliplatin, saccharated iron oxide Paclitaxel
996 (67.3%) 485 (32.7%) 460 (31.1%) 10 (0.7%) 9 (0.6%) 6 (0.4%) 3 (0.2%) 2 (0.1%) 2 (0.1%) 2 (0.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%)
All cycles are included in the table, so a patient may be represented more than once. If two agents are shown on one line, the patient received both agents in one cycle.
patients. The most common disorder was hypertension (n ¼ 113; 7.6%); no other condition occurred in more than 5% of patients.
Treatment In the analysis population, the mean duration of treatment was 162 (standard deviation [SD] 59) days and the median treatment duration was 173 (range 22 to 572) days. Most patients (n ¼ 880, 59.4%) completed eight cycles of treatment. Six or more cycles were completed by 1154 patients (77.9%). In the analysis population, approximately two-thirds of patients (n ¼ 996; 67.3%) received capecitabine as monotherapy. All other patients (n ¼ 485; 32.7%) received capecitabine in combination with one or more drugs. A summary of drugs given in combination with capecitabine is shown in Table 2. The agent most commonly selected for use in combination with capecitabine was oxaliplatin (460 cases). Bevacizumab was listed either alone or in combination with oxaliplatin or irinotecan in 22 cases, while other chemotherapeutic drugs were documented only sporadically (irinotecan, nine cases; epirubicin, three cases). Radiotherapy was carried out simultaneously with at least one treatment cycle in 112 patients (7.5%). A summary of capecitabine daily doses by the type of treatment regimen is presented in Table 3. In patients treated with capecitabine monotherapy, the median daily dose throughout treatment was 2500 mg/m2, although the mean daily dose decreased slightly from 2582 mg/m2 at the start of treatment to 2454 mg/m2 at cycle 8. In patients treated with combination therapy, www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 3. Capecitabine daily doses by type of treatment regimen.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Timepoint
Inclusion visit** n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 1 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 2 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 3 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 4 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 5 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 6 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 7 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 8 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day
Monotherapy
Combination therapy All combinationsy
With oxaliplatin
863 2581.5 (874.0) 2500.0
410 2189.4 (707.9) 2000.0
397 2177.4 (691.3) 2000.0
861 2537.7 (847.7) 2500.0
419 2166.7 (702.0) 2000.0
406 2154.3 (685.0) 2000.0
826 2561.7 (850.8) 2500.0
397 2165.6 (714.6) 2000.0
383 2151.1 (699.5) 2000.0
796 2544.4 (841.5) 2500.0
367 2144.4 (725.7) 2000.0
355 2134.2 (724.5) 2000.0
755 2528.6 (842.7) 2500.0
348 2154.9 (732.7) 2000.0
337 2144.3 (731.5) 2000.0
713 2480.0 (855.6) 2500.0
328 2157.8 (721.8) 2000.0
318 2153.2 (723.1) 2000.0
682 2460.5 (868.4) 2500.0
305 2159.2 (733.4) 2000.0
295 2155.2 (734.5) 2000.0
607 2451.5 (859.9) 2500.0
238 2097.7 (705.8) 2000.0
230 2097.7 (713.5) 2000.0
539 2454.1 (825.3) 2500.0
206 2069.5 (699.1) 2000.0
201 2066.3 (702.8) 2000.0
SD ¼ standard deviation. Patient classification by type of regimen was decided on the basis of the treatment planned for cycle 1. yAll patients on combination therapy with oxaliplatin are included in the combination therapy subgroup. **Planned doses.
the median daily capecitabine dose throughout treatment was 2000 mg/m2; the mean daily dose showed a small reduction from 2189 mg/m2 at the start of treatment to 2070 mg/m2 at cycle 8. Overall, 541 of 1467 evaluable patients (36.9%) required at least one dose adjustment during the total observation period. In patients requiring dose adjustments (n ¼ 541), most were due to adverse events, specifically hand–foot syndrome (n ¼ 180; 33.3%), diarrhea (n ¼ 75, 13.9%) or other events (n ¼ 281; 51.9%). Other reasons commonly given for performing dose adjustments were an individually planned treatment regimen (n ¼ 74; 13.7%) and good tolerability (n ¼ 74; 13.7%). The median number of dose adjustments per patient was 1 (range 1 to 8). Overall, 391 of 1477 evaluable patients (26.5%) had at least one treatment interruption over the total observation period. Among patients with treatment interruptions (n ¼ 391), 280 patients required one interruption, ! 2015 Informa UK Ltd www.cmrojournal.com
77 patients required two treatment interruptions and 34 patients required three or more treatment interruptions. The maximum number of treatment interruptions documented for a patient was nine. The median duration of all treatment interruptions per patient was 10 (range 1 to 127) days. Discontinuation of capecitabine was documented in 344 of 1481 patients (23.2%); 247 patients discontinued capecitabine alone and 97 patients discontinued capecitabine and combination drug(s). A further 77 patients discontinued combination drug(s) alone.
Safety A summary of all-grade and grade 3/4 adverse reactions reported during the observation period in the analysis population (n ¼ 1481) is presented in Table 4. The most common all-grade adverse reactions were hand–foot Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
735
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 4. Adverse reactions (N ¼ 1481).
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
No. patients (%)
Hand–foot syndrome Diarrhea Hemoglobin decrease Nausea Other Leucocyte decrease Pain Thrombocyte decrease Mucositis/stomatitis Granulocyte decrease Vomiting Bilirubin increase Alopecia Motor function* Fever
Grade 1–4
Grade 3/4
694 (46.9) 510 (34.4) 467 (31.5) 457 (30.9) 452 (30.5) 300 (20.3) 254 (17.2) 212 (14.3) 158 (10.7) 151 (10.2) 134 (9.0) 122 (8.2) 115 (7.8) 99 (6.7) 58 (3.9)
51 (3.4) 47 (3.2) 14 (0.9) 18 (1.2) 44 (3.0) 14 (0.9) 9 (0.6) 25 (1.7) 7 (0.5) 11 (0.7) 6 (0.4) 23 (1.6) 0 (0.0) 4 (0.3) 0 (0.0)
An adverse reaction was defined as a toxicity whose cause was reported as ‘Xeloda’, ‘unknown’ or ‘unassessable’. *Weakness or loss of function.
syndrome (46.9%), diarrhea (34.4%) and hemoglobin decreases (31.5%). Most adverse reactions were grade 1 or 2. The most common grade 3/4 adverse reactions were hand–foot syndrome (3.4%), diarrhea (3.2%) and thrombocyte decreases (1.7%). Other adverse reactions reported by investigators in free text on the CRF are shown in the Supplementary Table. Serious adverse events were reported in 96 of 1481 patients (6.5%). The most commonly reported events were diarrhea (n ¼ 28; 1.9%), nausea (n ¼ 10; 0.7%) and deep vein thrombosis (n ¼ 10; 0.7%). A total of 18 patients died during the study observation period. The causes of death were tumor-related (n ¼ 7), pneumonia with sepsis (n ¼ 2), heart failure (n ¼ 1), postoperative pulmonary embolism (n ¼ 1), pancreatitis (n ¼ 1), pneumonia (n ¼ 1), or no information given (n ¼ 5).
Patient expectations On study entry, patients were asked what they expected from treatment (Table 5). Expectations endorsed by patients were that oral therapy would improve the management of their daily routine (60.6%), eliminate the need for a port system (47.0%) and that there would be fewer side effects (44.7%). Some patients (15.5%) had no expectations. Patients who expected treatment to improve the management of their daily routine indicated that they hoped for ‘More time at home’ (72.7%), ‘More time for personal things’ (44.5%) and ‘More time flexibility at work’ (8.9%). At final documentation, patients were asked if their expectations had been met. The responses of patients who had stated specific expectations at study entry are 736
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
presented in Table 5. Specific expectations regarding improved management of daily routine were met in most patients (‘More time at home’, 71.3%; ‘More time for personal things’, 74.6%; ‘More time flexibility at work’, 77.2%). Over two-thirds (68.9%) of patients hoping for the treatment diary to make it easier to carry out treatment confirmed that they were helped by the diary. In addition, all patients were asked more general questions about fulfillment of their expectations; the responses to these questions in the analysis population are shown in Figure 1. Expectations regarding lifestyle and, in particular, the availability of contact persons at the center were often met, although many patients did not answer the questions or were ‘unassessable’. At the end of treatment, most patients (n ¼ 916; 61.8%) rated their satisfaction with the conduct of treatment as ‘very good’ or ‘good’ (Figure 2). Only a small proportion of patients (n ¼ 24; 1.6%) rated their experiences as ‘poor’ or ‘unsatisfactory’. Most patients (n ¼ 941; 63.5%) gave a rating of ‘very good’, ‘good’ or ‘satisfactory’ when asked if they had coped with the side effects of treatment (Figure 2). Eighty-seven patients (5.9%) rated their experiences as ‘poor’ or ‘unsatisfactory’.
Patient contact A summary of the details of telephone contacts, which were planned at study entry and which took place during the observation period, is presented in Table 6. For most patients (72.5%), it was agreed before the start of treatment that the center and patient would be in telephone contact between visits, while no telephone contact was planned for 27.5% (n ¼ 393 of 1427) of patients. At least one contact occurred during the observation period in 54.1% of patients. Before the start of treatment, it was planned that the investigator would be the contact person in over half of cases (50.6%), while the nursing staff were to serve as contacts for 23.3% of patients, and both the investigator and nursing staff for 26.2% of patients. It was planned that calls were to originate primarily from the patient (75.2%). During the observation period, the investigator was the patients’ main contact person at the center and most phone contacts were initiated by patients. The median number of calls per patient over the entire observation period was 2 (range 0 to 50; n ¼ 653). About half of the patients (n ¼ 658 of 1423; 46.2%) were given a treatment diary at study entry. At the final examination, most patients (n ¼ 477 of 601; 79.4%) were documented as completing the treatment diary fully and meticulously across all cycles. See Patient expectations for details of expectations regarding the treatment diary. www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 5. Expectations before and after treatment. Expectation
Before treatment n (n%)*
No need for port system Fewer side effects Conduct of treatment made easier through diary use Improved management of daily routine More time at home More time for personal things More time flexibility at work No expectations
After treatment n (n%)y
(N ¼ 1481)
Expectation met
Expectation not met
Unassessable
696 (47.0) 662 (44.7) 225 (15.2) 897 (60.6) 652 (72.7) 399 (44.5) 80 (8.9) 229 (15.5)
– – 146/212 (68.9) – 428/600 (71.3) 276/370 (74.6) 61/79 (77.2) –
– – 15/212 (7.1) – 67/600 (11.2) 34/370 (9.2) 8/79 (10.1) –
– – 51/212 (24.1) – 105/600 (17.5) 60/370 (16.2) 10/79 (12.7) –
100 90
Expectation met Expectation not met Unassessable
80
Question not answered
70 Percentage of patients
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
*Multiple responses permitted. yData for patients who had expectation before treatment.
60 50 40 30 20 10 0 Lifestyle expectations
Help from treatment diary
Someone always contactable at center in case of questions about treatment
Figure 1. Fulfillment of expectations after treatment (N ¼ 1481).
Discussion The purpose of this observational study was to answer five predefined questions relating to the use of capecitabinebased adjuvant therapy in patients with resected colon cancer in routine clinical care in Germany. The primary focus of the study was safety, and three of the questions related to adverse reactions. The first two of these questions were: ‘Are the reported adverse reaction rates consistent with the previously described adverse reaction profile?’ and ‘Is the safety profile identified in clinical research reproducible in routine clinical practice?’. ! 2015 Informa UK Ltd www.cmrojournal.com
Compared with patients in the X-ACT and XELOXA registration studies1,2, patients in the present study tended to be older (median age 71 years vs 61–63 years) and have a poorer ECOG performance status (ECOG 0, 42% vs 74%–85%). The ML20431 population also included some patients with stage II colon cancer, whereas X-ACT and XELOXA were restricted to stage III patients. Despite these differences, the adverse reactions most commonly documented in this study were consistent with the most common treatment-related adverse events reported in the X-ACT1 and XELOXA4 studies, although the reporting rates in the present study were generally lower. Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
737
Current Medical Research & Opinion Volume 31, Number 4
April 2015
100 90 80
Percentage of patients
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
60 60 50 40 30 20 10 0 1
2
3
4
5
6
No response
Satisfaction with conduct of treatment
1
2
3
4
5
6
No response
Coping with side effects
Figure 2. Satisfaction with the conduct of treatment and patient ability to cope with side effects of treatment (N ¼ 1481). 1 ¼ very good, 2 ¼ good, 3 ¼ satisfactory, 4 ¼ fair, 5 ¼ poor, 6 ¼ unsatisfactory.
Table 6. Telephone contact at study entry (planned) and during the observation period. Planned
Telephone contact Contact person Investigator Nursing staff Both Call initiator Center Patient Both
Observation period*
Total, n
n (%)
Total, n
n (%)
1427
1035 (72.5)
1472
797 (54.1)
507 507 507
256 (50.6) 118 (23.3) 133 (26.2)
1481 1481 1481
395 (26.7) 167 (11.3) 100 (6.8)
755 755 755
38 (5.0) 568 (75.2) 149 (19.7)
1481 1481 1481
129 (8.7) 409 (27.6) 62 (4.2)
*At least one contact. Patients were counted more than once if the contact person/initiator changed during the documentation period.
For example, all-grade and grade 3/4 diarrhea were reported in 46% and 11% of patients in the X-ACT trial with capecitabine monotherapy1 and in 60% and 19% of patients in the XELOXA trial with capecitabine plus oxaliplatin4 compared with 34% and 3% of patients in the present trial, respectively. Anemia which is recognized as a frequent (monotherapy) or very frequent (combination therapy) adverse event associated with capecitabine across all indications7,8 was reported in 32% of patients in this study. Lower reporting rates have been noted in other 738
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
observational studies possibly because of increased awareness of the toxicity profile of the study drug leading to better patient selection and earlier intervention6 or because of under-reporting. Capecitabine dose adjustments were required in 37% of patients in the present study, which is also consistent with the reporting rates in the phase III trials (XELOXA, 30%; X-ACT, 42%)3,4. These findings suggest that the safety profile of capecitabine-based adjuvant therapy documented in interventional clinical trials is reproducible in routine clinical practice, although the incidence rates, particularly for grade 3/4 events, are lower. The last study question about safety was ‘Do any previously undocumented adverse drug reactions occur with the treatment regimens used in practice?’. Most grade 3/4 adverse reactions captured in free text in the CRFs or reported separately as serious events have been previously described in association with capecitabine7. Some previously undocumented adverse events were observed but these were rare (i.e. reported in one or two patients). As the study was powered to detect 1/1000 events at least four times, it is likely that these can be viewed as random events. In addition, the patient population in the present study had a range of concurrent conditions that were not limited by any formal eligibility criteria. Some patients were also receiving concomitant medications, one or more other chemotherapeutic or targeted agents or www.cmrojournal.com ! 2015 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
radiotherapy in combination with capecitabine. It is possible that these also may have contributed to some of the rare events. The fourth study question was ‘What dosages, regimens (mono- and combination therapies) and administration schedules are used in routine practice?’ The dosage data indicated that the median capecitabine doses selected for patients treated with monotherapy (1250 mg/m2 twice daily) or combination therapy (1000 mg/m2 twice daily) were consistent with the dosage recommendations for this drug. There was a slight decrease in the mean capecitabine daily doses over the course of treatment indicating that dose reductions were made in some patients. The mean duration of treatment was 162 days, which is also consistent with the capecitabine prescribing information (168 days or 24 weeks). Most patients (59%) received eight cycles of therapy as recommended. Oxaliplatin was by far the most commonly used combination agent, which is consistent with the revised labeling issued for capecitabine in Europe in 2010. Bevacizumab, cetuximab and irinotecan were also selected as combination agents in a few patients, possibly because of their established efficacy in metastatic colorectal cancer, although all have subsequently been shown to have no efficacy in the adjuvant setting9–13. The data from this study confirm that the doses, schedules and regimens of capecitabine selected by investigators are consistent with the capecitabine prescribing information and labeling. The final study question was ‘What are the reasons for discontinuing treatment?’. Discontinuation of capecitabine was documented in 23% of patients. When participation in the study, and hence presumably treatment, ended prematurely, the reasons given were mostly related to tolerability. Other reasons given for early withdrawal from the study were as expected for an oncology population (i.e. refusal of further treatment, loss of contact, recurrence, progression, etc.). In addition, patients’ expectations of oral treatment were evaluated. At study entry, between 40% and 60% of patients expected that oral therapy with capecitabine would improve the management of their daily routine, eliminate the need for a port system, or have fewer side effects than intravenous treatment. At the end of treatment, most patients (62%) were satisfied with the conduct of treatment (‘very good’ or ‘good’ score). Specific expectations relating to improvements in the management of their daily routine were also met in a high proportion of patients (71% to 77%). Although the questions and rating system used in our study were unique, similar high rates of patient satisfaction with oral chemotherapy have been previously documented in the National Surgical Adjuvant Breast and Bowel (NSABP) C-06 study14. In this study, 70% of patients said that they were ‘very satisfied’ with oral treatment. ! 2015 Informa UK Ltd www.cmrojournal.com
April 2015
Experience with capecitabine has shown that it is essential that patients can recognize adverse events so that they can be managed appropriately. Patient education and ongoing contact with the oncology team is important when chemotherapeutic agents, like capecitabine, are taken on an outpatient basis over long periods15. Our study showed that there was at least one telephone contact made with 54% of patients during the observation period. At treatment end, a high proportion of patients (77%) indicated that there was always someone contactable at the center. In addition, a treatment diary was issued to just under half of the patients (46%). As well as providing a calendar for patients to record details of their treatment and any adverse events, the diary also includes information on common adverse events and the steps that should be taken if these occur. Most patients (79%) completed the diary reliably, and most patients (69%) who had expected the treatment diary to be helpful, confirmed that this was the case after treatment. These data suggest that oncology clinics and practices in Germany offer a high and effective level of support to patients receiving oral chemotherapy. It is possible that this was a contributing factor to the low rates of adverse reactions documented in this study. Our study was conducted to collect data that reflected the care received by patients under routine clinical circumstances. Investigators were completely free to decide which patients to treat with the study drug, what diagnostic measures to take, how to monitor treatment, and what comedications to prescribe. Almost 1500 patients were enrolled from 203 centers located all over Germany. The patients enrolled in our study tended to be older and have a poorer performance status than those in the capecitabine registration trials1,2 and our data provide insight into the safety of capecitabine-based adjuvant therapy in these more vulnerable patients. It is likely that the findings of this study are highly generalizable to a broad patient population typically observed in clinical practice in Germany, although their relevance to other countries is unknown. No data regarding treatment efficacy, in terms of diseasefree survival or overall survival, were collected in the present study. Patients were followed for approximately 6 months only, which would have been inadequate to assess any post-treatment survival outcomes. A small proportion of patients (1.6%) received additional chemotherapeutic or targeted agents in combination with capecitabine plus oxaliplatin which may have contributed to the occurrence of rare adverse events. A few patients (51.5%) had partial retrospectively documented data that was not part of the study plan. The possibility of selection bias cannot be excluded for these patients. The questions and scoring systems used to evaluate patients’ expectations and satisfaction were developed for the present study and were not formally validated. This observational study shows that the safety profile of capecitabine-based adjuvant therapy in a broad patient Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
739
Current Medical Research & Opinion Volume 31, Number 4
April 2015
population is consistent with that previously documented in phase III clinical trials. There was no strong evidence of previously unknown adverse reactions.
Transparency
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Declaration of funding ML20431 was sponsored by Roche Pharma AG, GrenzachWyhlen, Germany. Declaration of financial/other relationships D.G. has disclosed that she has received grant funding and been on a speaker’s bureau for Roche Pharma AG. B.T. has disclosed that she has been a consultant/advisor for Roche, Amgen and Vifor Pharma. C.-C.S. has disclosed that he has been a consultant/advisor for Roche, Sanofi, Amgen, and GlaxoSmithKline. T.W. has disclosed that he is an employee of Roche and owns stock in the company. C.S., G.J., A.-R.V., P.S., R.H., and H.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments In addition to the investigators in the author list, we would like to acknowledge the following investigators who also participated in this study: U. Abt, Burladingen; K. Akrivakis, Hamburg; A. Ammon, Go¨ttingen; H. Arzberger, Meiben; M. Abmann, Riesa; M. Becker, Porta Westfalica; M. Begemann, Hamburg; U. Behn, Haltern; R. Behrens, Halle (Saale); J. Behringer, Speyer; H. Berkermann, Eschwege; M. Bertram, Hamburg; M. Bischoff, Idar-Oberstein; K. Blumenstengel, Eisenach; B. Bohnsteen, Dessau; H. Bolouri, Kiel; D. Bosse, Mu¨nchen; F. Breuer, Frechen; L. Brinkmann, Laatzen; U. Bu¨ckner, Bochum; K.-U. Da¨bler, Freital; L. Dietze, Ko¨ln; H. Dietzfelbinger, Herrsching; S. Do¨rfel, Dresden; H.-W. Du¨bbers, Ahaus; E. Eggers, Torgau; P. Ehscheidt, Neuwied; M. Eichstaedt, Du¨ren; W. Elsel, Zwickau; H. Eschenburg, Gu¨strow; L. Fechner, Halle (Saale); H. Fiechtner, Stuttgart; T. Fietz, Singen; L. Fischer von Weikersthal, Amberg; U. Fleck, Luckenwalde; H. Forstbauer, Troisdorf; S. Frank-Gleich, Halle/Saale; S. Fries, Bamberg; S. Fru¨hauf, Osnabru¨ck; S. Fuxius, Heidelberg; S. Gebhard, Fulda; S. Gerhardt, Gera; J. Germeroth, Reichenbach; F. Gieseler, Kiel; T. Go¨hler, Dresden; M. Groschek, Wu¨rselen; M. Grundeis, Chemnitz; M. Gru¨ner, Weiden; J. Haessner, Wolfsburg; L. Hahn, Herne; C. Hancken, Stade; D. Hartwigsen, Flensburg; H. Hass, Scheidegg; H. Hebart, Mutlangen; S. HegewischBecker, Hamburg; P. Hegener-Tschochner, Du¨sseldorf; K. Heine, Wolfsburg; W. Heinz, Leonberg; M. Hensel, Mannheim; A. Herbrich, Dortmund; J. Hebling, Berlin; U. Hieber, Mannheim; C. Hinske, Wu¨rselen; M. Hoesl, Nu¨rnberg; H.-G. Ho¨ffkes, Fulda; J. Hoffmann, Ludwigshafen; H.-J. Hurtz, Halle/Saale; U. Hutzschenreuter, Nordhorn; E. Ho¨ring, Stuttgart; H. Hu¨lsheger, Peine; L. Jacobasch, Dresden; H.-P. Jungbluth, Neuwied; T. Kamp, Wendlingen; M. Karch, Simmern; J. Kern, Wu¨rzburg; M. Kindler, Berlin; D. Kingreen, Berlin; H. Kirchner, Hannover; A. Kirsch, Berlin; J. Kisro, 740
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
Lu¨beck; M. Klein, Wiesbaden; J. Knoblich, Lo¨rrach; Y.D. Ko, Bonn; U. Koch, Bad Soden; M. Koenigsmann, Hannover; A. Ko¨hler, Langen; A. Kohlstedt, Zwickau; G. Kojouharoff, Darmstadt; S. Korsten, Bergisch Galdbach-Bensberg; S. Kremers, Lebach; W. Ku¨hn, Berlin; I. Ku¨hne, Weibenfels; F. Kullmann, Weiden; K. Ku¨rner, Gifhorn; F. Lange, Bonn; C. Lerchenmu¨ller, Mu¨nster; R. Lipp, Hamburg; C. Longin, Berlin; S. Luft, Lehrte; B. Luhn, Hamburg; A. Lu¨ck, Rostock; C. Maas, Halberstadt; S. Mahlmann, Kaiserslautern; D. Mainka, Ko¨ln; C. Maintz, Wu¨rselen; F. Marquard, Celle; U. Martens, Heilbronn; B. Massner, Schriesheim; M. Matthias, Buckow; H. Messmann, Augsburg; D. Meyer, Go¨ttingen; G. Michl, Mu¨nchen; J. Mittermu¨ller, Germering; E. Moorahrend, Porta Westfalica; S. Mu¨ller-Hagen, Hamburg; A. Ohmenha¨user, Bo¨blingen; J. Ollech-Chwoyka, Ludwigslust; P. Panagiotou, Garbsen; J. Papke, Neustadt/Sachsen; V. Petersen, Heidenheim; B. Peuser, Leipzig; M. Plath, Augsburg; P. Porowski, Heilbronn; D. Pott, Bottrop; M. Pross, Berlin; L. Pru¨gl, Zwiesel; G. Puchtler, Rosenheim; J. Rauh, Witten; C. Reddemann, Leverkusen; G. Reich, Berlin; M. Reiser, Ko¨ln; B. Rendenbach, Trier; D. Reschke, Oldenburg; F. Risse, Remagen; S. Ro¨sel, Gu¨tersloh; O. Rubanov, Hameln; K. Ruffert, Jena; U. Sauer, Nordhorn; T. Schanz, Chemnitz; M. Schauer, Nu¨rnberg; U. Schellenberger, Wilhelmshaven; B. Scheuer, Pirmasens; R. Schlag, Wu¨rzburg; A. Schmidt, Cottbus; R. Schmits, Saarbru¨cken; J. Schmitz, Arnsberg; M. Schmitz, Mayen; U. Schneider, Berlin; B. Scho¨ttker, Wu¨rzburg; D. Schro¨der, Hannover; J. Schro¨der, Mu¨lheim; C. Schulz, Bad Kreuznach; M. Schulze, Zittau; M. Schwarz, Scho¨neck; A. Schwarzer, Leipzig; M. Schweigert, Berlin; C. Schweinitz, Gera; U. Schwinger, Stuttgart; K.-D. Schu¨rer, Leipzig; S. Schu¨tz, Bremerhaven; G. Seipelt, Bad Soden; J. Selbach, Duisburg; K. Sieg, Mu¨lheim; U. So¨ling, Kassel; J. Spes, Alto¨tting; C. Spohn, Halle; M. Stauch, Kronach; K. Stengele, Singen; N. Steudel, Halle (Saale); F. Strohbach, Berlin; P. Stu¨bs, Magdeburg; I. Tamm, Berlin; H. Tanzer, Bad Reichenhall; M. Teich, Chemnitz; H. Tessen, Goslar; K. Tischbirek, Wiesbaden; G. Triebkorn, Weibenfels; D. Tummes, Aachen; J. Uhlig, Naunhof; U. Vehling-Kaiser, Landshut; K. Verpoort, Hamburg; A. Vo¨lkl, Mu¨nchen; M. von Staden, Hamburg; W. Weber, Homberg (Efze); R. Weinberg, Aachen; G. Weibenborn, Twistringen; M. Welslau, Aschaffenburg; J. Wierecky, Hamburg; S. Wilhelm, Gu¨strow; F. Winkler, Laatzen; M. Wo¨hr, Plu¨derhausen; H. Wolf, Dresden; I. Wo¨llner, Mainz; J. Zimber, Nu¨rnberg; K. Zuchold, Berlin. Support for third-party writing assistance for this manuscript, provided by Miller Medical Communications, was funded by Roche Pharma AG. Previous presentation: Presented in part at the European Society for Medical Oncology (ESMO) 13th World Congress on Gastrointestinal Cancer, 22–25 June 2011, Barcelona, Spain.
References 1. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-704 2. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-71
www.cmrojournal.com ! 2015 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
3. Scheithauer W, McKendrick J, Begbie S, et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003;14:1735-43 4. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 2007;25:102-9 5. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110-15 6. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with Folfox, Xelox, Folfiri and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009;20:1842-7 7. Xeloda Summary of Product Characteristics, Roche Registration Limited, February 2006. Available at: http://www.ema.europa.eu/ema/index.jsp?curl¼pages/medicines/human/medicines/000316/human_med_001157. jsp&mid¼WC0b01ac058001d124 [Last accessed 9 December 2013] 8. Xeloda Highlights of Prescribing Information, Genentech USA Inc., October 2014. Available at: http://www.gene.com/patients/medicines/xeloda [Last accessed 22 October 2014] 9. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012;307:1383-93
! 2015 Informa UK Ltd www.cmrojournal.com
April 2015
10. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 2012;13:1225-33 11. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 2011;29:11-16 12. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007;25:3456-61 13. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009;27:3117-25 14. Kopec JA, Yothers G, Ganz PA, et al. 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. J Clin Oncol 2007;25:424-30 15. Chau I, Legge S, Fumoleau P. The vital role of education and information in patients receiving capecitabine (Xeloda). Eur J Oncol Nurs 2004;8 (Suppl 1):S41-53
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
741
Vol. 31, No. 4, 2015, 731–741
Article ST-0414.R1/1014030 All rights reserved: reproduction in whole or part not permitted
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Original article Observational study of adjuvant therapy with capecitabine in colon cancer Claus-Christoph Steffens MVZ Ha¨matologie/Onkologie Klinik Dr. Hancken, Stade, Germany
Barbara Tschechne Klinikum Neustadt am Ru¨benberge, Neustadt am Ru¨benberge, Germany
Christof Schardt Onkologische Praxis, Gelsenkirchen, Germany
Georg Jacobs Praxis fu¨r Ha¨matologie und Onkologie, Saarbru¨cken, Germany
Annette-Rosel Valdix Onkologische Schwerpunktpraxis, Schwerin, Germany
Peter Schmidt Onkologische Gemeinschaftspraxis Dr. Schmidt & Dr. Klaproth, Neunkirchen, Germany
Richard Hansen Praxis fu¨r Onkologie Kaiserslautern, Kaiserslautern, Germany
Hendrik Kro¨ning Schwerpunktpraxis fu¨r Ha¨matologie und Onkologie, Magdeburg, Germany
Tim Wohlfarth Roche Pharma AG, Grenzach-Wyhlen, Germany
Dorothee Guggenberger Onkologische Schwerpunktpraxis, Aachen, Germany Address for correspondence: Dr. Claus-Christoph Steffens MVZ, Ha¨matologie/ Onkologie Klinik Dr. Hancken, Harsefelder Strasse 8, 21680 Stade, Germany. Tel.: +49 4141-604-147; [email protected] Keywords: Adjuvant chemotherapy – Administration and dosage – Capecitabine – Colonic neoplasms – Oxaliplatin – Patient satisfaction – Safety Accepted: 27 January 2015; published online: 12 February 2015 Citation: Curr Med Res Opin 2015; 31:731–41
Abstract Objective: This observational study was conducted to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. Research and design methods: ML20431 was a prospective, multicenter, non-interventional, observational study. It was designed to answer five research questions relating to safety, dosage and administration, and discontinuation from capecitabine-based adjuvant therapy. Patients were required to have R0 resected stage III colon cancer and have started treatment with capecitabine-based adjuvant therapy based on a decision by the investigator. Patients were followed over an observation period of 6 months after initiation of therapy. Investigators were required to complete the study case report form at study entry, each treatment cycle, and at the final examination. Main outcome measures: A total of 1485 patients were included in the study, and 1481 patients were treated with capecitabine and formed the analysis population. Most patients had colon cancer (78.3%), followed by rectal cancer (16.4%). Most patients had stage III disease (69.3%); the remaining patients had stage II disease (30.7%). The most common all-grade adverse reactions were hand–foot syndrome (46.9%), diarrhea (34.4%), and hemoglobin decreases (31.5%). Grade 3/4 adverse reactions were infrequent (54%). Serious adverse events were reported in 96 patients (6.5%). Six or more cycles of treatment were completed by 77.9% of patients. Approximately two-thirds of patients (67.3%) received capecitabine monotherapy and the remainder (32.7%) received capecitabine in combination with 1 drugs, most commonly oxaliplatin (460 cases). Discontinuation of capecitabine was documented in 344 patients (23.2%). Study limitations: no efficacy data were collected; the questionnaires for patients’ expectations and satisfaction were not formally validated; and a few patients (51.5%) had some retrospective data. Conclusions: The safety profile of capecitabine-based adjuvant therapy in a broad patient population with colon cancer is similar to that previously documented in phase III clinical trials.
Introduction Capecitabine (Xeloda*), an oral fluoropyrimidine, is widely approved for adjuvant therapy in early-stage colon cancer. This is based on the findings from two randomized phase III clinical trials – X-ACT (Xeloda in Adjuvant Colon Cancer Therapy; M66001)1 and XELOXA (XELOX Adjuvant; NO16968)2. The X-ACT trial demonstrated that capecitabine was at least equivalent to intravenous 5-fluorouracil/leucovorin (5-FU/LV) in patients with resected stage III colon cancer1. In this study, capecitabine (1250 mg/m2 twice daily on *
! 2015 Informa UK Ltd www.cmrojournal.com
Xeloda is a registered trade name of F. Hoffmann La Roche
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
731
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
April 2015
days 1–14 every 21 days for 24 weeks) was compared with a bolus schedule of 5-FU/LV (Mayo Clinic regimen). The intention-to-treat population comprised 1987 patients (capecitabine, n ¼ 1004; 5-FU/LV, n ¼ 983). After 3 years, disease-free survival was equivalent in patients receiving capecitabine versus 5-FU/LV (hazard ratio 0.87, 95% confidence interval 0.75–1.00); the upper limit of the confidence interval was significantly below both predefined margins (1.25 and 1.20) for at least equivalence (p50.001). Capecitabine had an improved safety profile compared with bolus 5-FU/LV, and was associated with significantly less diarrhea, nausea or vomiting, stomatitis, alopecia, and neutropenia, but more hand–foot syndrome and hyperbilirubinemia3. The XELOXA study compared oxaliplatin (130 mg/m2 on day 1) plus capecitabine (1000 mg/m2 twice daily on days 1–14 plus every 21 days for 24 weeks) with a bolus schedule of 5-FU/LV (Mayo Clinic or Roswell Park regimens) in patients with resected stage III colon cancer2. The intention-to-treat population comprised 1886 patients (capecitabine plus oxaliplatin, n ¼ 944; 5-FU/ LV, n ¼ 942). The addition of oxaliplatin to capecitabine improved 3 year disease-free survival compared with 5-FU/ LV (hazard ratio 0.80; 95% confidence interval 0.69–0.93; p ¼ 0.0045). Most treatment-related adverse events occurred at similar rates in the study treatment arms; however, patients receiving capecitabine plus oxaliplatin experienced less diarrhea and alopecia, but more neurosensory toxicity, vomiting, and hand–foot syndrome than those receiving 5-FU/LV4. Historical data suggest that most patients prefer oral chemotherapy, provided that efficacy is not compromised5. This preference is based on the convenience of receiving chemotherapy at home and avoidance of intravenous access. However, chemotherapy at home also poses several challenges for the oncology care team. Education of patients is important so that they can recognize and report adverse events promptly. Ongoing support for patients from the practice is also necessary to assist with any concerns regarding treatment. This non-interventional, observational study (ML20431) was conducted to determine the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical practice conditions in Germany. As well as monitoring adverse events, details of capecitabine treatment (i.e. dose, duration, combination agents, etc.) were documented during the study observation period. Patient expectations and patient contact were also evaluated. The study was initiated in 2006, when only single-agent capecitabine was approved for adjuvant therapy, and finished in 2012, by which time capecitabine plus oxaliplatin had also been approved for use as adjuvant therapy in Europe. The study therefore covers a period when capecitabine monotherapy and, later, combination 732
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
therapy were possible choices available to participating investigators.
Patients and methods Study design ML20431 was a prospective, multicenter, non-interventional, observational study designed to document the safety of capecitabine-based adjuvant therapy in patients with resected colon cancer under routine clinical conditions. The study was conducted in hospital departments, outpatient clinics and oncology practices in Germany. The conduct of the study did not influence the treatment procedure of individual patients, and had no influence on medical decisions and procedures. Study investigators were completely free to decide which patients to treat with the study drug, which dosage to choose, which diagnostic measures to take, how to monitor the course of treatment, and which accompanying or additional medication(s) to prescribe. The appointments for each patient with their physician were determined individually. The study complied with the German Medicinal Products Act (‘Arzneimittelgesetz’; section 67, subsection 6). Although a formal review of the study observation plan by an ethics committee was not performed, it was permissible for study investigators to obtain advice from their local ethics committee regarding the observation plan.
Study questions The study was conducted to address the following questions: Are the reported adverse reaction rates consistent with the previously described adverse reaction profile? Is the safety profile identified in clinical research reproducible in routine clinical practice? Do any previously undocumented adverse drug reactions occur with the treatment regimens used in practice? What dosages, regimens (mono- and combination therapies) and administration schedules are used in routine practice? What are the reasons for discontinuing treatment?
Patients Patients who were enrolled had Union Internationale Contre le Cancer (UICC) stage III (Dukes’ C) colon cancer and required adjuvant drug treatment following successful (R0) surgery and for whom the investigator had made an individual decision, outside the study, to www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
start treatment with capecitabine. Treatment was to be based on daily medical requirements and the current prescribing information for relevant drugs. Patients were followed over an observation period of up to 6 months after the initial dose of adjuvant therapy.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Documentation and investigation variables The observation period was divided into study entry (or baseline), each treatment cycle and a final examination. Investigators were asked to complete the study case report form (CRF) at each of these time-points. The CRF was designed to reflect the normal course of treatment as closely as possible. Treatment Variables concerning treatment and administration included the duration of treatment, number of cycles, capecitabine dose, use of monotherapy or combination therapy, combination drugs given with capecitabine, treatment interruptions, duration of treatment interruptions, dose adjustments, reasons for dose adjustments, and treatment discontinuations. The details of treatment were recorded at study entry and at each treatment cycle. If treatment was discontinued early (i.e. before completion of eight cycles), the reason for premature withdrawal was documented. Safety In this study, adverse reactions were defined as toxicities whose cause was given as ‘Xeloda’, ‘not assessable’, or ‘unknown’. All adverse reactions were recorded on the CRF. The CRF contained a list of predefined toxicities (i.e. decreased hemoglobin, decreased leucocytes, decreased granulocytes, decreased thrombocytes, increased bilirubin, nausea, vomiting, diarrhea, mucocitis/stomatitis, motor function, alopecia, hand–foot syndrome, fever, pain). Any other toxicities could also be documented by the investigator using free text. The intensity of adverse reactions was graded according to the toxicity categories of the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. Serious adverse events were also reported separately on a dedicated form.
April 2015
more time at home, more time for personal things, more time flexibility at work. At the end of the observation period, patients were asked if their expectations regarding lifestyle, the treatment diary and patient support had been met. Patients were also asked to rate their overall satisfaction with the conduct of treatment and their ability to cope with side effects on a 6-point scale (1 ¼ very good, 2 ¼ good, 3 ¼ satisfactory, 4 ¼ fair, 5 ¼ poor, 6 ¼ unsatisfactory). At study entry, patients were asked if they planned to have any telephone contact with the center. In addition, patients were asked to clarify whether the contact was to be with the investigator or the nursing staff. Patients were also asked whether calls were to be made by the center, by themselves or both. Investigators also documented whether or not patients were given a treatment diary. At each treatment cycle and the final examination, the questions regarding telephone contact were repeated and patients were also asked if they had completed the treatment diary carefully and completely.
Statistical analysis The analysis population was defined as all prospectively documented patients who were treated with capecitabine. The sample size was based on the analysis of safety. The original planned sample size was 850 patients. This was amended to 1000 patients in September 2010 to allow for the revised labeling of capecitabine, i.e. use of capecitabine in combination with oxaliplatin. In a sample of 1000 patients, adverse reactions with an incidence of between 1/100 and 1/1000 were expected to occur with over 99.9% probability. This sample size was sufficient to observe such an adverse reaction or interaction at least four times with a probability of 99.0%; 95% confidence intervals for adverse reaction incidence rates would have a maximum width of 3.1%. It was anticipated that 320 patients would receive combination therapy with capecitabine and oxaliplatin; for this subgroup, events with an incidence of 1/100 were expected to occur at least once with a probability of 95%. The data were analyzed in a descriptive manner. Analyses were performed using SAS software, version 8.2.
Results Patient expectations and contact At study entry, each patient was asked specific questions about their expectations regarding oral treatment, i.e. freedom from port, fewer side effects, ability to manage daily routine better, and conduct of treatment made easier by use of a treatment diary. Patients indicating that they expected improved management of their daily routine were further asked about the possible advantages, i.e. ! 2015 Informa UK Ltd www.cmrojournal.com
Patient population A total of 1485 patients were included in the study at 203 centers in Germany between February 2006 and November 2012. Of these, 1481 patients were treated with capecitabine and formed the analysis population. The following protocol violations were documented in the analysis population: no successful surgery (n ¼ 119); Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
733
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 1. Baseline patient demographics and characteristics.
Table 2. Chemotherapeutic and targeted agents given in combination with capecitabine.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Analysis population (N ¼ 1481) Age, years Median (range) Gender, n (%) Male Female Body surface area, m2 Median (range) ECOG performance status, n (%) 0 1 2 3 Cancer diagnosis, n (%)* Colon cancer Rectal cancer Rectosigmoid cancer Colorectal cancer UICC stage, n (%) II III Time from surgical resection, n (%) 8 weeks 48 weeks Carcinoembryonic antigen, ng/mL Mean (SD) Employed, n (%) No Yes
71 (20–93) 820 (55.5) 657 (44.5) 1.8 (1.0–2.8) 594 (41.7) 710 (49.9) 110 (7.7) 9 (0.6) 1159 (78.3) 243 (16.4) 53 (3.6) 15 (1.0) 434 (30.7) 979 (69.3) 1012 (74.5) 346 (25.5) 2.6 (4.2) 1228 (86.9) 185 (13.1)
*Most common diagnoses listed only. ECOG ¼ Eastern Cooperative Oncology Group; SD ¼ standard deviation; UICC ¼ Union Internationale Contre le Cancer.
retrospective documentation (n ¼ 22); other diagnosis (n ¼ 8); no information on diagnosis (n ¼ 7); and no post-baseline value (n ¼ 1). The median duration of observation was 180 (range 4 to 583) days. In the analysis population, a total of 588 (39.7%) patients withdrew early from the study. Reasons for early withdrawal (multiple responses permitted) were: severe adverse reactions (n ¼ 178, 12.0%); refusal of treatment (n ¼ 125, 8.4%); end of treatment regimen (i.e. shorter than eight cycles, n ¼ 111, 7.5%); adverse event (n ¼ 57, 3.8%); no further contact with patient/patient did not attend (n ¼ 37, 2.5%); recurrence (n ¼ 27, 1.8%); death (n ¼ 18, 1.2%); progression (n ¼ 13, 0.9%); and other reasons (n ¼ 88; 5.9%). A summary of baseline patient demographics and disease characteristics is shown in Table 1. The median age of the patient population was 71 (range 20 to 93) years; approximately two-thirds of patients (n ¼ 1000; 67.8%) were over 65 years. The most common tumor diagnosis was colon cancer (78.3%) followed by rectal cancer (16.4%). While most patients (69.3%) had stage III disease, almost one-third (30.7%) had stage II disease. Most patients (86.9%) were no longer working. At least one coexisting condition was documented in 15.3% (n ¼ 227) of 734
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
Analysis population (N ¼ 1481) No combination therapy Combination therapy Oxaliplatin Bevacizumab, oxaliplatin Bevacizumab Irinotecan Bevacizumab, irinotecan Cetuximab, oxaliplatin Epirubicin, oxaliplatin 5-Fluorouracil Cisplatin, epirubicin Dexamethasone, oxaliplatin Folinic acid, oxaliplatin Melphalan Monoclonal antibodies, oxaliplatin Oxaliplatin, saccharated iron oxide Paclitaxel
996 (67.3%) 485 (32.7%) 460 (31.1%) 10 (0.7%) 9 (0.6%) 6 (0.4%) 3 (0.2%) 2 (0.1%) 2 (0.1%) 2 (0.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%) 1 (50.1%)
All cycles are included in the table, so a patient may be represented more than once. If two agents are shown on one line, the patient received both agents in one cycle.
patients. The most common disorder was hypertension (n ¼ 113; 7.6%); no other condition occurred in more than 5% of patients.
Treatment In the analysis population, the mean duration of treatment was 162 (standard deviation [SD] 59) days and the median treatment duration was 173 (range 22 to 572) days. Most patients (n ¼ 880, 59.4%) completed eight cycles of treatment. Six or more cycles were completed by 1154 patients (77.9%). In the analysis population, approximately two-thirds of patients (n ¼ 996; 67.3%) received capecitabine as monotherapy. All other patients (n ¼ 485; 32.7%) received capecitabine in combination with one or more drugs. A summary of drugs given in combination with capecitabine is shown in Table 2. The agent most commonly selected for use in combination with capecitabine was oxaliplatin (460 cases). Bevacizumab was listed either alone or in combination with oxaliplatin or irinotecan in 22 cases, while other chemotherapeutic drugs were documented only sporadically (irinotecan, nine cases; epirubicin, three cases). Radiotherapy was carried out simultaneously with at least one treatment cycle in 112 patients (7.5%). A summary of capecitabine daily doses by the type of treatment regimen is presented in Table 3. In patients treated with capecitabine monotherapy, the median daily dose throughout treatment was 2500 mg/m2, although the mean daily dose decreased slightly from 2582 mg/m2 at the start of treatment to 2454 mg/m2 at cycle 8. In patients treated with combination therapy, www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 3. Capecitabine daily doses by type of treatment regimen.
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Timepoint
Inclusion visit** n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 1 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 2 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 3 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 4 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 5 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 6 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 7 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day Cycle 8 n Mean (SD) dose, mg/m2/day Median dose, mg/m2/day
Monotherapy
Combination therapy All combinationsy
With oxaliplatin
863 2581.5 (874.0) 2500.0
410 2189.4 (707.9) 2000.0
397 2177.4 (691.3) 2000.0
861 2537.7 (847.7) 2500.0
419 2166.7 (702.0) 2000.0
406 2154.3 (685.0) 2000.0
826 2561.7 (850.8) 2500.0
397 2165.6 (714.6) 2000.0
383 2151.1 (699.5) 2000.0
796 2544.4 (841.5) 2500.0
367 2144.4 (725.7) 2000.0
355 2134.2 (724.5) 2000.0
755 2528.6 (842.7) 2500.0
348 2154.9 (732.7) 2000.0
337 2144.3 (731.5) 2000.0
713 2480.0 (855.6) 2500.0
328 2157.8 (721.8) 2000.0
318 2153.2 (723.1) 2000.0
682 2460.5 (868.4) 2500.0
305 2159.2 (733.4) 2000.0
295 2155.2 (734.5) 2000.0
607 2451.5 (859.9) 2500.0
238 2097.7 (705.8) 2000.0
230 2097.7 (713.5) 2000.0
539 2454.1 (825.3) 2500.0
206 2069.5 (699.1) 2000.0
201 2066.3 (702.8) 2000.0
SD ¼ standard deviation. Patient classification by type of regimen was decided on the basis of the treatment planned for cycle 1. yAll patients on combination therapy with oxaliplatin are included in the combination therapy subgroup. **Planned doses.
the median daily capecitabine dose throughout treatment was 2000 mg/m2; the mean daily dose showed a small reduction from 2189 mg/m2 at the start of treatment to 2070 mg/m2 at cycle 8. Overall, 541 of 1467 evaluable patients (36.9%) required at least one dose adjustment during the total observation period. In patients requiring dose adjustments (n ¼ 541), most were due to adverse events, specifically hand–foot syndrome (n ¼ 180; 33.3%), diarrhea (n ¼ 75, 13.9%) or other events (n ¼ 281; 51.9%). Other reasons commonly given for performing dose adjustments were an individually planned treatment regimen (n ¼ 74; 13.7%) and good tolerability (n ¼ 74; 13.7%). The median number of dose adjustments per patient was 1 (range 1 to 8). Overall, 391 of 1477 evaluable patients (26.5%) had at least one treatment interruption over the total observation period. Among patients with treatment interruptions (n ¼ 391), 280 patients required one interruption, ! 2015 Informa UK Ltd www.cmrojournal.com
77 patients required two treatment interruptions and 34 patients required three or more treatment interruptions. The maximum number of treatment interruptions documented for a patient was nine. The median duration of all treatment interruptions per patient was 10 (range 1 to 127) days. Discontinuation of capecitabine was documented in 344 of 1481 patients (23.2%); 247 patients discontinued capecitabine alone and 97 patients discontinued capecitabine and combination drug(s). A further 77 patients discontinued combination drug(s) alone.
Safety A summary of all-grade and grade 3/4 adverse reactions reported during the observation period in the analysis population (n ¼ 1481) is presented in Table 4. The most common all-grade adverse reactions were hand–foot Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
735
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 4. Adverse reactions (N ¼ 1481).
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
No. patients (%)
Hand–foot syndrome Diarrhea Hemoglobin decrease Nausea Other Leucocyte decrease Pain Thrombocyte decrease Mucositis/stomatitis Granulocyte decrease Vomiting Bilirubin increase Alopecia Motor function* Fever
Grade 1–4
Grade 3/4
694 (46.9) 510 (34.4) 467 (31.5) 457 (30.9) 452 (30.5) 300 (20.3) 254 (17.2) 212 (14.3) 158 (10.7) 151 (10.2) 134 (9.0) 122 (8.2) 115 (7.8) 99 (6.7) 58 (3.9)
51 (3.4) 47 (3.2) 14 (0.9) 18 (1.2) 44 (3.0) 14 (0.9) 9 (0.6) 25 (1.7) 7 (0.5) 11 (0.7) 6 (0.4) 23 (1.6) 0 (0.0) 4 (0.3) 0 (0.0)
An adverse reaction was defined as a toxicity whose cause was reported as ‘Xeloda’, ‘unknown’ or ‘unassessable’. *Weakness or loss of function.
syndrome (46.9%), diarrhea (34.4%) and hemoglobin decreases (31.5%). Most adverse reactions were grade 1 or 2. The most common grade 3/4 adverse reactions were hand–foot syndrome (3.4%), diarrhea (3.2%) and thrombocyte decreases (1.7%). Other adverse reactions reported by investigators in free text on the CRF are shown in the Supplementary Table. Serious adverse events were reported in 96 of 1481 patients (6.5%). The most commonly reported events were diarrhea (n ¼ 28; 1.9%), nausea (n ¼ 10; 0.7%) and deep vein thrombosis (n ¼ 10; 0.7%). A total of 18 patients died during the study observation period. The causes of death were tumor-related (n ¼ 7), pneumonia with sepsis (n ¼ 2), heart failure (n ¼ 1), postoperative pulmonary embolism (n ¼ 1), pancreatitis (n ¼ 1), pneumonia (n ¼ 1), or no information given (n ¼ 5).
Patient expectations On study entry, patients were asked what they expected from treatment (Table 5). Expectations endorsed by patients were that oral therapy would improve the management of their daily routine (60.6%), eliminate the need for a port system (47.0%) and that there would be fewer side effects (44.7%). Some patients (15.5%) had no expectations. Patients who expected treatment to improve the management of their daily routine indicated that they hoped for ‘More time at home’ (72.7%), ‘More time for personal things’ (44.5%) and ‘More time flexibility at work’ (8.9%). At final documentation, patients were asked if their expectations had been met. The responses of patients who had stated specific expectations at study entry are 736
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
presented in Table 5. Specific expectations regarding improved management of daily routine were met in most patients (‘More time at home’, 71.3%; ‘More time for personal things’, 74.6%; ‘More time flexibility at work’, 77.2%). Over two-thirds (68.9%) of patients hoping for the treatment diary to make it easier to carry out treatment confirmed that they were helped by the diary. In addition, all patients were asked more general questions about fulfillment of their expectations; the responses to these questions in the analysis population are shown in Figure 1. Expectations regarding lifestyle and, in particular, the availability of contact persons at the center were often met, although many patients did not answer the questions or were ‘unassessable’. At the end of treatment, most patients (n ¼ 916; 61.8%) rated their satisfaction with the conduct of treatment as ‘very good’ or ‘good’ (Figure 2). Only a small proportion of patients (n ¼ 24; 1.6%) rated their experiences as ‘poor’ or ‘unsatisfactory’. Most patients (n ¼ 941; 63.5%) gave a rating of ‘very good’, ‘good’ or ‘satisfactory’ when asked if they had coped with the side effects of treatment (Figure 2). Eighty-seven patients (5.9%) rated their experiences as ‘poor’ or ‘unsatisfactory’.
Patient contact A summary of the details of telephone contacts, which were planned at study entry and which took place during the observation period, is presented in Table 6. For most patients (72.5%), it was agreed before the start of treatment that the center and patient would be in telephone contact between visits, while no telephone contact was planned for 27.5% (n ¼ 393 of 1427) of patients. At least one contact occurred during the observation period in 54.1% of patients. Before the start of treatment, it was planned that the investigator would be the contact person in over half of cases (50.6%), while the nursing staff were to serve as contacts for 23.3% of patients, and both the investigator and nursing staff for 26.2% of patients. It was planned that calls were to originate primarily from the patient (75.2%). During the observation period, the investigator was the patients’ main contact person at the center and most phone contacts were initiated by patients. The median number of calls per patient over the entire observation period was 2 (range 0 to 50; n ¼ 653). About half of the patients (n ¼ 658 of 1423; 46.2%) were given a treatment diary at study entry. At the final examination, most patients (n ¼ 477 of 601; 79.4%) were documented as completing the treatment diary fully and meticulously across all cycles. See Patient expectations for details of expectations regarding the treatment diary. www.cmrojournal.com ! 2015 Informa UK Ltd
Current Medical Research & Opinion Volume 31, Number 4
April 2015
Table 5. Expectations before and after treatment. Expectation
Before treatment n (n%)*
No need for port system Fewer side effects Conduct of treatment made easier through diary use Improved management of daily routine More time at home More time for personal things More time flexibility at work No expectations
After treatment n (n%)y
(N ¼ 1481)
Expectation met
Expectation not met
Unassessable
696 (47.0) 662 (44.7) 225 (15.2) 897 (60.6) 652 (72.7) 399 (44.5) 80 (8.9) 229 (15.5)
– – 146/212 (68.9) – 428/600 (71.3) 276/370 (74.6) 61/79 (77.2) –
– – 15/212 (7.1) – 67/600 (11.2) 34/370 (9.2) 8/79 (10.1) –
– – 51/212 (24.1) – 105/600 (17.5) 60/370 (16.2) 10/79 (12.7) –
100 90
Expectation met Expectation not met Unassessable
80
Question not answered
70 Percentage of patients
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
*Multiple responses permitted. yData for patients who had expectation before treatment.
60 50 40 30 20 10 0 Lifestyle expectations
Help from treatment diary
Someone always contactable at center in case of questions about treatment
Figure 1. Fulfillment of expectations after treatment (N ¼ 1481).
Discussion The purpose of this observational study was to answer five predefined questions relating to the use of capecitabinebased adjuvant therapy in patients with resected colon cancer in routine clinical care in Germany. The primary focus of the study was safety, and three of the questions related to adverse reactions. The first two of these questions were: ‘Are the reported adverse reaction rates consistent with the previously described adverse reaction profile?’ and ‘Is the safety profile identified in clinical research reproducible in routine clinical practice?’. ! 2015 Informa UK Ltd www.cmrojournal.com
Compared with patients in the X-ACT and XELOXA registration studies1,2, patients in the present study tended to be older (median age 71 years vs 61–63 years) and have a poorer ECOG performance status (ECOG 0, 42% vs 74%–85%). The ML20431 population also included some patients with stage II colon cancer, whereas X-ACT and XELOXA were restricted to stage III patients. Despite these differences, the adverse reactions most commonly documented in this study were consistent with the most common treatment-related adverse events reported in the X-ACT1 and XELOXA4 studies, although the reporting rates in the present study were generally lower. Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
737
Current Medical Research & Opinion Volume 31, Number 4
April 2015
100 90 80
Percentage of patients
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
60 60 50 40 30 20 10 0 1
2
3
4
5
6
No response
Satisfaction with conduct of treatment
1
2
3
4
5
6
No response
Coping with side effects
Figure 2. Satisfaction with the conduct of treatment and patient ability to cope with side effects of treatment (N ¼ 1481). 1 ¼ very good, 2 ¼ good, 3 ¼ satisfactory, 4 ¼ fair, 5 ¼ poor, 6 ¼ unsatisfactory.
Table 6. Telephone contact at study entry (planned) and during the observation period. Planned
Telephone contact Contact person Investigator Nursing staff Both Call initiator Center Patient Both
Observation period*
Total, n
n (%)
Total, n
n (%)
1427
1035 (72.5)
1472
797 (54.1)
507 507 507
256 (50.6) 118 (23.3) 133 (26.2)
1481 1481 1481
395 (26.7) 167 (11.3) 100 (6.8)
755 755 755
38 (5.0) 568 (75.2) 149 (19.7)
1481 1481 1481
129 (8.7) 409 (27.6) 62 (4.2)
*At least one contact. Patients were counted more than once if the contact person/initiator changed during the documentation period.
For example, all-grade and grade 3/4 diarrhea were reported in 46% and 11% of patients in the X-ACT trial with capecitabine monotherapy1 and in 60% and 19% of patients in the XELOXA trial with capecitabine plus oxaliplatin4 compared with 34% and 3% of patients in the present trial, respectively. Anemia which is recognized as a frequent (monotherapy) or very frequent (combination therapy) adverse event associated with capecitabine across all indications7,8 was reported in 32% of patients in this study. Lower reporting rates have been noted in other 738
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
observational studies possibly because of increased awareness of the toxicity profile of the study drug leading to better patient selection and earlier intervention6 or because of under-reporting. Capecitabine dose adjustments were required in 37% of patients in the present study, which is also consistent with the reporting rates in the phase III trials (XELOXA, 30%; X-ACT, 42%)3,4. These findings suggest that the safety profile of capecitabine-based adjuvant therapy documented in interventional clinical trials is reproducible in routine clinical practice, although the incidence rates, particularly for grade 3/4 events, are lower. The last study question about safety was ‘Do any previously undocumented adverse drug reactions occur with the treatment regimens used in practice?’. Most grade 3/4 adverse reactions captured in free text in the CRFs or reported separately as serious events have been previously described in association with capecitabine7. Some previously undocumented adverse events were observed but these were rare (i.e. reported in one or two patients). As the study was powered to detect 1/1000 events at least four times, it is likely that these can be viewed as random events. In addition, the patient population in the present study had a range of concurrent conditions that were not limited by any formal eligibility criteria. Some patients were also receiving concomitant medications, one or more other chemotherapeutic or targeted agents or www.cmrojournal.com ! 2015 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
radiotherapy in combination with capecitabine. It is possible that these also may have contributed to some of the rare events. The fourth study question was ‘What dosages, regimens (mono- and combination therapies) and administration schedules are used in routine practice?’ The dosage data indicated that the median capecitabine doses selected for patients treated with monotherapy (1250 mg/m2 twice daily) or combination therapy (1000 mg/m2 twice daily) were consistent with the dosage recommendations for this drug. There was a slight decrease in the mean capecitabine daily doses over the course of treatment indicating that dose reductions were made in some patients. The mean duration of treatment was 162 days, which is also consistent with the capecitabine prescribing information (168 days or 24 weeks). Most patients (59%) received eight cycles of therapy as recommended. Oxaliplatin was by far the most commonly used combination agent, which is consistent with the revised labeling issued for capecitabine in Europe in 2010. Bevacizumab, cetuximab and irinotecan were also selected as combination agents in a few patients, possibly because of their established efficacy in metastatic colorectal cancer, although all have subsequently been shown to have no efficacy in the adjuvant setting9–13. The data from this study confirm that the doses, schedules and regimens of capecitabine selected by investigators are consistent with the capecitabine prescribing information and labeling. The final study question was ‘What are the reasons for discontinuing treatment?’. Discontinuation of capecitabine was documented in 23% of patients. When participation in the study, and hence presumably treatment, ended prematurely, the reasons given were mostly related to tolerability. Other reasons given for early withdrawal from the study were as expected for an oncology population (i.e. refusal of further treatment, loss of contact, recurrence, progression, etc.). In addition, patients’ expectations of oral treatment were evaluated. At study entry, between 40% and 60% of patients expected that oral therapy with capecitabine would improve the management of their daily routine, eliminate the need for a port system, or have fewer side effects than intravenous treatment. At the end of treatment, most patients (62%) were satisfied with the conduct of treatment (‘very good’ or ‘good’ score). Specific expectations relating to improvements in the management of their daily routine were also met in a high proportion of patients (71% to 77%). Although the questions and rating system used in our study were unique, similar high rates of patient satisfaction with oral chemotherapy have been previously documented in the National Surgical Adjuvant Breast and Bowel (NSABP) C-06 study14. In this study, 70% of patients said that they were ‘very satisfied’ with oral treatment. ! 2015 Informa UK Ltd www.cmrojournal.com
April 2015
Experience with capecitabine has shown that it is essential that patients can recognize adverse events so that they can be managed appropriately. Patient education and ongoing contact with the oncology team is important when chemotherapeutic agents, like capecitabine, are taken on an outpatient basis over long periods15. Our study showed that there was at least one telephone contact made with 54% of patients during the observation period. At treatment end, a high proportion of patients (77%) indicated that there was always someone contactable at the center. In addition, a treatment diary was issued to just under half of the patients (46%). As well as providing a calendar for patients to record details of their treatment and any adverse events, the diary also includes information on common adverse events and the steps that should be taken if these occur. Most patients (79%) completed the diary reliably, and most patients (69%) who had expected the treatment diary to be helpful, confirmed that this was the case after treatment. These data suggest that oncology clinics and practices in Germany offer a high and effective level of support to patients receiving oral chemotherapy. It is possible that this was a contributing factor to the low rates of adverse reactions documented in this study. Our study was conducted to collect data that reflected the care received by patients under routine clinical circumstances. Investigators were completely free to decide which patients to treat with the study drug, what diagnostic measures to take, how to monitor treatment, and what comedications to prescribe. Almost 1500 patients were enrolled from 203 centers located all over Germany. The patients enrolled in our study tended to be older and have a poorer performance status than those in the capecitabine registration trials1,2 and our data provide insight into the safety of capecitabine-based adjuvant therapy in these more vulnerable patients. It is likely that the findings of this study are highly generalizable to a broad patient population typically observed in clinical practice in Germany, although their relevance to other countries is unknown. No data regarding treatment efficacy, in terms of diseasefree survival or overall survival, were collected in the present study. Patients were followed for approximately 6 months only, which would have been inadequate to assess any post-treatment survival outcomes. A small proportion of patients (1.6%) received additional chemotherapeutic or targeted agents in combination with capecitabine plus oxaliplatin which may have contributed to the occurrence of rare adverse events. A few patients (51.5%) had partial retrospectively documented data that was not part of the study plan. The possibility of selection bias cannot be excluded for these patients. The questions and scoring systems used to evaluate patients’ expectations and satisfaction were developed for the present study and were not formally validated. This observational study shows that the safety profile of capecitabine-based adjuvant therapy in a broad patient Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
739
Current Medical Research & Opinion Volume 31, Number 4
April 2015
population is consistent with that previously documented in phase III clinical trials. There was no strong evidence of previously unknown adverse reactions.
Transparency
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Declaration of funding ML20431 was sponsored by Roche Pharma AG, GrenzachWyhlen, Germany. Declaration of financial/other relationships D.G. has disclosed that she has received grant funding and been on a speaker’s bureau for Roche Pharma AG. B.T. has disclosed that she has been a consultant/advisor for Roche, Amgen and Vifor Pharma. C.-C.S. has disclosed that he has been a consultant/advisor for Roche, Sanofi, Amgen, and GlaxoSmithKline. T.W. has disclosed that he is an employee of Roche and owns stock in the company. C.S., G.J., A.-R.V., P.S., R.H., and H.K. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article. CMRO peer reviewers on this manuscript have no relevant financial or other relationships to disclose. Acknowledgments In addition to the investigators in the author list, we would like to acknowledge the following investigators who also participated in this study: U. Abt, Burladingen; K. Akrivakis, Hamburg; A. Ammon, Go¨ttingen; H. Arzberger, Meiben; M. Abmann, Riesa; M. Becker, Porta Westfalica; M. Begemann, Hamburg; U. Behn, Haltern; R. Behrens, Halle (Saale); J. Behringer, Speyer; H. Berkermann, Eschwege; M. Bertram, Hamburg; M. Bischoff, Idar-Oberstein; K. Blumenstengel, Eisenach; B. Bohnsteen, Dessau; H. Bolouri, Kiel; D. Bosse, Mu¨nchen; F. Breuer, Frechen; L. Brinkmann, Laatzen; U. Bu¨ckner, Bochum; K.-U. Da¨bler, Freital; L. Dietze, Ko¨ln; H. Dietzfelbinger, Herrsching; S. Do¨rfel, Dresden; H.-W. Du¨bbers, Ahaus; E. Eggers, Torgau; P. Ehscheidt, Neuwied; M. Eichstaedt, Du¨ren; W. Elsel, Zwickau; H. Eschenburg, Gu¨strow; L. Fechner, Halle (Saale); H. Fiechtner, Stuttgart; T. Fietz, Singen; L. Fischer von Weikersthal, Amberg; U. Fleck, Luckenwalde; H. Forstbauer, Troisdorf; S. Frank-Gleich, Halle/Saale; S. Fries, Bamberg; S. Fru¨hauf, Osnabru¨ck; S. Fuxius, Heidelberg; S. Gebhard, Fulda; S. Gerhardt, Gera; J. Germeroth, Reichenbach; F. Gieseler, Kiel; T. Go¨hler, Dresden; M. Groschek, Wu¨rselen; M. Grundeis, Chemnitz; M. Gru¨ner, Weiden; J. Haessner, Wolfsburg; L. Hahn, Herne; C. Hancken, Stade; D. Hartwigsen, Flensburg; H. Hass, Scheidegg; H. Hebart, Mutlangen; S. HegewischBecker, Hamburg; P. Hegener-Tschochner, Du¨sseldorf; K. Heine, Wolfsburg; W. Heinz, Leonberg; M. Hensel, Mannheim; A. Herbrich, Dortmund; J. Hebling, Berlin; U. Hieber, Mannheim; C. Hinske, Wu¨rselen; M. Hoesl, Nu¨rnberg; H.-G. Ho¨ffkes, Fulda; J. Hoffmann, Ludwigshafen; H.-J. Hurtz, Halle/Saale; U. Hutzschenreuter, Nordhorn; E. Ho¨ring, Stuttgart; H. Hu¨lsheger, Peine; L. Jacobasch, Dresden; H.-P. Jungbluth, Neuwied; T. Kamp, Wendlingen; M. Karch, Simmern; J. Kern, Wu¨rzburg; M. Kindler, Berlin; D. Kingreen, Berlin; H. Kirchner, Hannover; A. Kirsch, Berlin; J. Kisro, 740
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
Lu¨beck; M. Klein, Wiesbaden; J. Knoblich, Lo¨rrach; Y.D. Ko, Bonn; U. Koch, Bad Soden; M. Koenigsmann, Hannover; A. Ko¨hler, Langen; A. Kohlstedt, Zwickau; G. Kojouharoff, Darmstadt; S. Korsten, Bergisch Galdbach-Bensberg; S. Kremers, Lebach; W. Ku¨hn, Berlin; I. Ku¨hne, Weibenfels; F. Kullmann, Weiden; K. Ku¨rner, Gifhorn; F. Lange, Bonn; C. Lerchenmu¨ller, Mu¨nster; R. Lipp, Hamburg; C. Longin, Berlin; S. Luft, Lehrte; B. Luhn, Hamburg; A. Lu¨ck, Rostock; C. Maas, Halberstadt; S. Mahlmann, Kaiserslautern; D. Mainka, Ko¨ln; C. Maintz, Wu¨rselen; F. Marquard, Celle; U. Martens, Heilbronn; B. Massner, Schriesheim; M. Matthias, Buckow; H. Messmann, Augsburg; D. Meyer, Go¨ttingen; G. Michl, Mu¨nchen; J. Mittermu¨ller, Germering; E. Moorahrend, Porta Westfalica; S. Mu¨ller-Hagen, Hamburg; A. Ohmenha¨user, Bo¨blingen; J. Ollech-Chwoyka, Ludwigslust; P. Panagiotou, Garbsen; J. Papke, Neustadt/Sachsen; V. Petersen, Heidenheim; B. Peuser, Leipzig; M. Plath, Augsburg; P. Porowski, Heilbronn; D. Pott, Bottrop; M. Pross, Berlin; L. Pru¨gl, Zwiesel; G. Puchtler, Rosenheim; J. Rauh, Witten; C. Reddemann, Leverkusen; G. Reich, Berlin; M. Reiser, Ko¨ln; B. Rendenbach, Trier; D. Reschke, Oldenburg; F. Risse, Remagen; S. Ro¨sel, Gu¨tersloh; O. Rubanov, Hameln; K. Ruffert, Jena; U. Sauer, Nordhorn; T. Schanz, Chemnitz; M. Schauer, Nu¨rnberg; U. Schellenberger, Wilhelmshaven; B. Scheuer, Pirmasens; R. Schlag, Wu¨rzburg; A. Schmidt, Cottbus; R. Schmits, Saarbru¨cken; J. Schmitz, Arnsberg; M. Schmitz, Mayen; U. Schneider, Berlin; B. Scho¨ttker, Wu¨rzburg; D. Schro¨der, Hannover; J. Schro¨der, Mu¨lheim; C. Schulz, Bad Kreuznach; M. Schulze, Zittau; M. Schwarz, Scho¨neck; A. Schwarzer, Leipzig; M. Schweigert, Berlin; C. Schweinitz, Gera; U. Schwinger, Stuttgart; K.-D. Schu¨rer, Leipzig; S. Schu¨tz, Bremerhaven; G. Seipelt, Bad Soden; J. Selbach, Duisburg; K. Sieg, Mu¨lheim; U. So¨ling, Kassel; J. Spes, Alto¨tting; C. Spohn, Halle; M. Stauch, Kronach; K. Stengele, Singen; N. Steudel, Halle (Saale); F. Strohbach, Berlin; P. Stu¨bs, Magdeburg; I. Tamm, Berlin; H. Tanzer, Bad Reichenhall; M. Teich, Chemnitz; H. Tessen, Goslar; K. Tischbirek, Wiesbaden; G. Triebkorn, Weibenfels; D. Tummes, Aachen; J. Uhlig, Naunhof; U. Vehling-Kaiser, Landshut; K. Verpoort, Hamburg; A. Vo¨lkl, Mu¨nchen; M. von Staden, Hamburg; W. Weber, Homberg (Efze); R. Weinberg, Aachen; G. Weibenborn, Twistringen; M. Welslau, Aschaffenburg; J. Wierecky, Hamburg; S. Wilhelm, Gu¨strow; F. Winkler, Laatzen; M. Wo¨hr, Plu¨derhausen; H. Wolf, Dresden; I. Wo¨llner, Mainz; J. Zimber, Nu¨rnberg; K. Zuchold, Berlin. Support for third-party writing assistance for this manuscript, provided by Miller Medical Communications, was funded by Roche Pharma AG. Previous presentation: Presented in part at the European Society for Medical Oncology (ESMO) 13th World Congress on Gastrointestinal Cancer, 22–25 June 2011, Barcelona, Spain.
References 1. Twelves C, Wong A, Nowacki MP, et al. Capecitabine as adjuvant treatment for stage III colon cancer. N Engl J Med 2005;352:2696-704 2. Haller DG, Tabernero J, Maroun J, et al. Capecitabine plus oxaliplatin compared with fluorouracil and folinic acid as adjuvant therapy for stage III colon cancer. J Clin Oncol 2011;29:1465-71
www.cmrojournal.com ! 2015 Informa UK Ltd
Curr Med Res Opin Downloaded from informahealthcare.com by Kainan University on 04/08/15 For personal use only.
Current Medical Research & Opinion Volume 31, Number 4
3. Scheithauer W, McKendrick J, Begbie S, et al. Oral capecitabine as an alternative to i.v. 5-fluorouracil-based adjuvant therapy for colon cancer: safety results of a randomized, phase III trial. Ann Oncol 2003;14:1735-43 4. Schmoll HJ, Cartwright T, Tabernero J, et al. Phase III trial of capecitabine plus oxaliplatin as adjuvant therapy for stage III colon cancer: a planned safety analysis in 1,864 patients. J Clin Oncol 2007;25:102-9 5. Liu G, Franssen E, Fitch MI, Warner E. Patient preferences for oral versus intravenous palliative chemotherapy. J Clin Oncol 1997;15:110-15 6. Van Cutsem E, Rivera F, Berry S, et al. Safety and efficacy of first-line bevacizumab with Folfox, Xelox, Folfiri and fluoropyrimidines in metastatic colorectal cancer: the BEAT study. Ann Oncol 2009;20:1842-7 7. Xeloda Summary of Product Characteristics, Roche Registration Limited, February 2006. Available at: http://www.ema.europa.eu/ema/index.jsp?curl¼pages/medicines/human/medicines/000316/human_med_001157. jsp&mid¼WC0b01ac058001d124 [Last accessed 9 December 2013] 8. Xeloda Highlights of Prescribing Information, Genentech USA Inc., October 2014. Available at: http://www.gene.com/patients/medicines/xeloda [Last accessed 22 October 2014] 9. Alberts SR, Sargent DJ, Nair S, et al. Effect of oxaliplatin, fluorouracil, and leucovorin with or without cetuximab on survival among patients with resected stage III colon cancer: a randomized trial. JAMA 2012;307:1383-93
! 2015 Informa UK Ltd www.cmrojournal.com
April 2015
10. de Gramont A, Van Cutsem E, Schmoll HJ, et al. Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol 2012;13:1225-33 11. Allegra CJ, Yothers G, O’Connell MJ, et al. Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J Clin Oncol 2011;29:11-16 12. Saltz LB, Niedzwiecki D, Hollis D, et al. Irinotecan fluorouracil plus leucovorin is not superior to fluorouracil plus leucovorin alone as adjuvant treatment for stage III colon cancer: results of CALGB 89803. J Clin Oncol 2007;25:3456-61 13. Van Cutsem E, Labianca R, Bodoky G, et al. Randomized phase III trial comparing biweekly infusional fluorouracil/leucovorin alone or with irinotecan in the adjuvant treatment of stage III colon cancer: PETACC-3. J Clin Oncol 2009;27:3117-25 14. Kopec JA, Yothers G, Ganz PA, et al. 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. J Clin Oncol 2007;25:424-30 15. Chau I, Legge S, Fumoleau P. The vital role of education and information in patients receiving capecitabine (Xeloda). Eur J Oncol Nurs 2004;8 (Suppl 1):S41-53
Capecitabine-based adjuvant therapy in colon cancer Steffens et al.
741
