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Clinical Benefit and Quality of Life in Patients With Advanced Pancreatic Cancer Receiving Gemcitabine Plus Capecitabine Versus Gemcitabine Alone: A Randomized Multicenter Phase III Clinical Trial—SAKK 44/00–CECOG/PAN.1.3.001

Jürg Bernhard, Daniel Dietrich, Werner Scheithauer, Daniela Gerber, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard C. Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tàmas, Gabriela V. Kornek, Dieter Koeberle, Richard Herrmann

From the Swiss Group for Clinical Cancer Research Coordinating Center, Bern; Inselspital, Bern University Hospital, Bern; Kantonsspital, St Gallen; Oncology Institute of Southern Switzerland, Bellinzona; Centre Hospitalier Universitaire Vaudoise, Lausanne; Universitätsspital, Zurich; University Hospital, Basel; Kantonsspital, Aarau, Switzerland; Medical University of Vienna, Vienna; Krankenanstalt Rudolfstiftung, Wien, Austria; Szt László Hospital, Budapest, Hungary; University of Uppsala, Uppsala, Sweden; Fondazione Istituto di Ricovero e Cura a Carattere Scientifico Istituto Nazionale dei Tumori, Milan, Italy; Sourasky Medical Center, Tel Aviv; Rabin Medical Center, Petach Tikva, Israel; and Universitätsklinikum, Dresden, Germany

Corresponding author: Jürg Bernhard, PhD, International Breast Cancer Study Group Coordinating Center, Effingerstr 40, 3008 Bern, Switzerland; e-mail: juerg.bernhard{at}ibcsg.org

	ABSTRACT

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Purpose To compare clinical benefit response (CBR) and quality of life (QOL) in patients receiving gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem for advanced/metastatic pancreatic cancer.

Patients and Methods Patients were randomly assigned to receive GemCap (oral Cap 650 mg/m² twice daily on days 1 through 14 plus Gem 1,000 mg/m² in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m² in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks) for 24 weeks or until progression. CBR criteria and QOL indicators were assessed over this period. CBR was defined as improvement from baseline for 4 consecutive weeks in pain (pain intensity or analgesic consumption) and Karnofsky performance status, stability in one but improvement in the other, or stability in pain and performance status but improvement in weight.

Results Of 319 patients, 19% treated with GemCap and 20% treated with Gem experienced a CBR, with a median duration of 9.5 and 6.5 weeks, respectively (P < .02); 54% of patients treated with GemCap and 60% treated with Gem had no CBR (remaining patients were not assessable). There was no treatment difference in QOL (n = 311). QOL indicators were improving under chemotherapy (P < .05). These changes differed by the time to failure, with a worsening 1 to 2 months before treatment failure (all P < .05).

Conclusion There is no indication of a difference in CBR or QOL between GemCap and Gem. Regardless of their initial condition, some patients experience an improvement in QOL on chemotherapy, followed by a worsening before treatment failure.

	INTRODUCTION

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For patients with advanced or metastatic pancreatic cancer, the Swiss Group for Clinical Cancer Research and the Central European Cooperative Oncology Group compared the efficacy and safety of gemcitabine (Gem) plus capecitabine (Cap) versus single-agent Gem in a randomized clinical trial.¹ The safety of both regimens was similar. GemCap failed to improve overall survival at a statistically significant level. In the subgroup of patients with good baseline Karnofsky performance score (KPS), median overall survival was improved by GemCap. GemCap was considered a valuable alternative to Gem for these patients.

Given the poor prognosis of advanced pancreatic cancer and the symptom burden, symptom palliation and balancing the trade-offs between quality of life (QOL) and survival are of paramount importance. In 1996, Rothenberg et al² introduced the concept of clinical benefit response (CBR) in a phase II trial on single-agent Gem as an end point of effectiveness in advanced pancreatic cancer. This was followed in 1997 by the landmark phase III trial by Burris et al.³ They rigorously defined CBR based on pain (patient-rated intensity and analgesic consumption) and KPS as primary criteria and weight loss as a secondary criterion and reported CBR in favor of single-agent Gem as first-line therapy compared with fluorouracil. CBR from single-agent Gem has been confirmed in three phase III trials in advanced pancreatic cancer.^3-5 In other GI tumors, CBR has been used as an end point based on different definitions.

How beneficial is CBR?⁶ CBR does not include chemotherapy adverse effects and thus may overestimate the palliative effects.^7,8 CBR may also underestimate these effects because other important symptoms or domains of well-being are not included, such as psychological distress.^7,8 These shortcomings have contributed to the increasing use of QOL end points in pancreatic cancer trials. Depending on domain or symptom and time point of assessment, an improvement in QOL under single-agent Gem has been reported in phase II^9,10 and III^11,12 trials, whereas two phase III trials^13,14 showed either no change or a worsening. We prospectively compared CBR and QOL in patients receiving GemCap versus Gem in the trial indicated earlier¹ and investigated the association among these end points.

	PATIENTS AND METHODS

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The Trial
In this multicenter phase III trial, patients with primary inoperable or metastatic pancreatic adenocarcinoma were stratified by KPS (90 to 100 v 60 to 80), disease extent (locally advanced v metastatic), presence or absence of pain, and enrolling center and then randomly assigned to GemCap (oral Cap 650 mg/m² twice daily on days 1 through 14 plus Gem 1,000 mg/m² in a 30-minute infusion on days 1 and 8 every 3 weeks) or Gem (1,000 mg/m² in a 30-minute infusion weekly for 7 weeks, followed by a 1-week break, and then weekly for 3 weeks every 4 weeks). Treatment was continued until disease progression or for a maximum of 24 weeks except in the case of unacceptable toxicity. Treatment could be resumed later at the discretion of the investigator. Informed consent was obtained from all patients, and ethical committee approval was given by all participating centers. Trial protocol and conduct are described elsewhere.¹

CBR and QOL were secondary end points. Our hypothesis was that there would be a difference in CBR and QOL between the randomly assigned treatment groups. Inclusion criteria included a baseline assessment by the patient before random assignment, with a diary completed for 4 days at home and a QOL form completed at the hospital. The diary and the QOL form were translated by a forward-backward procedure to obtain conceptual equivalence for the main languages in the participating centers (Finnish, French, German, Hebrew, Hungarian, Italian, and Swedish). Patients were asked to complete a weekly diary for 24 weeks after random assignment at home and a QOL form weekly for the first 7 weeks and subsequently before each administration of Gem for 24 weeks after random assignment at the hospital. To avoid any interference with the standard assessment of CBR, the QOL form had to be completed at the hospital before diagnostic procedures.

CBR
For assessment of CBR, we applied the definition by Burris et al³ (Appendix Table A1, online only), which consists of pain and KPS as primary criteria and weight as a secondary criterion, as summarized in Figure 1. An improvement in pain required either a positive change in both pain intensity and analgesic consumption or a positive change in either factor and a stable situation in the other. Stable pain required a stable situation in both factors. A worsening in pain was defined by a negative change in one or both factors. CBR required either an improvement in both pain and KPS or an improvement in either factor and a stable situation in the other. A nonresponse was defined by a worsening in one or both factors. For patients with a stable situation in both factors, a CBR required a positive change in weight. A nonresponse was defined by any other result. If assessable, each patient was determined to have either a CBR or nonresponse.

View larger version (30K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Definition of clinical benefit response (CBR).

Statistics
QOL forms that were filled in more than 3 days before or after day 1 of a cycle were excluded. The association of CBR and treatment group was investigated using the ² test. A post hoc power analysis showed that a total of 300 patients would be sufficient to detect a difference in CBR rates of 15% or more between treatment groups with a power of 80% and a significance level of 5% when the true response rates are less than 40%. CBR duration was compared between treatment groups using the Mann-Whitney U test.

For each QOL indicator, a linear mixed-effects model for repeated measures data was used to estimate treatment effects over time and at specific time periods. We used the square roots of the scores to reduce skewing and to stabilize the variances for all indicators. The time scale was divided into successive 4-week periods. Baseline measurements were included as time 0. Multiple measurements per patient within a 4-week period were averaged, and the number of forms per patient in a 4-week period was used as a weight variable in the mixed model. Because the longitudinal pattern of the QOL scores differed by treatment duration, the effect of treatment arm, the period of a given assessment, and interactions between arm and periods were modeled within the maximum number of periods a patient was on trial treatment. The arm effect was divided into a baseline and an on-treatment effect. The effects of maximum number of periods and of cultural/language group were tested globally. For treatment burden (primary QOL end point), the effect of baseline KPS was investigated. We report means and SEs of untransformed data (scale range, 0 to 100). We considered a mean change of 8 points from baseline as clinically meaningful.²⁵ Power was analyzed post hoc. To detect a difference of 8 points between arms at a single time point with a sample size of 80 to 100 patients per arm at this time point, we had a power of 70% to 80% when assuming a standard deviation of 20 and a significance level of 5%. The same sample size in a repeated measures design, relevant for a mixed model, had a power of 70% to 80% to detect an average treatment effect of 6 points over time when assuming a standard deviation of 20, an intraclass correlation of 0.5, and a significance level of 5%.

	RESULTS

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Patient Description and Baseline Characteristics
Of 319 randomly assigned patients (GemCap, n = 160; Gem, n = 159), four did not receive trial treatment, and four had no visit forms (remaining GemCap, n = 156; Gem, n = 155). Of the remaining 311 patients, 97% had a baseline diary (GemCap, n = 154; Gem, n = 153), and 96% had a baseline QOL form (GemCap, n = 153; Gem, n = 152). Baseline characteristics were balanced according to treatment arm (Table 1). A majority of patients had metastatic disease and pain requiring analgesic medication according to the treating physician. The median analgesic consumption over the 4 days before random assignment was 0 morphine-equivalent mg/d (25% to 75% quartile range for GemCap and Gem: 0 to 0.4 and 0 to 1 mg/d, respectively), with 22% of patients receiving weak and 25% receiving strong opioids. Patients randomly assigned to GemCap and Gem estimated their pain intensity as 18 and 17, respectively.

CBR
Nineteen percent of all patients had a CBR, 57% did not respond, and 24% were not assessable as a result of missing data in one or more factors of CBR (Table 2). In the subsample defined according to the original trial,³ indicating a worse condition at baseline, the overall CBR rate was 26%. Taking into account the assessable patients only, 25% had a CBR in the total sample, and 36% had a CBR in the subsample. The CBR rates were similar between the randomly assigned treatments (P = .8). The median duration of CBR was 9.5 weeks (25% to 75% quartile range, 6 to 21 weeks) in patients receiving GemCap and 6.5 weeks (25% to 75% quartile range, 4 to 11.5 weeks) in patients receiving Gem (difference in medians, 3 weeks; P < .02).

QOL
Table 3 lists the estimated mean scores from the linear mixed-effects models for baseline and selected intervals. There was no baseline difference in QOL. The baseline scores for coping effort were particularly impaired, followed by tiredness, mood, and functional performance. There was no indication of a difference in QOL between the randomly assigned treatment groups over the whole observation period or at any of the assessment periods, as shown for treatment burden in Figure 2A. It should be noted that 26% of patients did not respond to this indicator before actually having received treatment.

View larger version (15K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Mean scores (SE, ± 1.96) of (A) treatment burden and (B) coping by treatment group during the first 6 months of treatment. Higher values indicate less treatment burden or less effort to cope (ie, better condition). Gem, gemcitabine; GemCap, gemcitabine and capecitabine.

All indicators showed statistically significant time effects (P < .05), with a clinically meaningful overall improvement in mood and coping effort (Fig 2B) in both treatment groups, mostly within 2 to 5 months after starting treatment. In physical well-being, tiredness, und functional performance, the criterion for a meaningful change was present in GemCap only. Treatment burden scores remained almost stable (Fig 2A). There was no significant time x treatment interaction in any of the indicators.

The median time to treatment failure was 4.3 months in the GemCap arm and 3.9 months in the Gem arm¹ (ie, the majority of patients experienced treatment failure during our observation period of 6 months). The impact of the changing disease status on QOL at any time point within this period was taken into account by the time on trial treatment. The changes over time differed substantially by the time on treatment in all indicators (all P < .05). After the initial improvement, there was a consistent worsening, mostly 1 to 2 months before treatment failure, as shown for pain and mood in Figure 3. We explored the change between baseline and treatment failure according to the treatment duration period. With some variation among these periods and the different indicators, approximately two thirds of the patients reported stable or improving values regardless of the treatment duration, as shown in Appendix Figure A1 (online only).

View larger version (19K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 3. Mean scores of (A) pain and (B) mood by time on trial treatment during the first 6 months (both treatment groups combined). The length of the solid colored lines indicates the time on trial treatment. The light blue line indicates the scores of the total sample over the 6 months. Higher values indicate less pain or better mood (ie, better condition; scale range, 0 to 100).

	DISCUSSION

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We prospectively compared CBR and QOL in patients receiving GemCap versus Gem and investigated the association among these end points. There was no indication of a treatment difference, with the exception of a minor prolongation in CBR in favor of GemCap. Similarly, in other phase III trials in advanced pancreatic cancer, no difference in QOL was found between single-agent Gem and a combination therapy.^11,12,14,26 A comparison of Gem with the matrix metalloproteinase inhibitor BAY 12-9566 favored Gem with respect to QOL, likely as a result of better disease control.¹³

Patients with good KPS receiving GemCap had a median survival gain of 2.7 months compared with patients receiving Gem.¹ The prolonged survival of GemCap should outweigh the adverse effects of the combination therapy to achieve a favorable risk-to-benefit ratio. In the subgroups of patients with good or poor KPS, there was no indication of a treatment difference regarding CBR or QL. However, the subgroups are too small for formal testing.

To minimize the potential bias associated with early withdrawal from study treatment and to investigate patients' underlying trajectories of palliation, we chose an intensive assessment schedule over 6 months for both CBR and QOL. This schedule, with QOL assessments in shorter intervals than in previous trials, revealed consistent time effects. QOL improved during chemotherapy and deteriorated again before treatment failure was documented by the clinician. Our findings indicate that patients receiving only a few cycles may also benefit from chemotherapy, with roughly two thirds of patients still experiencing stable or improving QOL at treatment failure.

Various time schedules of QOL assessment in other trials may have contributed to inconsistent findings, especially the worsening in QOL during single-agent Gem reported by Moore et al.¹³ In our trial, overall, patients' subjective experience during chemotherapy was more determined by the course of disease and the tumor symptoms and their palliation than by adverse effects. The dominant impact of tumor symptoms for patients' well-being became apparent in the clear discrimination of QOL by CBR. However, the adverse effects should not be underestimated. The treatment burden scores were substantially affected over the whole observation period. Noteworthy, treatment burden did not differ by CBR.

Our patient sample indicated less pain, lower analgesic consumption, and better KPS at baseline than that reported by Burris et al.³ Our CBR rate in patients receiving single-agent Gem is similar to that reported by Burris et al³ (24%) or Reni et al⁵ (25%). Burris et al³ reported a mean duration of CBR of 18 weeks for these patients, with a median time to progressive disease of 9 weeks. Our median duration of CBR in patients with Gem was 6.5 weeks, with a median time to treatment failure of 3.9 months. These conflicting findings may not be explained by the different baseline status only and remain unclear.

The algorithm of CBR was vulnerable to the loss of assessable patients as a result of its complexity. Although we had a high submission rate of diaries, we lost roughly one quarter of our sample for this analysis as a result of missing data in one or more factors of CBR. Missing data in using diaries is a known problem.²⁷ The daily assessment of pain and analgesic consumption is demanding for the patients and not suitable over several months.

A further limitation of CBR as a trial end point is the difficulty in interpretation as a result of the restriction to pain and functional status as primary criteria and the rigid definition.^7,8 The different QOL indicators showed distinct patterns over time, and the extent of discrimination by CBR varied among the indicators. These findings highlight the necessity of including other factors for outcome in addition to pain, KPS, and weight. High psychological distress is common in pancreatic cancer.²² The process of coping is crucial in mediating a patient's perception of his or her QOL and is strongly determined by the perceived threat and the possibilities of control.²⁸ Besides physical domains and treatment burden, we emphasized mood and coping as important outcomes of palliation.

A limitation of the QOL analysis is the restriction to a few key indicators. A comprehensive QOL assessment, consisting of a cancer-specific questionnaire and a module specific for pancreatic cancer,^29,30 would provide more detailed information on symptoms, adverse effects, and broader domains of functioning and well-being but was not feasible in addition to the diaries. As an alternative to a comprehensive standard assessment, which is better suited for widely spaced single-point estimates, we used simple global indicators that are feasible even for weekly assessments. These indicators may detect different treatment effects on single dimensions, allowing for a straight overall comparison of the treatment groups in a longitudinal model.

In conclusion, there was no indication for a difference in CBR or QOL between the randomly assigned treatment groups. Regardless of their initial condition, some patients experienced an improvement in QOL on chemotherapy by symptom control. One to 2 months before treatment failure, QOL worsened. Longitudinal QOL data provided more comprehensive information on palliation than CBR.

	AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: Arie Figer, Roche (C) Stock Ownership: None Honoraria: Werner Scheithauer, Roche; Arie Figer, Roche; Claus-Henning Köhne, Roche, Sanofi-aventis; Gabriela V. Kornek, Roche, Merck & Co, Sanofi-aventis, Pfizer Inc, Eli Lilly & Co; Richard Herrmann, Roche Research Funding: Arie Figer, Roche; Richard Herrmann, Roche Expert Testimony: None Other Remuneration: Arie Figer, Roche

	AUTHOR CONTRIBUTIONS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION AUTHORS' DISCLOSURES OF... AUTHOR CONTRIBUTIONS Appendix REFERENCES

 
Conception and design: Jürg Bernhard, Daniel Dietrich, Richard Herrmann

Financial support: Richard Herrmann

Administrative support: Daniela Gerber, Richard Herrmann

Provision of study materials or patients: Werner Scheithauer, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard C. Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tàmas, Gabriela V. Kornek, Dieter Koeberle, Richard Herrmann

Collection and assembly of data: Jürg Bernhard, Werner Scheithauer, Daniela Gerber, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard C. Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tàmas, Gabriela V. Kornek, Dieter Koeberle, Richard Herrmann

Data analysis and interpretation: Jürg Bernhard, Daniel Dietrich, Daniela Gerber, Bengt Glimelius, Richard Herrmann

Manuscript writing: Jürg Bernhard, Daniel Dietrich, Daniela Gerber

Final approval of manuscript: Jürg Bernhard, Daniel Dietrich, Werner Scheithauer, Daniela Gerber, György Bodoky, Thomas Ruhstaller, Bengt Glimelius, Emilio Bajetta, Johannes Schüller, Piercarlo Saletti, Jean Bauer, Arie Figer, Bernhard C. Pestalozzi, Claus-Henning Köhne, Walter Mingrone, Salomon M. Stemmer, Karin Tàmas, Gabriela V. Kornek, Dieter Koeberle, Richard Herrmann

	Appendix

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The following centers and investigators participated in this study: Switzerland: Aarau (C. Caspar, W. Mingrone); Basel (R. Herrmann, L. Jost, A. Lohri, C. Ludwig); Berne (M. Borner, D. Rauch); Chur (F. Egli); Geneva (A. Roth); Lausanne (J. Bauer, R. Popescu); St. Gallen (D. Köberle, R. Morant, T. Ruhstaller); Ticino (M. Bonomo, P. Saletti, C. Sessa); Zurich (H. Adam, L. Widmer, B. Pestalozzi); Austria: Feldkirch (A. Lang); Vienna (W. Scheithauer, J. Schüller); Finland: Oulo (T. Turpeenniemi-Hujanen); Tampere (P. Kellokompu-Lehtinen); Turku (S. Pyrhönen); Germany: Dresden (C.H. Köhne, G. Kornek); Hungary: Budapest (G. Bodoky, K. Tamas); Israel: Petach Tikva (S. Stemmer); Tel-Aviv (A. Figer, M. Inbar); Italy: Milano (E. Bajetta); Napoli (P. Comella); Sweden: Uppsala (B. Glimelius).

View larger version (44K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig A1. Proportion (%) of patients with a clinically meaningful worsening or improvement in quality-of-life indicators between baseline and treatment failure according to months on trial treatment. A meaningful change is defined as a mean change of eight points from baseline in either direction.

	ACKNOWLEDGMENTS

 
We thank Susanne Cina for central data management and trial coordination.

	NOTES

 
Supported by Roche Pharma Switzerland, Eli Lilly Switzerland, and the Swiss Federal Government.

Presented at the 9th World Conference of Psycho-Oncology, September 16-20, 2007, London, United Kingdom.

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

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Submitted December 24, 2007; accepted April 3, 2008.

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