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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
J Pain Symptom Manage. Author manuscript; available in PMC 2010 April 20.
Published in final edited form as:
PMCID: PMC2856704
NIHMSID: NIHMS169575

Patient-Reported Outcomes as a Component of the Primary Endpoint in a Double-Blind, Placebo-Controlled Trial in Advanced Pancreatic Cancer

Abstract

In this randomized, double-blind, placebo-controlled study comparing gemcitabine + tipifarnib (G + t) or gemcitabine + placebo (G + p) in patients with pancreatic cancer, the primary endpoint of time to deterioration (TTD) was based primarily on patient-reported outcomes. Deterioration was defined as death or worsening of disease-related symptoms, based on patient-reported outcomes of pain intensity and analgesic use in a daily diary, plus investigator-rated weekly performance status. Secondary endpoints included survival and safety. Two hundred and forty-four patients were treated for a total of 4780 weeks, during which the diary was completed daily. Overall, the completion of the diary was found to be feasible: patients completed approximately 95% of scheduled diary entries. Baseline characteristics were well balanced between the two treatment arms. The primary endpoint of TTD was not significantly different between the G + t arm (69 days) and the G + p arm (91 days, P = 0.40). Survival was not significantly different between the G + t arm (202 days) and the G + p arm (221 days, P = 0.66). The combination of G + t had an acceptable toxicity profile, with primarily neutropenia and thrombocytopenia.

Methodologically, measurement of patient-reported outcomes is feasible and useful in assessing the effect of anti-cancer therapy in pancreatic cancer if comprehensive initial and ongoing training is provided to all people involved, including not only the patients but also the study personnel.

Keywords: Patient-reported outcomes, pancreatic cancer, farnesyltransferase inhibitor

Introduction

Self-reported data, referred to as patient-reported outcomes (PROs) in the context of clinical trials and health care, include any report directly coming from the person affected by the disease under study or the therapy itself. Mostly, PROs are limited to quality-of-life (QoL) questionnaires. However, PROs comprise all data obtained directly from patients by interview, self-completed questionnaires, diaries, or Web-based forms. Such outcomes need to be correlated with, and compared to, other clinical outcomes, but these PROs often have more meaning to the affected persons and their direct relatives than objective disease assessments.1 Regulatory agencies have become more interested in this matter, as exemplified by approvals of drugs with PROs in their product information.2

The therapeutic options in pancreatic cancer often are limited by advanced age at diagnosis, poor condition, disease-related symptoms, and intrinsic chemoresistance, and objective responses are difficult to assess with conventional imaging. It is recognized that worthwhile palliation of symptoms, even in the absence of survival advantage, may confer benefit to the patient with pancreatic cancer. Pain is probably the most important single symptom confronting physicians in the management of cancer, particularly pancreatic cancer.3,4 To assess the clinical relevance of new therapeutics, endpoints for the management of pain and other symptoms need to be explored and validated.

Gemcitabine monotherapy has become the cornerstone of treatment in pancreatic cancer, based on improvement of the major symptoms of pancreatic cancer (weight loss and pain) and a modest survival advantage.3,5 In clinical studies, oral tipifarnib (ZARNESTRA®, R115777 Tibotec Therapeutics, Ortho Biotech, L.P., Bridgewater, NJ), a first-in-class farnesyltransferase inhibitor, was well tolerated, with mainly reversible myelosuppression, fatigue, and skin rash.6,7 A Phase I study defined the addition of tipifarnib 200 mg twice daily to the standard regimen of gemcitabine as the recommended dose for further testing.8 The objective of the double-blind, placebo-controlled study reported here was to test whether the addition of tipifarnib to gemcitabine would improve PROs in pancreatic cancer.

Patients and Methods

Patient Population

The study included patients with pathologically confirmed, locally advanced or metastatic, chemotherapy-naïve adenocarcinoma of the pancreas. Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0 to 2, adequate bone marrow, and adequate hepatic and renal function were required.

Patients used a daily diary to report pain intensity on a 100 mm pain intensity visual analog scale (VAS) from the Memorial Pain Assessment Card (MPAC),9 as well as daily analgesic use. Patients completed their first diary during a screening week, which was to occur within two weeks before randomization. The screening week was used not only to determine patient eligibility, but also to allow the patient to become acquainted with use of the study diary. The average pain intensity VAS during the screening week had to be <60 mm (patients could be pain-free) and stable. Stable pain was defined as ≤10% relative or ≤5-mm absolute shift from start to end of the screening week. Patients could be using any analgesic at baseline as long as the dose was stable, defined as a relative change of <10% or an absolute change of <10 mg morphine equivalent (ME)10,11 during the screening week.

The study design was approved by an institutional review board or independent ethics committee for each study center. Signed informed consent was obtained from each patient before study entry and each patient was counseled in detail on the requirement for completion of a daily diary for the duration of the study therapy.

Treatment

Patients were randomized centrally to the gemcitabine + tipifarnib (G + t) arm or the gemcitabine + placebo (G + p) arm through a dynamic randomization procedure, with stratification for the presence or absence of metastatic disease, ECOG-PS (0 vs. 1 vs. 2), and investigator site.

Tipifarnib and placebo were supplied by Johnson & Johnson Pharmaceutical Research & Development as 100 mg film-coated tablets. The starting dose was 200 mg twice daily in a continuous daily dosing schedule. Tablets were recommended to be taken with food. Gemcitabine (Gemzar®, Eli Lilly Indianapolis, IN) was purchased from commercial sources and administered at a starting dose of 1000 mg/m2 intravenously weekly for seven weeks, followed by one week of rest, and then weekly for three weeks of each subsequent four-week period. Rules for dose modifications were identical to those described in the survival study of G + t vs. G + p.12

Data Collection

Patients completed the PRO diary of pain intensity VAS and analgesic use once daily. Investigators recorded ECOG-PS scores and vital signs once weekly. The FACT-HEP questionnaire14 was completed at screening and at the start of every cycle. On the second week of each cycle, a short eight-item questionnaire derived from the FACT-HEP was to be completed, including overall pain, back pain, discomfort in stomach, fatigue, lack of energy, weight loss, nausea, and jaundice. These items were identified by pancreatic cancer-treating health professionals, including the participating investigators and their study staff, as being the most relevant to pancreatic cancer patients. Physical examination, clinical chemistry, and complete blood counts were obtained at screening, at the beginning of every new cycle, and at treatment termination; complete blood counts also were performed weekly during study treatment. All clinically relevant abnormalities were reported as adverse events and graded according to the National Cancer Institute Common Toxicity Criteria, version 2.0 (NCI CTC 2.0).

Statistical Analysis

The primary endpoint of the study was time to deterioration (TTD), based on the PROs of pain intensity and analgesic use, and investigator assessments of ECOG-PS. Weekly averages for the PROs were calculated from the available data; the weekly average was considered missing if more than half of the daily values were missing in a given week. Worsening of pain intensity VAS was defined as an increase of ≥33% and ≥15 mm over best value, to a weekly average of ≥35 mm.13 Worsening of analgesic use was defined as an increase of ≥50% and ≥30 mg ME over best value, or a shift from non-opioid to opioid analgesia (>20 mg ME). Worsening of ECOG-PS was defined as an increase from 0 to ≥2, an increase from 1–2 to ≥3, or death (irrespective of cause).

The overall weekly value was “deteriorated” if any of the three components had worsened, “not deteriorated” if none of the components had worsened, and “missing” if one or two components were missing and the other component(s) had not worsened. Overall deterioration was defined as three consecutive weeks during which the overall weekly value was deteriorated at the first week and either deteriorated or missing for the two subsequent weeks. The TTD was calculated from the date of randomization to the date of overall deterioration (intent-to-treat analysis). Patients who did not reach overall deterioration were censored at their last not-deteriorated value. If a patient discontinued for reasons other than deterioration, he was followed for TTD until start of subsequent therapy, or actual deterioration.

Two different analyses were performed, handling missing weekly values differently. In the primary analysis, TTD was calculated from the date of randomization to either the start of overall deterioration if the week before deterioration had been categorized as not deteriorated or if data were missing for one or more weeks immediately preceding overall deterioration, the first week of these missing values. In the sensitivity analysis, patients with missing values immediately preceding overall deterioration were censored at the last not-deteriorated value. Treatment comparison of TTD was performed using a two-sided log-rank test stratified for ECOG-PS and disease status. Kaplan-Meier estimates were used to estimate the probability of no deterioration over time. The hazard ratio of G + t over G + p was estimated by a stratified Cox regression model.

To detect a hazard ratio of 1.57 for the primary efficacy endpoint with 80% power for a two-sided test with a 5% significance level, 154 events on TTD in 224 patients were required. The median TTD was assumed to be 1.75 months for the control arm and 2.75 months for the G + t arm.

Clinical benefit response (CBR) was calculated from pain intensity VAS scores, analgesic use, ECOG-PS, and body weight, as described by Burris et al.,5 and was compared between the two treatment arms by a Cochran-Mantel-Haenszel test, stratified for performance status and disease status. Overall survival was calculated from the date of randomization to the date of death. Living patients were censored at the date of last contact. Treatment comparison of survival time was performed using the same methodology as for TTD.

Results

Patient Disposition and Baseline Characteristics

A total of 244 patients entered this study at 75 sites in 2000 and 2001. Two patients (G + p) never received treatment. At analysis cutoff (July 1, 2003), no patients were still on treatment. Demographic data are shown in Table 1. All factors were well balanced between the two groups. Most patients (78% on the G + t arm and 80% on the G + p arm) had abdominal/back pain at trial entry. This correlated very closely to average weekly pain intensity VAS scores by PRO at baseline: 16% of patients had a screening pain intensity of 0–1 mm without any analgesic use and 21% had average weekly pain of 0–3 mm without analgesic use. Either pain intensity or analgesic consumption was not stable as required at baseline in 19 patients (10 G + t; 9 G + p), with a recent increase in 15 patients, a recent decrease in two patients, and compensatory shifts (decreased pain intensity with increased analgesia) in two patients.

Table 1
Baseline Characteristics

Treatment Duration and Dose Intensity

Median duration of treatment was shorter in the G + t group (12 weeks; range 1–69) than in the G + p group (21 weeks; range 1–83). The most common primary reasons for treatment termination in the G + t and G + p groups were disease progression (52% and 61%, respectively), drug-related adverse events (19% and 10%), non-drug-related adverse events (9% and 6%), and death on treatment (6% and 5%). None of the deaths was considered treatment-related and most were due to progressive disease.

Efficacy Results

In total, 193 patients had deterioration according to the primary analysis, including 92 (74%) patients on the G + t arm and 101 (84%) patients on the G + p arm (Table 2). Most patients did not have deterioration based on only one of the parameters; most cases of deterioration (80%) involved simultaneous worsening of all three parameters.

Table 2
Reason for Deterioration

The median TTD was 69 days (95% confidence interval [CI]: 44–86 days) for the G + t arm and 91 days (95% CI: 71–128 days) for the G + p arm (Fig. 1a). There was no statistically significant difference in TTD between the two treatment groups (stratified log-rank P = 0.40, hazard ratio [HR] = 1.13 with 95% CI: 0.85–1.52).

Fig. 1
Time to deterioration: a) primary analysis and b) sensitivity analysis.

Under the definition of the sensitivity analysis, 103 patients had deterioration, including 48 (39%) patients on the G + t arm and 55 (46%) patients on the G + p arm. The median TTD in the sensitivity analysis was 150 days (95% CI: 80–410) for the G + t arm and 172 days (95% CI: 126–197) for the G + p arm (Fig. 1b). There was no statistically significant difference in TTD between the two treatment groups in the sensitivity analysis (stratified log-rank P = 0.58, HR = 1.12 with 95% CI: 0.75–1.66).

Of the 230 patients for whom CBR could be assessed, CBR responses were observed for 25 (21%) patients on the G + t arm and 30 (27%) patients on the G + p arm (P = 0.36). At the time of analysis, 189 patients had died, including 88 (71%) patients on the G + t arm and 101 (84%) patients on the G + p arm. The median survival time was 202 days (95% CI: 145–253 days) for the G + t arm and 221 days (95% CI: 190–263 days) for the G + p arm (P = 0.66, HR = 1.07 with 95% CI: 0.796–1.431). Disease progression was the primary cause of death (86% and 85% of deaths, respectively, on the G + t and G + p arms).

QoL was assessed with the FACT-HEP questionnaires on a biweekly interval (shortened, eight-item questionnaire) and monthly interval (full questionnaire). However, 28 (12%) patients missed the baseline QoL assessment, 77 (32%) patients completed fewer than two QoL questionnaires within the first two months, and fewer than 60% of patients had more than two QoL assessments during the study. Furthermore, pain was a major parameter for the questionnaire used, but daily diaries of pain intensity showed no difference between the two arms. Also, in a similar study that was performed in a similar patient population with a larger sample size during the same period,8 no difference in QoL was reported. Therefore, QoL was not analyzed further in the present study.

Safety Results

Adverse events were reported in 99% patients, but toxicity was acceptable and similar between treatment arms (Table 3). The difference between treatment groups in incidences for diarrhea, anorexia, dehydration, hypokalemia, and peripheral neuropathy was mainly due to grade 1–2 events. No patients died due to drug-related adverse events.

Table 3
Adverse Events and Laboratory Abnormalities (>15% in Either Arm)

Discussion

Advanced pancreatic cancer has a poor prognosis and therapeutic options are limited. Gemcitabine has become the cornerstone of first-line therapy after demonstration of a significant improvement in CBR and a modest improvement in overall survival compared to weekly 5-fluorouracil.5 In subsequent studies totaling approximately 750 patients, median survival with gemcitabine was 5.4–6.1 months.15 Attempts to improve on this by combining gemcitabine with other compounds have not been successful,4 except the combination of gemcitabine + erlotinib, which resulted in a significant, albeit very modest, two-week median survival benefit.16 In some studies CBR was reported, but no difference was observed when compared to gemcitabine alone.

The pursuit of patient-oriented clinical benefit parameters has continued in pancreatic cancer due to the difficulty in assessing objective response, and due to the impact of disease-related symptoms on QoL. Therefore, this randomized Phase II study was conducted with the intent of using PROs as a main component of the primary outcome measure. TTD was selected as the primary endpoint because it assesses the evolution over time of the major consequences of pancreatic cancer: pain; the use of (opioid) analgesics; and overall ECOG-PS, which is primarily determined by the levels of energy, fatigue, gastrointestinal symptoms, and pain. TTD is not limited to the first four weeks of therapy, but takes into account the evolution from before the start of the study until the discontinuation of study medication. Although the results of the present study did not demonstrate differences in PROs or other endpoints between the two arms, they were informative and raise feasibility and logistical issues that may be useful in the design of subsequent studies in the treatment of (pancreatic) cancer.

In pancreatic cancer, PROs are not well developed beyond CBR as described by Burris et al.5 The deterioration parameters used in this study were the result of extensive discussions among the investigators of this study, other clinical investigators working in the field of pancreatic cancer, and pain specialists. As not all patients with pancreatic cancer present with disease-related symptoms, but virtually all patients develop them, the TTD endpoint was used rather than CBR, because CBR requires an improvement from baseline. Additionally, it was hypothesized that deterioration would represent a true clinical state experienced by the patient with progression of disease. Support for this notion was provided by the data obtained in this study, with most patients demonstrating concordant deterioration in all three parameters of pain intensity, analgesic use, and performance status. In only 5% of patients, the worsening in one parameter dominated the clinical picture and determined the protocol-specified deterioration. Therefore, it is likely that the cutoff values used in determining deterioration of these parameters are clinically meaningful and potentially useful in future studies.

At the start of the study, it was unknown how feasible the collection of PRO data with diaries would be, and how compliant a severely sick population with advanced cancer would be in completing a one-page diary every day. This critical study requirement mandated that the sponsor develop a training and implementation plan among all sites. Therefore, significant effort was put into the training of the site personnel, with multiple international and local/national investigator meetings. Of importance was the emphasis put on the training of the study nurses and study coordinators, using mock diaries. The site personnel were instructed to review with the patient the completion of the diary at the end of the screening week and regularly thereafter. This allowed for early correction and education of the site personnel or the patient regarding diary entry. Monitors from the sponsor visited the sites before the initial data collection, allowing for the early recognition of any issues with the completion of the diaries or in the calculation of equianalgesic doses. Finally, the diary pages were collected continuously, at every visit, entered into the database, and verified/checked centrally for any systematic mistakes. Any issue concerning the diaries was then communicated to the investigators in a monthly Investigator Letter. These efforts resulted in exceptional compliance rates for the diary: during 4780 weeks of therapy in this study, patients completed approximately 95% of all diaries on pain intensity or analgesic use. Clearly, such multifaceted approaches need to be incorporated in studies using PROs.

Aside from instructional and compliance procedures, there were several “lessons learned” during the conduct of this study that are noteworthy for any future user of PROs in general, and pain diaries in particular. Patients made regular mistakes in the reporting of the use of fentanyl patches, as these are applied every third day: some patients reported their use every day the patch was in place, others noted it only on the day a new patch was applied, whereas a third group of patients explicitly denied the use of any analgesics on the intercurrent days. A suggested alternative for the fentanyl patch might be a dedicated check box on the diary that captures both dose and frequency.

A few other logistical issues merit mention here. As the study ran in several countries, and it was not (and could not be) mandatory that patients complete the diary in English, there were translation issues that required special attention. Examples of this were diary entries of “aucun médicament,” “pro Tag,” or “lunes, miércoles e viernes,” which could be coded erroneously as new drugs but actually mean “no drug,” “per day,” and “Monday, Wednesday, and Friday,” respectively. The most problematic issue was the use of the ddMMMyyyy abbreviation for reporting of dates because “JUI” in French could mean either Juin (June) or Juillet (July).

Other regularly encountered problems included the completion of the VAS in pencil (leading to an inferior scanned image), and the use of a tick-sign ([check]) or non-crossing line (/) instead of the required straight crossing line (+) on the pain intensity VAS. This was rapidly recognized and was, in most cases, remedied by repeat instruction of the patient by the site staff. A suggested solution could be to add clear graphical instructions on the hardboard cover of the diary.

All baseline data were well balanced between the two groups in this study and similar to other studies with gemcitabine.5,12,17,18 The incidence of baseline pain, scored by the patients as >1 mm on the VAS, in this study (84%) was lower than that in the study by Burris et al.,5 because tumor-related pain was not a requirement for the current study. The survival data of the G + p arm in this study was at the upper end of the range reported in other randomized studies.5,15,17,18 By contrast, the CBR rate of 21% for G + t and 27% for G + p in the present study was similar to the original study of gemcitabine in pancreatic cancer,5 but lower than the rates of 33%–53% reported in more recent studies.4 These differences reinforce the need for randomization in clinical studies of this disease, where survival may be influenced by stage migration and CBR rate may be influenced by differences in data quality and ascertainment. The toxicity profile observed on the G + p arm of the present study is similar to that reported in previous studies5,12 in this population. The tipifarnib-gemcitabine combination was well tolerated. Consistent with previous reports, myelosuppression, mainly reversible neutropenia, was the predominant toxicity of the combination.8,12 However, the combination did not prolong TTD or survival when compared to single-agent gemcitabine.

Despite the negative conclusions for the experimental therapy in this trial, the study demonstrated that a primarily PRO-based endpoint of TTD was both feasible and relevant for patients with pancreatic cancer. Based on the experience gained from this study, it is clear that comprehensive initial and ongoing training of all people involved, including both patients and investigators, is a conditio sine qua non for the successful application of this methodology. Clearly, new therapies are needed for this disease and the PRO methods used here can be applied in future studies.

Acknowledgments

The authors thank Jonathan N. Latham for his assistance in editing this manuscript.

This study was supported by Johnson & Johnson Pharmaceutical Research & Development, LLC.

Appendix

Investigators who entered patients on this study include the following:

Australia: Beale P, Concord Hospital, Sydney; Bell D, Royal North Shore Hospital, St. Leonards; Goldstein D, Prince of Wales Hospital, Sydney; Strickland A, Melbourne.

Austria: Neumann H, Krankenhaus der Barmherzigen Brüder, St. Veit; Wöll E, Universitäre Klinik, Innsbruck.

France: Burtin P, Hôtel Dieu, Angers; Cals L, Toulon; Dorval E, Hôpital Trousseau, Tours; Douillard J, Saint-Herblain; Favre R, Hôpital de la Timone, Marseille; Husseini F, CH Louis Pasteur, Colmar; Khayat D, Hôpital Pitié Salpétrière, Paris; Rougier P, Hôpital Ambroise Paré, Boulogne Billancourt; Trillet-Lenoir V, Centre Hospitalier Lyon-Sud, Lyon.

Germany: Ballo H, Onkologische Gemeinschaftspraxis, Offenbach; Gregor M, Universität Tübingen, Tübingen; Kettner E, Krankenhaus Altstadt, Magdeburg; Kindler M, Onkologische Schwerpunkt Praxis, Berlin; Kirsch A, Onkologischer Schwerpunkt, Berlin; Marschner N, Klinik für Tumorbiologie, Freiburg; Mross K, Klinik für Tumorbiologie, Freiburg; Schmiegel W, Knappschafts-Krankenhaus Med. Uni Klinik, Bochum; Schöffski P, Med Hochschule, Hannover; Steinmetz T, Gemeinschaftspraxis, Köln.

Portugal: Damasceno M, Hospital S. Joao, Porto; Guedes MF, Hospital Distrital, Figueira Da Foz; Sottomayor C, Hospital Pedro Hispano, Matosinhos.

Spain: Cortes Funes H, Hospital Doce de Octubre, Madrid; Gonzales Baron M, Hospital Universitario La Paz, Madrid; Lopez M, Santa Maria NAI, Orense; Mel J, Santa Maria NAI, Orense; Perez Manga G, Hospital Gregorio Marañon, Madrid.

South Africa: Goedhals L, National Hospital, Bloemfontein; Jacobs C, Eastern Cape Oncology Centre, Port Elizabeth; Pienaar F, Panorama Mediclinic, Cape Town; Ruff P, Johannesburg General Hospital, Johannesburg.

Sweden: Glimelius B, Onkologiska Kliniken Akademiska Sjukhuset, Uppsala; Starkhammar H, Universitetsjukhuset, Linkoping.

United Kingdom: Bridgewater J, North Middlesex Hospital, London; Eatock M, Belfast City Hospital, Belfast.

United States of America: Belt R, Kansas City, MO; Celano P, Cancer Center at Greater Baltimore Medical Center, Baltimore, MD; DeLeo M, Berkshire Hematology/Oncology, Pittsfield, MA; DelPrete S, Hematology/Oncology PC, Stamford, CT; Eckhardt G, University of Colorado Health Sciences Center, Aurora, CO; Foulke R, Carolinas Research Associates, Charlotte, NC; Gurtler J, East Jefferson Hospital, Metairie, LA; Hajdenberg J, Pasco Pellinas Cancer Center, Tarpon Springs, FL; Haller D, University of Pennsylvania Cancer Center, Philadelphia, PA; Hanson D, Baton Rouge, LA; Just R, La Jolla, CA; Justics G, Fountain Valley, CA; Khojasteh A, Capital Comprehensive Cancer Care Clinic, Jefferson City, MO; Kuebler J, Columbus Community Hospital, Columbus, OH; Kuperminc M, Virginia Physicians Inc., Richmond, VA; Langdon R, Omaha, NE; Lipson A, Hershey Medical Center, Hershey, PA; Modiano M, Arizona Clinical Research Center, Tucson, AZ; Rivkin S, Seattle, WA; Rosemurgy A, Tampa General Hospital, Tampa, FL; Rosenberg R, Arizona Clinical Research Center, Tucson, AZ; Safran H, Providence, RI; Saltzman M, Innovative Medical Research of South Florida, Miami Shores, FL; Schwartzberg L, The West Clinic, Memphis, TN; Sherrill B, Greensboro, NC; Stern J, Hillcrest Hospital/Cleveland Clinic, Cleveland, OH; Strupp J, Nashville, TN; Wong L, Temple, TX.

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