• Germond C, Maroun J, Moore M, Zwaal C, Wong S, Gastrointestinal Cancer Disease Site Group. Use of gemcitabine in the treatment of advanced pancreatic adenocarcinoma. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jun 24. 21 p. (Practice guideline report; no. 2-10). [27 references]

Advanced or unresectable pancreatic adenocarcinoma

Assessment of Therapeutic Effectiveness
Treatment

Gastroenterology
Oncology

Physicians

To make recommendations about the use of gemcitabine for patients with unresectable or advanced pancreatic adenocarcinoma

Adults with unresectable or advanced pancreatic adenocarcinoma

Gemcitabine

Primary Outcomes

Clinical benefit response, a composite of measurements of pain (analgesic consumption and pain intensity), Karnofsky performance status, and weight (see Appendix 1 of the original guideline document)

Secondary Outcomes

• Median survival
• One-year survival
• Median progressive-free survival
• Tumour response rate
• Symptomatic response
• Time to progressive disease

Hand-searches of Published Literature (Primary Sources)
Hand-searches of Published Literature (Secondary Sources)
Searches of Electronic Databases

1998 Guideline

Two phase I trials, one trial with both a phase I and phase II design, six phase II trials, and one randomized controlled trial (RCT) were initially reviewed.

2005 Update

Fifteen new randomized controlled trials were obtained during updating.

Expert Consensus (Committee)

Not applicable

Meta-Analysis of Randomized Controlled Trials
Systematic Review with Evidence Tables

1998 Guideline

As overall survival was reported for only one randomized controlled trial (RCT) and one phase II trial, no pooled estimate for survival across studies was calculated. Partial response rates were pooled across phase II trials to obtain a more precise estimate of the effect of gemcitabine. The pooled partial response rate provides an estimate of the activity of gemcitabine and should not be interpreted as a surrogate measure for overall survival or quality of life. The data were pooled by summing the number of partial responses across phase II trials and dividing this number by the total number of patients included in all phase II trials. The result was converted to a percentage and the 95% confidence intervals (CI) were calculated.

2005 Update

Updating activities obtained 15 new RCTs allowing for pooling of data. Overall survival at one-year was pooled using the Review Manager 4.2.1 meta-analysis software program (version date: April 9, 2003; © The Cochrane Collaboration). The random effects model was used for all comparisons, and results were expressed as relative risk ratios with a 95% confidence interval and p-value.

Expert Consensus

1998 Guideline

The Gastrointestinal Cancer Disease Site Group (DSG) discussion centred around the one available randomized controlled trial. The DSG was concerned that the methodology used to assess clinical benefit had not been independently validated. Group members also felt that the potential for bias existed because trial physicians were aware of the treatment that patients received. The possibility that 5-fluorouracil (FU) may have worsened outcome compared to no treatment could have been addressed by having a no-treatment control arm, although a worsened outcome was considered unlikely. The DSG generally agreed that the study was clinically sound and that gemcitabine appears to be useful in the treatment of advanced pancreatic cancer, possibly benefiting asymptomatic patients by prolonging progression-free survival. The DSG was aware of the limitations of the data because only one trial has been published but thought that the final design was generally sound and that this trial remains the best available evidence to date for a patient population for which no other effective treatment exists. The emerging literature on this topic will be followed closely.

2005 Update

Adding known cytotoxic agents to gemcitabine has not yet resulted in a detectable one-year survival benefit, and carries the disadvantage of added toxicity. The study by Berlin et al suggests some improvement with the addition of 5-fluorouracil (p=ns), as does the study by Moore et al, which suggests an improvement with the addition of erlotinib (p=ns); therefore trials comparing gemcitabine monotherapy against a combination treatment also containing gemcitabine should be further explored in future randomized controlled trials (RCTs). The emerging literature on this topic will be followed closely.

Not applicable

A formal cost analysis was not performed and published cost analyses were not reviewed.

External Peer Review
Internal Peer Review

Practitioner Feedback

Based on the evidence described in the original report and the draft recommendations presented in the original guideline document, feedback was sought from Ontario clinicians.

Practitioner feedback was obtained through a mailed survey of 63 practitioners in Ontario. The survey consisted of items evaluating the methods, results, and interpretive summary used to inform the draft recommendations and whether the draft recommendations should be approved as a practice guideline. Written comments were invited. Follow-up reminders were sent at two weeks (post card) and four weeks (complete package mailed again). The results of the survey were reviewed by the Gastrointestinal Cancer Disease Site Group.

The final recommendations were approved by the Gastrointestinal Cancer Disease Site Group and the Practice Guidelines Coordinating Committee.

Gemcitabine should be offered as treatment to patients with advanced or unresectable pancreatic cancer. There is evidence from one randomized controlled trial that gemcitabine improves symptoms and modestly improves survival in patients with advanced or unresectable pancreatic cancer. These patients were symptomatic, had a life expectancy of at least twelve weeks, and a Karnofsky performance status of at least 50% (equivalent to an Eastern Cooperative Oncology Group [ECOG] performance status of less than 3).

A clinical algorithm is provided for assessment of clinical benefit.

The recommendations are supported by randomized controlled trials and meta-analyses.

• A total of 16 randomized controlled trials (RCTs) were obtained for this review. Three RCTs compared gemcitabine with other single-agents, and to date, only the trial by Burris et al (comparing gemcitabine with 5-fluorouracil [5-FU]) has detected a statistically significant difference favouring gemcitabine. Eleven trials obtained compared gemcitabine with combined treatment regimens that all included gemcitabine in the comparison arm and none of these trials detected any significant difference in one-year survival between the treatment arms. A single trial compared gemcitabine alone against a combination of 5-fluorouracil, leucovorin calcium, epirubicin, and carboplatin and no difference in one-year survival was detected between the treatment arms. Another single trial obtained compared gemcitabine plus concurrent radiotherapy with 5-fluorouracil plus concurrent radiotherapy and no difference in one-year survival between the treatment arms was detected.
• Pooling the one-year mortality data from the trials with one-year survival data available did not detect any overall statistically significant difference between the groups for gemcitabine alone versus another single-agent (relative risk [RR]=0.89; 95%CI, 0.79, 1.02; p=0.09), gemcitabine alone versus gemcitabine plus another single agent (RR=1.04; 95%CI, 1.00, 1.09; p=0.05), gemcitabine alone versus other combined treatment not containing gemcitabine (RR=1.22 (95%CI, 0.99, 1.51; p=0.06), or combined gemcitabine treatment versus other combined treatment not containing gemcitabine (RR=0.65 (96%CI, 0.94, 1.08; p=0.83).

The most common grade 3/4 (World Health Organization [WHO] or National Cancer institute-Common Toxicity Criteria [NCI-CTC] scale) adverse effects experienced with the administration of gemcitabine were neutropenia, anemia, leukopenia, thrombocytopenia, diarrhea, nausea, vomiting, and mucositis. One trial reported grade 3/4 anorexia.

Care has been taken in the preparation of the information contained in this document. Nonetheless, any person seeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances or seek out the supervision of a qualified clinician. Cancer Care Ontario makes no representation or warranties of any kind whatsoever regarding their content or use or application and disclaims any responsibility for their application or use in any way.

An implementation strategy was not provided.

End of Life Care
Living with Illness

Effectiveness

• Germond C, Maroun J, Moore M, Zwaal C, Wong S, Gastrointestinal Cancer Disease Site Group. Use of gemcitabine in the treatment of advanced pancreatic adenocarcinoma. Toronto (ON): Cancer Care Ontario (CCO); 2005 Jun 24. 21 p. (Practice guideline report; no. 2-10). [27 references]

Not applicable: The guideline was not adapted from another source.

1998 May 22 (revised 2005 Jun 24)

Program in Evidence-based Care - State/Local Government Agency [Non-U.S.]

The Program in Evidence-based Care (PEBC) is a project supported by Cancer Care Ontario and the Ontario Ministry of Health and Long-Term Care.

Cancer Care Ontario
Ontario Ministry of Health and Long-Term Care

Provincial Gastrointestinal Cancer Disease Site Group

Members of the Gastrointestinal Cancer Disease Site Group disclosed potential conflict of interest information.

None available

This summary was completed by ECRI on August 19, 1999. The information was verified by the guideline developer as of September 17, 1999. This NGC summary was updated by ECRI on December 17, 2001 and most recently on June 23, 2003. The most recently updated information was verified by the guideline developer as of July 16, 2003. This summary was updated again on April 19, 2004. The information was verified by the guideline developer on April 29, 2004. This NGC summary was updated on August 18, 2006. The updated information was verified by the guideline developer on August 23, 2006.