Goldstein_subbed 17/7/09 14:32 Page 75
Advances in Treatment Options for Patients with Pancreatic Cancer
irinotecan or 5-FU; the inclusion of studies not previously reviewed in tolerable and in the form of a skin rash; importantly, those who
earlier meta-analyses could help to explain this. The platinum results demonstrated this toxicity were associated with a better outcome.
have led to several studies of new-generation platinum agents such Prospective predictive factors to identify those most likely to benefit will
as oxaliplatin. In a randomized phase III study, Louvet et al. assigned maximize cost-efficacy and increase the utilization of such therapies.
patients to either gemox (gemcitabine 1,000mg/m
2
on day one and Recently, a large phase III study utilizing a monoclonal antibody to the
oxaliplatin 100mg/m
2
on day two every two weeks) or gemcitabine EGFR added to gemcitabine in over 700 patients showed no differences
1,000mg/m
2
weekly alone. Gemox showed a superior response rate, in OS or PFS between treatment arms, although time to treatment failure
PFS, and clinical benefit; however, OS did not reach statistical was significantly prolonged with combination therapy.
52
significance. Given that the landmark Burris trial that led to
gemcitabine becoming the standard of care was based on clinical There have also been disappointing results with the angiogenesis
benefit, this suggests that further studies with gemox are warranted.
39
inhibitor bevacizumab. The CALGB 80303 study compared gemcitabine
plus bevacizumab versus gemcitabine alone in patients with advanced
Of note are two capecitabine studies. A Swiss study compared pancreatic cancer and showed no significant difference in treatment
gemcitabine and capecitabine versus gemcitabine alone. While there response or survival outcomes (HR 0.90, 95% CI 0.65-1.23; p=0.36 in
was no overall difference in survival rates, in subsequent sub-group favor of control).
53
Another study comparing gemcitabine in combination
analysis, with its acknowledged limitations, patients with a good with erlotinib versus the same combination plus bevacizumab showed
performance status (Karnofsky performance status [KPS] 90–100) had PFS increase of one month (p=0.0002), but no increase in OS.
54
A recent
a significant prolongation of median survival of 10.1 versus 7.4 randomized phase II study utilizing a new vascular endothelial growth
months (p=0.014).
40
No added gain in terms of quality of life or clinical factor inhibitor—axitinib—has shown important improvement over
benefit was seen for the combination.
41
gemcitabine alone, and may represent a new direction if the current
phase III trial is also positive.
55
A larger UK study has to date reported only its interim analysis.
The investigators used gemcitabine 1,000mg/m
2
weekly on days one, Conclusion
eight, and 15 every four weeks in combination with capecitabine We concluded that chemotherapy has a role in advanced disease.
1,660mg/m
2
/day for 21 days every four weeks, and showed Gemcitabine provides both local benefit and modest survival gains
significantly improved OS with the combination regime over and is the optimal single agent. In those with adequate performance
gemcitabine alone (HR 0.80, 95% CI 0.65–0.98; p=0.026). After status, combination with either platinum agents or capecitabine has
adjusting for baseline stratification factors, the survival advantage modest superiority to gemcitabine alone. Adjuvant therapy is an
remained (HR 0.77, 95% CI 0.63–0.95; p=0.014). Median survival for important advance over surgery alone. The role of chemoradiation in
gemcitabine and gemcitabine–capecitabine was six and 7.4 months, locally advanced disease remains uncertain, but requires
respectively, and one-year survival rates were 19 and 26%, investigation and support. However, despite improvements in
respectively.
42
The final results of this trial are yet to be published. An treatment, median survival in pancreatic cancer is poor, with
additional randomized phase II study of capecitabine combinations treatments making only a modest difference in survival. Ongoing
showed both efficacy and safety for both oxaliplatin and gemcitabine, research is needed, particularly in genomic profiling, biomarker
but no clear priority for any combination.
43
identification, and optimal use of targeted therapies, to select those
patients who will derive maximal benefit. ■
More recently, mature information has established a role for second-
line chemotherapy for appropriately selected patients. The
Carole Harris, MD, is a Medical Oncology Registrar at St
combination of capecitabine and erlotinib showed some modest
George Hospital in Sydney. She is interested in targeted
benefit, with a response rate of only 10% but a median survival of 6.5 therapies and gastrointestinal malignancy, and plans to
months.
44
This was followed by preliminary results of a randomized
start her PhD next year to develop this interest further. Dr
Harris has a degree in pharmacy.
trial of 5-FU and leucovorin versus 5-FU and oxaliplatin, with PFS of 13
versus nine weeks and an OS benefit of 26 versus 13 weeks.
45
Targeted therapies have also been trialed in pancreatic cancer, although
David Goldstein, MD, is a senior staff specialist in the
to date these have not been included in any meta-analyses.
46–50
Agents
Department of Medical Oncology at Prince of Wales
trialed in phase III trials include ras-farnesyltransferase inhibitors
Hospital in Sydney. He is Immediate Past President of the
Clinical Oncology Society of Australia (COSA) and was the
(tipifarnib), matrix metalloproteinase inhibitors (marimastat, Bay
previous Chairperson of the Gastrointestinal Malignancies
12–9566), and a gastrin vaccine, none of which showed increased
Group and of COSA. He is an active contributor to many
benefit from the addition of a targeted agent to gemcitabine. More
pancreatic cancer trials and has co-authored a number of
publications related to both trials and laboratory research
recently, a promising result was shown with erlotinib, an EGFR tyrosine
in this malignancy. His research interests include novel
kinase inhibitor. Erlotinib in combination with gemcitabine was superior
modes of growth inhibition, for which he has an ongoing
to single-agent gemcitabine in terms of OS (HR 0.81; p=0.025) and PFS
laboratory program, multimodality therapy in pancreatico-biliary cancers, post-treatment
fatigue, cross-cultural attitudes to cancer and their potential effects on outcomes. Dr
(HR 0.76; p=0.003).
51
There was also improved one-year survival of 24
Goldstein is also an advocate of cancer-service delivery to regional Australia as a result
versus 17% in favor of the combined regime. Of note, there was
of his own experiences as a provider of outreach rural services.
increased toxicity associated with erlotinib, but this was usually
US ONCOLOGY 75
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