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Editorial
Predictive or non-predictive, prognostic or non-prognostic:
Dilemmas generated through small retrospective studies
Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY
J Gastrointest Oncol 2010; 1: 72-73. DOI: 10.3978/j.issn.2078-6891.2010.021
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In this issue of the Journal of Gastrointestinal Oncology,
Katkoori et al report on the impact of the pro-apoptotic
protein Bax and its ratio to the anti-apoptotic portein Bcl2
(Bax/Bcl2) by immunohistochemistry grading on the
outcome of patients with colorectal cancer treated with
curative intent surgery or curative intent surgery followed
by 5-FU-based chemotherapy (1). The chemotherapy group
was selected from a patient population treated with curative
intent surgery followed by at least 3 months of infusional
5-FU based chemotherapy or 6 months of bolus 5-FU-based
chemotherapy between the years 1987-1993. The surgical
control group was matched to the chemotherapy group by
age, sex, stage, ethnicity, differentiation, and tumor location.
The investigators demonstrate a better survival outcome in
patients with increased Bax expression vs low Bax expression
in the absence of chemotherapy (surgery only). A trend
towards a worsened survival outcome is noted in patients
with increased Bax expression vs low Bax expression in the
presence of chemotherapy. Furthermore, a low Bax/Bcl2
ratio was associated with a better survival outcome in
comparison to high Bax/Bcl2 ratio in the presence of 5-FU
based chemotherapy. The authors conclude that patients
with higher Bax expression may not benefit from adjuvant
chemotherapy.
One has to recognize that there are several limitations
to the Katkoori study. First, the study suf fers from
a small and heterogeneous population. Twenty-five
percent of patients investigated in this study had stage
IV disease. Therefore, data ex trapolation from this heterogeneous population to adjuvant treatment in stage
II-III disease cannot be applied. If the intent of the study
is to investigate the impact of Bax on the effectiveness
of adjuvant chemotherapy, it would have been advisable
to limit the study population to stages II-III disease.
Second, it is impossible from the current study design
to conduct a meaningful evaluation of the impact of
Bax or Bax/Bcl2 or p53 on OS within the surgical and
chemotherapy groups. Since patient characteristics among
the various biomarker groups had not been matched for
other known risk variables of relapse within the surgery
and chemotherapy groups, it would be possible that the
divergence in outcome was due to an imbalance in other
patient characteristics rather than due to Bax of Bax/Bcl2.
Third, the study assumes no differences between various
arms of 5-FU-based therapy in the chemotherapy arm, a
finding refuted by prior randomized studies.
Is Bax prognostic? In the surgical group that did not
receive chemotherapy, patients with elevated Bax had
an improved survival. This would suggest that Bax overexpression
is a positive prognostic factor. This could only
be hypothesized if the high and low-Bax patients in the
surgery-only arm were matched by stage, grade, and other
relevant risk factors. This was not the case.
Is Bax/bcl-2 predictive of 5-FU response? In the patient
undergoing surgery followed by 5-FU, patients with low
bax/bcl-2 has a superior outcome than patients with
high Bax/Bcl2. This would suggest that high bax/blc-2 is
predictive of 5-FU resistance. This can only be hypothesized
if the two groups were matched for other risks of recurrence
or progression. This was not the case.
Stage heterogeneit y, sma l l sample si ze, and the
heterogeneity of 5-FU-based therapy, significantly limit
the results from this study. In addition, the results do not
support findings from a larger series evaluating the impact
of Bax and Bcl2 expression on 5-FU-treated colorectal
cancer patients (2). In a study of 188 patients treated
with 5-FU based chemotherapy, low Bax expression was associated with a worsened outcome and patients with high
Bax expression and low Bcl2 had the best outcome (2).
How do we move forward? This study illustrates the
limitations of analyzing subjectively graded variables in
a heterogeneous colorectal cancer population. It is time
to recognize the complex interactions between variable
prognostic markers of progression and disease resistance.
Such interactions can only be tested in large patient
populations whose baseline characteristics and outcomes
were collected in a prospective controlled manner. A
quantitative multi-gene RT-PCR assay for the prediction of
recurrence in stage II colon cancer was recently developed
by Genome Science using the QUASAR study population
(3). While this assay is somewhat successful in categorizing
stage II colon cancer into 3 distinct categories of risk of
relapse, it failed to predict for benefit or lack off with 5-FU
therapy. Oncotype DX profiling is one step in the right
direction, but more work is clearly needed.
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References
Cite this article as:
Fakih M. Predictive or non-predictive, prognostic or non-prognostic:
Dilemmas generated through small retrospective studies. J Gastrointest Oncol. 2010;1(2):72-73. DOI:10.3978/j.issn.2078-6891.2010.021
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