AC Berger

BL Brucher

D Cunningham

D Kelsen

DM Parkin

JA Ajani

Jaffer A. Ajani

JS Macdonald

K Ott

L Leichman

LR Chirieac

M Gibson

M Sasako

NP Rizk

PR Rohatgi

T Sjoblom

English

PubMed

Crossref

Can We Understand the Clinical Biology of Gastric Cancer and Exploit it? May be, but It is a Challenge!

Springer - Publisher Connector

Can We Understand the Clinical Biology of Gastric Cancer
and Exploit it? May be, but It is a Challenge!
Jaffer A. Ajani, M.D.
Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd,
Houston, Texas 77030, USA
Gastric cancer remains a signiﬁcant health problem
worldwide,1 and yet the progress has been much
slower against gastric cancer than against other can-
cers (colon, breast, lung, and prostate); however, the
other cancers are more common in the West. Reasons
for this discrepancy are many, but it is clear that if a
cancer type is common in the West, it gets attention
from the pharmaceutical companies and the U.S.
Government. Our approach to localized gastric can-
cer has been typical of that for many other localized
cancers; that is, we attempt a good clinical staging
process and treat all deﬁned stages similarly (empir-
icism). Whether we use preoperative therapy, surgery,
or postoperative adjuvant therapy, one thing is cer-
tain: all patients with >T1 cancers when offered
uniform therapy end up with diverse outcomes.
Without much insight, we simply follow our patients
to see who survives and who dies. We also witness
unpredictable and sometime extraordinary toxicities
(complications) experienced by our patients. The
question is how can we possibly get out of this modus
operandi? Recent molecular studies have demon-
strated surprising intertumoral molecular heteroge-
neity that was unexpected, creating even more
challenges than we thought previously.2 In gastric
cancer, our limited knowledge restricts us even fur-
ther, but it may be time to face that challenge.
The article byMansour et al.3 provides some clues as
to how one could possibly go about this. In this issue of
the Journal, the authors from the Memorial Sloan
Kettering Cancer Center relate their experience in 168
patients with curatively resected gastric cancer who
received various combinations of cytotoxics preoper-
atively (and sometime postoperatively). The authors
systematically examined the resected specimens to
judge the degree of residual cancer and correlated the
degree of ‘‘response’’ to disease-speciﬁc-survival
(DSS). The authors found that the 3-year DSS was
signiﬁcantly different in the univariate but not in the
multivariate analysis. No overall survival correlations
are stated, and I am assuming that none existed. They
observed that the presence of metastatic lymph nodes
and perineural invasion were independently predictive
of DSS in the multivariate analysis. The authors con-
clude that prediction and prognostication in patients
with localized gastric cancer are complicated, and one
may have to lean on multiple parameters (clinical and
biologic) to make advances.
There are many issues worth pondering. Clearly,
studies in esophageal cancer have taught us a great
deal,4–8 and some studies in gastric cancer9–13 seem to
show similar results. Tounderstand this succinctly, one
must recognize that all the elements of heterogeneous
clinical biologic expressions are embodied in the pri-
mary cancer, and these manifest based on the level of
injury one inﬂicts on it. Chemotherapy is less likely to
lead to a manifestation of a higher level of heteroge-
neity compared with chemoradiation therapy (this is
well known in esophageal and gastric cancers). As in
the Mansour et al. study, and there are numerous
examples published already; the most recent is one by
Received July 11, 2007; accepted July 13, 2007; published online:
October 12, 2007.
Commentary to Doi: 10.1245/s10434-007-9574-6
Address correspondence and reprint requests to: Jaffer A. Ajani,
M.D.; E-mail: Jajani@mdanderson.org
Published by Springer Science+Business Media, LLC  2007 The Society of
Surgical Oncology, Inc.
Annals of Surgical Oncology 14(12):3290–3292
DOI: 10.1245/s10434-007-9575-5
3290
Stahl et al.14 showing that the rate of pathologic
complete response (pathCR) or even substantial re-
sponse (1–50% residual cancer) is low with chemo-
therapy alone compared with chemoradiation. I
believe this might be one reasonMonsour et al. did not
see substantial correlation between patient outcome
and residual cancer in the surgical specimen. The rate
of pathCR is higher when one uses preoperative
chemoradiation in esophageal cancers5–7,14 or gastric
cancer9–11 than when chemotherapy is used. This
means that amore potent therapy seems to uncover the
true nature of clinical biology of the gastric cancer
better than a less potent therapy. When that happens,
we begin to see the correlation between the degree of
residual cancer and patient outcome.4,6,9–11,15
I agree with Mansour et al. that we should explore
new ways to predict response. Positron emission
tomography (PET) is one method, but there are
considerable limitations of PET in gastric cancer.
Nearly 45% of the cancers are not PET-avid,16 and
10% of the time, the fundus may have physiologic
(false-positive) PET uptake (that may complicate
interpretations). Thus the number of patients we can
work with remains less than optimum and, therefore,
creates another challenge. However, more speciﬁc
imaging studies (evaluating proliferation, apoptosis,
or oxygenation) might prove useful in this setting. In
addition, studying the cancer biology might allow us
to individualize therapy and follow-up.
Preoperative therapy strategy has been around for a
long time,17–19 but it is only now that we are seeing
some of the results of prospective evaluation,20,21 and
the strategy needs considerable reﬁnements and up-
grades. Clearly, the preoperative chemoradiation ap-
proach presents itself as a worthy preoperative
strategy to be compared with preoperative chemo-
therapy alone or with postoperative chemoradiation.
The positive results from some preoperative and
postoperative approaches20–23 have created an
excitement as well as some confusion. The NCCN
guideline (www.nccn.org) for localized gastric cancer
has taken the position to accept surgery as primary
therapy (to allow for postoperative adjuvant che-
moradiotherapy or enrollment into the ongoing clin-
ical trial) or preoperative approach (when the
multidisciplinary infrastructure is in place). In con-
trast, in the countries where gastric cancer is common
(Japan, Korea, Chile, Peru, China, etc.), the preop-
erative approach is not practiced and postoperative
therapy is not a standard. We have a long way to go to
unify our approaches to localized gastric carcinoma.
Finally, the residual cancer after preoperative
chemoradiation can tell us a great deal about the
clinical biology of gastric cancer. It can be a useful
tool to communicate the prediction of patient out-
come with our colleagues, patients, and families but it
can also teach us a great deal about designing
sophisticated trials that might prove beneﬁcial for our
patients. It is time to make noise in support of
adoption of a routine multidisciplinary approach to
localized gastric cancer and to explore gastric cancer
biology.
REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statis-
tics, 2002. CA Cancer J Clin 2005; 55:74–108.
2. Sjoblom T, Jones S, Wood DL, et al. The consensus coding
sequences of human breast and colorectal cancers. Science
2006; 314:268–74.
3. Mansour JC, Tang L, Shah M, et al. Does graded histologic
response after neoadjuvant chemotherapy predict survival
for completely resected gastric cancer? Ann Surg Oncol 2007
doi:10.1245/s10434-007-9574-6.
4. Rizk NP, Venkatraman E, Bains MS, et al. American Joint
Committee on cancer staging does not accurately predict sur-
vival in patients receiving multimodality therapy for esopha-
geal adenocarcinoma. J Clin Oncol 2007; 10:507–12.
5. Gibson M, Burtness B, Heath E, et al. Effect of neoadjuvant
chemoradiotherapy on pathologic stage and survival in pa-
tients with locally advanced esophageal cancer. Proc Am Soc
Clin Oncol 2004; 22:14S, (4032).
6. Chirieac LR, Swisher SG, Ajani JA, et al. Posttherapy path-
ologic stage predicts survival in patients with esophageal car-
cinoma receiving preoperative chemoradiation. Cancer 2005;
103:1347–55.
7. Berger AC, Farma J, Scott WJ, et al. Complete response to
neoadjuvant chemoradiotherapy in esophageal carcinoma is
associated with signiﬁcantly improved survival. J Clin Oncol
2005; 23:8706–12.
8. Brucher BL, Becker K, Lordick F, et al. The clinical impact of
histopathologic response assessment by residual tumor cell
quantiﬁcation in esophageal squamous cell carcinomas. Cancer
2006; 15:2119–27.
9. Ajani JA, Mansﬁeld PF, Janjan N, et al. Multi-institutional
trial of preoperative chemoradiotherapy in patients with
potentially resectable gastric carcinoma. J Clin Oncol 2004;
22:2774–80.
10. Ajani JA, Mansﬁeld PF, Crane CH, et al. Paclitaxel-based
chemoradiotherapy in localized gastric carcinoma: degree of
pathologic response and not clinical parameters dictated pa-
tient outcome. J Clin Oncol 2005; 23:1237–44.
11. Ajani JA, Winter K, Okawara GS, et al. Phase II trial of
preoperative chemoradiation in patients with localized gastric
adenocarcinoma (RTOG 9904): quality of combined modality
therapy and pathologic response. J Clin Oncol 2006; 24:3953–8.
12. Rohatgi PR, Mansﬁeld PF, Crane CH, et al. Surgical pathol-
ogy stage by American Joint Commission on Cancer criteria
predicts patient survival after preoperative chemoradiation for
localized gastric carcinoma. Cancer 2006; 107:1475–82.
13. Rohatgi PR, Mansﬁeld PF, Crane CH, et al. Clinical stage
after preoperative chemoradiation is a better predictor of pa-
tient outcome than the baseline stage for localized gastric
cancer. Cancer 2007; 110:989–95.
14. Stahl M, Walz M, Stuschke M, et al. Preoperative chemo-
therapy (CTX) versus preoperative chemoradiotherapy
(CRTX) in locally advanced esophagogastric adenocarcino-
EDITORIAL 3291
Ann. Surg. Oncol. Vol. 14, No. 12, 2007
mas: First results of a randomized phase III trial. 2007 ASCO
Annual Meeting Proceedings. J Clin Oncol 2007.
15. Rohatgi PR, Swisher SG, Correa AM, et al. Failure patterns
correlate with the proportion of residual carcinoma after pre-
operative chemoradiotherapy for carcinoma of the esophagus.
Cancer 2005; 104:1349–55.
16. Ott K, Fink U, Becker K, et al. Prediction of response to
preoperative chemotherapy in gastric carcinoma by metabolic
imaging: results of a prospective trial. J Clin Oncol 2003;
21:4604–10.
17. Ajani JA, Ota DM, Jessup JM, et al. Resectable gastric car-
cinoma. An evaluation of preoperative and postoperative
chemotherapy. Cancer 1991; 68:1501–6.
18. Leichman L, Silberman H, Leichman CG, et al. Preoperative
systemic chemotherapy followed by adjuvant postoperative
intraperitoneal therapy for gastric cancer: a University of
Southern California pilot program. J Clin Oncol 1992;
10:1933–42.
19. KelsenD,KarpehM, SchwartzG, et al. Neoadjuvant therapy of
high-risk gastric cancer: a phase II trial of preoperative FAMTX
and postoperative intraperitoneal ﬂuorouracil-cisplatin plus
intravenous ﬂurouracil. J Clin Oncol 1996; 14:1818–28.
20. Boige V, Pignon J, Saint-Aubert B, et al. Final results of a
randomized trial comparing preoperative 5-ﬂuorouracil (F)/
cisplatin (P) to surgery alone in adenocarcinoma of stomach
and lower esophagus (ASLE): FNLCC ACCORD07-FFCD
9703 trial. 2007 ASCO Annual Meeting.
21. Cunningham D, Allum WH, Stenning SP, et al. Perioperative
chemotherapy versus surgery alone for resectable gastro-
esophageal cancer. N Engl J Med 2006; 355:11–20.
22. Macdonald JS, Smalley SR, Benedetti J, et al. Chemoradio-
therapy after surgery compared with surgery alone for ade-
nocarcinoma of the stomach or gastroesophageal junction. N
Engl J Med 2001; 345:725–30.
23. Sasako M, Yamaguchi T, Kinorshita T, et al. Randomized
phase III trial comparing S-1 monotherapy versus surgery
alone for stage II/III gastric cancer patients after curative D2
gastrectomy (ACTS-GC study). (Abstract No. 8). 2007 ASCO
Gastrointestinal Cancers Symposium Orlando, FL: American
Society of Clinical Oncology; 2007.
EDITORIAL3292
Ann. Surg. Oncol. Vol. 14, No. 12, 2007


file:///data/core-remote/dit/data/Springer-OA/pdf/9c7/aHR0cDovL2xpbmsuc3ByaW5nZXIuY29tLzEwLjEyNDUvczEwNDM0LTAwNy05NTc1LTUucGRm.pdf

Can We Understand the Clinical Biology of Gastric Cancer and Exploit it? May be, but It is a Challenge!

Abstract

Similar works

Full text

Available Versions

Crossref

Springer - Publisher Connector