Therapy localized gastric cancer--a CLASSIC shift in the paradigm
NEWS & VIEWS
7. Bernal, W., Auzinger, G., Dhawan, A. &
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Pharmacol. 73, 285–294 (2012).9. Ostapowicz, G. A. et al. Results of a prospective
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THERAPY
Localized gastric cancer—a CLASSIC shift in the paradigm? Mariela A. Blum and Jaffer A. Ajani
The management of localized gastric cancer has evolved globally to region-specific approaches with little convergence. The unifying theme, however, is that surgery alone is insufficient for best outcomes, and adjunctive therapy must be offered. Multidisciplinary evaluation before therapy is highly recommended, but postoperative approaches are not conducive to this scenario.
Blum, M. A. & Ajani, J. A. Nat. Rev. Gastroenterol. Hepatol. 9, 194–195 (2012); published online 6 March 2012; doi:10.1038/nrgastro.2012.35
Localized gastric cancer (LGC) pres-ents considerable challenges because it is best treated with multiple modalities and multi d isciplinary collaborations. However, practice cultures in many regions have not embraced the multidisciplinary evalua-tion of patients with LGC before start-ing therapy. Preoperative approaches by their very nature require multi d isciplinary evalua t ion, whereas postoperative therapy does not. In addition, surgical quality control (that is, specific requirements for particular surgical procedures or approaches) has remained an important issue in investigations of LGC; whilst studies in Western regions (USA and Europe) have implemented no surgical quality control,1,2 it has been an impor-tant routine in Asia—surgeons follow a minimum surgical standard (anatomic dissection of nodes) in most Asian coun-tries.3–5 The Asian approach to LGC has consistently been a postoperative one.3–5 We briefly summarize two recent reports on the subject of adjunctive therapy for resected gastric cancer,4,5 but highlight in particular data on postoperative chemotherapy for LGC by Bang and colleagues4 as some of the latest information to be released. Bang et al.4 reported that adjuvant chemo t herapy, compared with observa-tion, prolonged disease-free survival at
3 years of patients with gastric cancer after
a D2 gastrectomy—the CLASSIC trial. 1,035 patients with LGC (stage II to IIIB)
were enrolled in this trial. D2 gastrec-
tomy was a requirement (median number
of nodes evaluated was ~45) and patients
were randomly assigned to receive either
6 months of capecitabine and oxali p latin
every 3 weeks or observation (surgery
alone).4 The disease-free survival at 3 years
(the primary end point) was significantly
prolonged in patients who received chemo-
therapy compared with those who did not
(74% versus 59%; hazard ratio 0.56 with
95% CI 0.44–0.72; P <0.0001). Overall
survival was not prolonged by adjuvant
chemotherapy. Furthermore, of those in
the chemotherapy plus surgery group, 56%
had grade 3 or 4 adverse events compared
with only 6% in those who did not receive
adjuvant chemotherapy (surgery only with
observation). Hematological toxicities,
peripheral neuropathy, nausea and vomiting
constituted these common adverse events.
The CLASSIC trial4 is somewhat similar
to the Japanese (ACTS-GC) trial that
investigated postoperative therapy with
the fluoropyrimidine derivative S-1 and
was based on the primary end point of
overall survival, which established S-1 as
a standard therapy for LGC after D2 gas-
trectomy.3,6 Two major differences exist
between the CLASSIC and the ACTS-GC
trials: primary end point (disease-free sur-
vival versus overall survival); and dura-
tion and type of therapy (6 months versus
12 months duration; capcitabine plus
oxaliplatin versus S1, respectively).3,4,6 The
ACTS-GC trial6 results established level 1
evidence for adjuvant therapy after D2 gas-
trectomy and the CLASSIC trial will join
these ranks once an overall survival advan-
tage has been established with adjuvant
chemotherapy. The ARTIST trial5 in Korea
tried, and failed, to replicate the findings of
the Western approach utilized in Intergroup
0116.1 However, the ARTIST trial5 differed
in three key elements from this particular
study:1 chemotherapy as control (compared
with observation only after surgery in the
Intergroup study1); inclusion of many early
stage patients (~50% of stage IB to II in the
ARTIST trial5 compared with only 31%
with this disease stage in the Intergroup
study1); and D2 gastrectomy as a require-
ment compared with no requirement for
any specific type of surgery—that is, no
surgical quality control—in the Intergroup
study.1 The results of the latest trials from
Asia3–6 raise intriguing considerations. We
can now speculate about D2 gastrectomy
for LGC: chemoradiation does not seem to
add much value if a D2 dissection is per-
formed5 and the CLASSIC4 and ACTS-GC3,6
trial results suggest that adjuvant chemo-
therapy works well after a D2 gastrectomy.
Perhaps the removal of as many nodes as
possible7 enables chemotherapy to become
effective and obliterates the advantage of
chemoradiation? No explanation, however,
exists to this quandary at present and many
questions remain.
Armed with this new knowledge, can we
enforce a convergence between the evolved
approaches in different regions worldwide?
Should we even attempt to converge these
approaches, or should we simply exploit our
strengths? These are difficult questions to
answer. D2 gastrectomy is not a standard
of care (and is highly debated) in Western
countries, unlike in the Bang et al.4 study
discussed above. D2 dissection will prob-
ably not be uniformly implemented world-
wide, at least in the USA, where the scarcity
of patients with gastric cancer hampers the
implementation of D2 gastrectomy and
US surgeons question the value of D2 dis-
section on the basis of previous random-
ized trial results.8 Adjuvant chemotherapy ‘‘…disease-free survival
at 3 years … was significantly
prolonged in patients who received chemotherapy…’’
NEWS & VIEWS
will, therefore, probably not benefit many patients in Western regions because of the lack of quality control in the surgical approach (that is, the incomplete dissection or evaluation of the nodes). Therefore, con-tinued recommendation of post o perative chemoradiation is appropriate in these regions. We emphasize that the pre o perative approach has the highest appeal because it demands multidisciplinary collaboration and, ultimately, improves patient outcomes. Finally, in a relentless pursuit of the Western approach, the ARTIST investi-gators have proposed yet another trial of postoperative chemoradiation in patients with lymph-node-positive LGC. We cannot condone this strategy as we are at the cusp of taking advantage of the advances in genomics, genetics and proteomics to indi-vidualize therapy for patients with gastric cancer.9,10 We should instead divert our resources to gain in-depth understanding of the molecular biology of LGC and the effects of patient genetics. Only through such knowledge can we optimize therapy for our patients. Expending our resources to mount yet another empiric trial should not be our priority—the era of one size fits all is behind us.
Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA (M. A. Blum,
J. A. Ajani).
Correspondence to: J. A. Ajani
jajani@https://www.wendangku.net/doc/d011587205.html,
Competing interests
The authors declare no competing interests.
1. Macdonald, J. S. et al. Chemoradiotherapy after
surgery compared with surgery alone for
adenocarcinoma of the stomach or
gastroesophageal junction. N. Engl. J. Med.
345, 725–730 (2001).
2. Cunningham, D. et al. Perioperative
chemotherapy versus surgery alone for
resectable gastroesophageal cancer.
N. Engl. J. Med.355, 11–20 (2006).
3. Sakuramoto, S. et al. Adjuvant chemotherapy
for gastric cancer with S-1, an oral
fluoropyrimidine. N. Engl. J. Med.357,
1810–1820 (2007).
4. Bang, Y. J. et al. Adjuvant capecitabine and
oxaliplatin for gastric cancer after D2
gastrectomy (CLASSIC): a phase 3 open-label,
randomised controlled trial. Lancet379,
315–321 (2012).
5. Lee, J. et al. Phase III trial comparing
capecitabine plus cisplatin versus capecitabine
plus cisplatin with concurrent capecitabine
radiotherapy in completely resected gastric
cancer with D2 lymph node dissection:
the ARTIST Trial. J. Clin. Oncol.30, 268–273
(2012).
6. Sasako, M. et al. Five-year outcomes of a
randomized phase III trial comparing adjuvant
chemotherapy with S-1 versus surgery alone in
stage II or III gastric cancer. J. Clin. Oncol.29,
4387–4393 (2011).
7. Kattan, M. W., Karpeh, M. S., Mazumdar, M. &
Brennan, M. F. Postoperative nomogram for
disease-specific survival after an R0 resection
for gastric carcinoma. J. Clin. Oncol.21,
3647–3650 (2003).
8. Ajani, J. A., Blum, M. A., Estrella, J. S., Das, P. &
Fournier, K. F. Gastric cancer: apples will always
be apples. J. Clin. Oncol. https://www.wendangku.net/doc/d011587205.html,/
10.1200/JCO.2011.40.9607.
9. Cho, J. Y. et al. Gene expression signature-
based prognostic risk score in gastric cancer.
Clin. Cancer Res.17, 1850–1857 (2011).
10. Tan, I. B. et al. Intrinsic subtypes of gastric
cancer, based on gene expression pattern,
predict survival and respond differently to
chemotherapy. Gastroenterology141,
476–485.e411 (2011).
COLONOSCOPY
Diagnostic yield of flexible sigmoidoscopy and CTC
Perry J. Pickhardt
A recent study demonstrates that concurrent flexible sigmoidoscopy in conjunction with CT colonography (CTC) does not improve the diagnostic yield for left-sided colorectal neoplasia compared with CTC alone. This study provides further evidence that CTC is not only more sensitive than the double contrast barium enema, but could be superior to endoscopy for initial evaluation.
Pickhardt, P. J. Nat. Rev. Gastroenterol. Hepatol.9, 195–196 (2012); published online 6 March 2012;
doi:10.1038/nrgastro.2012.40
Double contrast barium enema (DCBE) and
flexible sigmoidoscopy are considered to
be complementary tests for colorectal neo-
plasia and have been used in conjunction.
DCBE enables minimally invasive evalua-
tion of the proximal colon, and flexible sig-
moidoscopy increases the diagnostic yield
for left-sided evaluation. However, because
CT colonography (CTC) has now replaced
DCBE as the radiologic study of choice
for colorectal evaluation, the question of
whether the addition of flexible sigmoido-
scopy to CTC gives increased diagnostic
yield has become relevant. Selinger and
colleagues investigated this issue in a ret-
rospective analysis of symptomatic patients
who underwent concurrent CTC and flex-
ible sigmoidoscopy.1 Their main conclu-
sion was that flexible sigmoidoscopy did
not provide a sufficient additional yield to
warrant being used to supplement CTC.
The patient cohort represented a gener-
ally older (mean age 67 years), symptomatic
population rather than an asymptomatic
screening population (which in my experi-
ence averages around 58 years). Data from
a total of 294 patients who underwent both
CTC and flexible sigmoidoscopy (with a
median time interval between procedures
of 15 days) were included for retrospec-
tive analysis. The main outcome mea-
sures were left-sided cancers and ‘serious
pathology’—defined as any cancer or large
adenoma (≥10 mm). Detected lesions that
were proximal to the splenic flexure at CTC
were excluded from analysis as these would
presumably be beyond the reach of flex-
ible sigmoidoscopy. One low rectal cancer
was missed with CTC but identified using
flexible sigmoidoscopy; no large adeno-
mas were detected with flexible sigmoido-
scopy that had been missed during CTC,
resulting in an additional yield of serious
pathology of 0.34% when using flexible
sigmoidoscopy. In comparison, eight left-
sided cancers were detected with CTC but
not flexible sigmoido s copy. Five of the eight
missed cancers were thought to be related to
incomplete coverage at flexible sigmoido-
scopy, reflecting the fact that intubation of
the splenic flexure was achieved in only 46%
of cases.
Some limitations of this study should
be considered. With the exception of large
adenomas, polyp sizes were not reported,
making the assessment of less important
findings (such as nonadvanced adenomas)
more difficult. Furthermore, it seems that
no formal matching protocol was applied
to compare lesions detected with CTC and
those found with flexible sigmoidoscopy.
It would be interesting to know how many
important lesions were detected proximal
to the splenic flexure at CTC, because total
colonic examination is clearly an advantage
that CTC has over flexible sigmoidoscopy.