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Preoperative Chemoradiotherapy for Esophageal or Junctional Cancer

31 May 2012-The New England Journal of Medicine (MASSACHUSETTS MEDICAL SOC)-Vol. 366, Iss: 22, pp 2074-2084

TL;DR: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer and the regimen was associated with acceptable adverse-event rates.
Abstract: A B S T R AC T BACKGROUND The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy–surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy– surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy–surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P = 0.003). CONCLUSIONS Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.)
Topics: Chemoradiotherapy (68%)

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original article
The
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2074
Preoperative Chemoradiotherapy
for Esophageal or Junctional Cancer
P. van Hagen, M.C.C.M. Hulshof, J.J.B. van Lanschot, E.W. Steyerberg,
M.I. van Berge Henegouwen, B.P.L. Wijnhoven, D.J. Richel,
G.A.P. Nieuwenhuijzen, G.A.P. Hospers, J.J. Bonenkamp, M.A. Cuesta,
R.J.B. Blaisse, O.R.C. Busch, F.J.W. ten Kate, G.-J. Creemers, C.J.A. Punt,
J.T.M. Plukker, H.M.W. Verheul, E.J. Spillenaar Bilgen, H. van Dekken,
M.J.C. van der Sangen, T. Rozema, K. Biermann, J.C. Beukema,
A.H.M. Piet, C.M. van Rij, J.G. Reinders, H.W. Tilanus,
and A. van der Gaast, for the CROSS Group*
The authors’ full names, degrees, and affili-
ations are listed in the Appendix. Address
reprint requests to Dr. van der Gaast at
the Department of Medical Oncology,
Erasmus University Medical Center/Daniel
den Hoed Cancer Center, P.O. Box 2040,
3000 CA Rotterdam, the Netherlands, or at
a.vandergaast@erasmusmc.nl.
* The members of the Chemoradiothera-
py for Oesophageal Cancer Followed by
Surgery Study (CROSS) Group are list-
ed in the Supplementary Appendix,
available at NEJM.org.
N Engl J Med 2012;366:2074-84.
Copyright © 2012 Massachusetts Medical Society.
ABSTR ACT
BACKGROUND
The role of neoadjuvant chemoradiotherapy in the treatment of patients with esopha-
geal or esophagogastric-junction cancer is not well established. We compared chemo-
radiotherapy followed by surgery with surgery alone in this patient population.
METHODS
We randomly assigned patients with resectable tumors to receive surgery alone or
weekly administration of carboplatin (doses titrated to achieve an area under the
curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of
body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions,
5 days per week), followed by surgery.
RESULTS
From March 2004 through December 2008, we enrolled 368 patients, 366 of whom
were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squa-
mous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the
366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery,
and 188 to surgery alone. The most common major hematologic toxic effects in the
chemoradiotherapy–surgery group were leukopenia (6%) and neutropenia (2%); the
most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%).
Complete resection with no tumor within 1 mm of the resection margins (R0) was
achieved in 92% of patients in the chemoradiotherapy–surgery group versus 69% in
the surgery group (P<0.001). A pathological complete response was achieved in 47 of
161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative
complications were similar in the two treatment groups, and in-hospital mortality was
4% in both. Median overall survival was 49.4 months in the chemoradiotherapy–
surgery group versus 24.0 months in the surgery group. Overall survival was sig-
nificantly better in the chemoradiotherapy–surgery group (hazard ratio, 0.657; 95%
confidence interval, 0.495 to 0.871; P = 0.003).
CONCLUSIONS
Preoperative chemoradiotherapy improved survival among patients with potentially
curable esophageal or esophagogastric-junction cancer. The regimen was associated
with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF
Kankerbestrijding]; Netherlands Trial Register number, NTR487.)
The New England Journal of Medicine
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Preoperative Chemoradiotherapy for Esophageal Cancer
n engl j med 366;22 nejm.org may 31, 2012
2075
W
ith new diagnoses in more than
480,000 patients annually, esophageal
cancer is the eighth most common can-
cer worldwide.
1
It is a highly lethal disease, causing
more than 400,000 deaths per year.
2
The incidence
of esophageal adenocarcinoma is rapidly rising,
whereas that of squamous-cell carcinoma remains
unchanged.
3
Despite adequate preoperative stag-
ing, 25% of patients treated with primary sur-
gery have microscopically positive resection mar-
gins (R1), and the 5-year survival rate rarely
exceeds 40%.
4
The role of neoadjuvant chemoradiotherapy has
been debated for several decades. In most random-
ized trials, no survival benefit could be shown, and
the trials were criticized for inadequate trial de-
sign, samples that were too small, and poor out-
comes in the surgery-alone group. Meta-analyses
suggest a survival benefit from neoadjuvant chemo-
radiotherapy, albeit frequently at the cost of in-
creased postoperative morbidity and mortality.
5,6
We previously reported a phase 2 trial of neo-
adjuvant chemoradiotherapy consisting of weekly
administration of carboplatin and paclitaxel with
concurrent radiotherapy.
7
This regimen was as-
sociated with a low rate of serious toxic effects,
and a complete resection with no tumor within
1 mm of the resection margins (R0) was achieved
in all patients who underwent resection. These re-
sults encouraged us to initiate a multicenter, ran-
domized, controlled, phase 3 study comparing
neoadjuvant chemoradiotherapy followed by sur-
gery with surgery alone in patients with poten-
tially curable esophageal or esophagogastric-
junction carcinoma.
8
METHODS
ELIGIBILITY CRITERIA
Patients with histologically confirmed, potentially
curable squamous-cell carcinoma, adenocarci-
noma, or large-cell undifferentiated carcinoma of
the esophagus or esophagogastric junction (i.e.,
tumors involving both the cardia and the esopha-
gus on endoscopy) were eligible for inclusion in
the study. The upper border of the tumor had to be
at least 3 cm below the upper esophageal sphincter.
Patients who had proximal gastric tumors with
minimal invasion of the esophagus were excluded.
The length and width of the tumor could not ex-
ceed 8 cm and 5 cm, respectively. Only patients
with tumors of clinical stage T1N1 or T2-3N0-1
and no clinical evidence of metastatic spread
(M0), according to the International Union
against Cancer (UICC) tumor–node–metastasis
(TNM) classification,
9
were enrolled. Eligible pa-
tients were 18 to 75 years of age, had a World
Health Organization (WHO) performance status
score of 2 or lower (on a scale of 0 to 5, with 0
indicating fully active, 1 unable to carry out
heavy physical work, and 2 up and about more
than half the day but unable to work), and had
lost 10% or less of body weight. Patients also had
to have adequate hematologic, renal, hepatic, and
pulmonary function, as well as no history of other
cancer or previous radiotherapy or chemotherapy.
All patients provided written informed consent.
The institutional review board at each participating
center approved the study protocol.
8
The protocol,
including the statistical analysis plan, is available
with the full text of this article at NEJM.org. No
commercial support was involved in the study;
the drugs were purchased. No one who is not an
author contributed to the manuscript. The first,
fourth, and last authors vouch for the accuracy
and completeness of the reported data and the
fidelity of the study to the protocol.
STAGING
All patients underwent pretreatment staging. This
included a history taking; physical examination;
pulmonary-function tests, routine hematologic
and biochemical tests; upper gastrointestinal en-
doscopy with histologic biopsy and endoscopic
ultrasonography; computed tomography of the
neck, chest, and upper abdomen; and external ul-
trasonography of the neck, with fine-needle aspi-
ration of lymph nodes when cancer was suspected.
For the final analysis, the available endoscopic re-
ports were centrally reviewed.
TREATMENT
Chemotherapy
On days 1, 8, 15, 22, and 29, carboplatin targeted
at an area under the curve of 2 mg per milliliter
per minute and paclitaxel at a dose of 50 mg per
square meter of body-surface area were adminis-
tered intravenously. All patients were intravenously
premedicated with dexamethasone, clemastine,
and ranitidine as well as standard antiemetic
agents. The patients were closely monitored for
toxic effects of chemotherapy with the use of the
National Cancer Institute’s Common Terminolo-
gy Criteria for Adverse Events, version 3.0.
10
The New England Journal of Medicine
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Radiotherapy
A total radiation dose of 41.4 Gy was given in 23
fractions of 1.8 Gy each, with 5 fractions admin-
istered per week, starting on the first day of the
first chemotherapy cycle. All patients were treated
by means of external-beam radiation. A detailed
description of the methods of administration of
chemotherapy and radiotherapy can be found in
Appendix 1 in the Supplementary Appendix, avail-
able at NEJM.org.
Surgery
Patients in the chemoradiotherapy–surgery group
underwent surgery as soon as possible after com-
pletion of chemoradiotherapy (preferably, within
4 to 6 weeks), and patients in the surgery group
were treated as soon as possible after randomiza-
tion. A transthoracic approach with two-field
lymph-node dissection was performed for tumors
extending proximally to the tracheal bifurcation.
For tumors involving the esophagogastric junction,
a transhiatal resection was preferred. Peritruncal
dissection was carried out with both approaches.
For all other tumors, the approach depended on the
characteristics of the patient and on local prefer-
ences. Gastric-tube reconstruction with a cervical
anastomosis was the preferred technique for re-
storing the continuity of the digestive tract.
PATHOLOGICAL ANALYSIS
Reports on pathological examination had to de-
scribe the tumor type and extension, lymph nodes,
and resection margins. In the absence of macro-
scopic tumor, any abnormal-appearing tissue
was paraffin-embedded in total in order to make
an adequate assessment for the presence of re-
sidual tumor and the effects of therapy.
To grade the response to therapy, we classified
the degree of histomorphologic regression into
four categories as follows: grade 1, no evidence of
vital residual tumor cells (pathological complete
response); grade 2, less than 10% vital residual
tumor cells; grade 3, 10 to 50%; and grade 4,
more than 50%.
11,12
If a vital tumor was present
at 1 mm or less from the proximal, distal, or cir-
cumferential resection margin, it was considered
to be microscopically positive (R1).
FOLLOW-UP
During the first year after treatment was com-
pleted, patients were seen every 3 months. In the
second year, follow-up took place every 6 months,
and then at the end of each year until 5 years af-
ter treatment. Late toxic effects, disease recur-
rence, and death were documented. Recurrences
were scored at the moment of the first recur-
rence. During follow-up, diagnostic investiga-
tions were performed only when recurrence was
suspected.
STATISTICAL ANALYSIS
We calculated that 175 patients were needed in
each group in order to detect a difference in me-
dian overall survival of 22 months in the chemo-
radiotherapy–surgery group versus 16 months in
the surgery group (two-sided test; alpha level,
0.05; beta level, 0.80). Stratification factors in-
cluded histologic tumor type, treatment center,
lymph-node (N) stage as determined by endo-
scopic ultrasonography, and WHO performance
score. Block randomization was performed cen-
trally by telephone or at the central trial office,
368 Underwent randomization
837 Patients were assessed for esophageal
or EGJ cancer
469 Were excluded
2 Withdrew consent
7 Did not receive any
chemoradiotherapy
180 Were assigned to chemo-
radiotherapy and surgery
188 Were assigned to surgery
alone
178 Were included
in the analysis
188 Were included
in the analysis
171 Received chemoradiotherapy
168 Underwent surgery
161 Underwent resection
186 Underwent surgery
161 Underwent resection
Figure 1. Study Enrollment.
Of the 368 patients who underwent randomization, 178 in the chemoradio-
therapy–surgery group and 188 in the surgery group were included in the
intention-to-treat analysis. A resection was not possible in 7 patients in the
chemoradiotherapy–surgery group and in 25 in the surgery group because
the primary tumor or lymph nodes were identified as unresectable during
surgery. EGJ denotes esophagogastric junction.
The New England Journal of Medicine
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Preoperative Chemoradiotherapy for Esophageal Cancer
n engl j med 366;22 nejm.org may 31, 2012
2077
according to computer-generated randomization
lists for each stratum, with random block sizes
of 4 or 6.
Data were analyzed according to the intention-
to-treat principle. The primary end point was
overall survival. All other described outcomes
were secondary end points. No post hoc analyses
were performed. Survival was calculated from
Table 1. Characteristics of Patients with Resectable Esophageal or Esophagogastric-Junction Cancer, According to
Treatment Group.*
Characteristic
Chemoradiotherapy and Surgery
(N = 178)
Surgery Alone
(N = 188)
Age — yr
Median 60 60
Range 36–79 36–73
Male sex — no. (%) 134 (75) 152 (81)
Tumor type — no. (%)
Adenocarcinoma 134 (75) 141 (75)
Squamous-cell carcinoma 41 (23) 43 (23)
Other 3 (2) 4 (2)
Tumor length — cm†
Median 4 4
Interquartile range 3–6 3–6
Tumor location — no. (%)†
Esophagus
Proximal third 4 (2) 4 (2)
Middle third 25 (14) 24 (13)
Distal third 104 (58) 107 (57)
Esophagogastric junction 39 (22) 49 (26)
Missing data 6 (3) 4 (2)
Clinical T stage — no. (%)‡
cT1 1 (1) 1 (1)
cT2 26 (15) 35 (19)
cT3 150 (84) 147 (78)
cT4 0 1 (1)
Could not be determined§ 1 (1) 4 (2)
Clinical N stage — no. (%)¶
N0 59 (33) 58 (31)
N1 116 (65) 120 (64)
Could not be determined§ 3 (2) 10 (5)
WHO performance status score — no. (%)‖
0 144 (81) 163 (87)
1 34 (19) 25 (13)
* Percentages may not add up to 100 because of rounding. WHO denotes World Health Organization.
Tumor length and location were determined by means of endoscopy.
Clinical tumor (cT) stage was assessed by means of endoscopic ultrasonography or computed tomography (CT) and was
classified according to the International Union against Cancer (UICC) tumor–node–metastasis (TNM) classification.
9
§ This category included patients in whom the tumor could not be fully investigated by means of a transducer for endoscopic
ultrasonography owing to a stenosis caused by the tumor.
Clinical lymph-node (N) stage was assessed by means of endoscopic ultrasonography, CT, or
18
F-fluorodeoxyglucose
positron-emission tomography and was classified according to UICC TNM classification.
9
WHO performance status scores are on a scale of 0 to 5, with lower numbers indicating better performance status; 0 indi-
cates fully active, and 1 unable to carry out heavy physical work.
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2078
the date of randomization until death. All data
collected through December 2010 were included
in the analysis, which guaranteed a potential
minimal follow-up of 2 years.
The Kaplan–Meier method was used to esti-
mate survival, with the log-rank test to deter-
mine significance. A Cox proportional-hazards
model was used to estimate the treatment effect
with adjustment for prognostic factors for sur-
vival. Moreover, Cox models were used to iden-
tify possible interactions in treatment effect
between subgroups, both with and without
adjustment for prognostic factors. Subgroups
were predefined according to sex, histologic
subtype of tumor, clinical N stage, and WHO
performance score. Statistical analysis was per-
formed with the use of SPSS software, version
17.0 (SPSS).
RESULTS
CHARACTERISTICS OF THE PATIENTS
From March 2004 through December 2008, we
enrolled 368 patients in the study, of whom 180
were randomly assigned to the chemoradiother-
apy–surgery group, and 188 to the surgery group.
Two patients who were randomly assigned to
the chemoradiotherapy–surgery group withdrew
consent and were not included in the analysis
(Fig. 1).
Prognostic factors were well balanced be-
tween the two treatment groups (
Table 1
). In
both groups, the median age was 60 years; 134
of 178 patients (75%) in the chemoradiotherapy–
surgery group were men, as compared with 152
of 188 patients (81%) in the surgery group. Most
patients (275 of 366 [75%]) had an adenocarci-
Table 2. Adverse Events during Neoadjuvant Chemoradiotherapy and after Surgery.*
Event
Chemoradiotherapy
and Surgery
(N = 171)
Surgery Alone
(N = 186)
Postoperative events — no. of patients/total no. (%)†
Pulmonary complications‡ 78/168 (46) 82/186 (44)
Cardiac complications§ 36/168 (21) 31/186 (17)
Chylothorax¶ 17/168 (10) 11/186 (6)
Mediastinitis‖ 5/168 (3) 12/186 (6)
Anastomotic leakage** 36/161 (22) 48/161 (30)
Death
In hospital 6/168 (4) 8/186 (4)
After 30 days 4/168 (2) 5/186 (3)
Events of any grade during chemoradiotherapy — no. of patients (%)
Anorexia 51 (30)
Alopecia 25 (15)
Constipation 47 (27)
Diarrhea 30 (18)
Esophageal perforation 1 (1)
Esophagitis 32 (19)
Fatigue 115 (67)
Nausea 91 (53)
Neurotoxic effects 25 (15)
Vomiting 43 (25)
Leukopenia 103 (60)
Neutropenia 16 (9)
Thrombocytopenia 92 (54)
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Citations
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Journal ArticleDOI
01 Sep 2015-Lancet Oncology
TL;DR: Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy in patients with clinically resectable, locally advanced cancer of the oesophagus or Oesophagogastric junction and shows a significant increase in 5-year overall survival.
Abstract: Summary Background Initial results of the ChemoRadiotherapy for Oesophageal cancer followed by Surgery Study (CROSS) comparing neoadjuvant chemoradiotherapy plus surgery versus surgery alone in patients with squamous cell carcinoma and adenocarcinoma of the oesophagus or oesophagogastric junction showed a significant increase in 5-year overall survival in favour of the neoadjuvant chemoradiotherapy plus surgery group after a median of 45 months' follow-up. In this Article, we report the long-term results after a minimum follow-up of 5 years. Methods Patients with clinically resectable, locally advanced cancer of the oesophagus or oesophagogastric junction (clinical stage T1N1M0 or T2–3N0–1M0, according to the TNM cancer staging system, sixth edition) were randomly assigned in a 1:1 ratio with permuted blocks of four or six to receive either weekly administration of five cycles of neoadjuvant chemoradiotherapy (intravenous carboplatin [AUC 2 mg/mL per min] and intravenous paclitaxel [50 mg/m 2 of body-surface area] for 23 days) with concurrent radiotherapy (41·4 Gy, given in 23 fractions of 1·8 Gy on 5 days per week) followed by surgery, or surgery alone. The primary endpoint was overall survival, analysed by intention-to-treat. No adverse event data were collected beyond those noted in the initial report of the trial. This trial is registered with the Netherlands Trial Register, number NTR487, and has been completed. Findings Between March 30, 2004, and Dec 2, 2008, 368 patients from eight participating centres (five academic centres and three large non-academic teaching hospitals) in the Netherlands were enrolled into this study and randomly assigned to the two treatment groups: 180 to surgery plus neoadjuvant chemoradiotherapy and 188 to surgery alone. Two patients in the neoadjuvant chemoradiotherapy group withdrew consent, so a total of 366 patients were analysed (178 in the neoadjuvant chemoradiotherapy plus surgery group and 188 in the surgery alone group). Of 171 patients who received any neoadjuvant chemoradiotherapy in this group, 162 (95%) were able to complete the entire neoadjuvant chemoradiotherapy regimen. After a median follow-up for surviving patients of 84·1 months (range 61·1–116·8, IQR 70·7–96·6), median overall survival was 48·6 months (95% CI 32·1–65·1) in the neoadjuvant chemoradiotherapy plus surgery group and 24·0 months (14·2–33·7) in the surgery alone group (HR 0·68 [95% CI 0·53–0·88]; log-rank p=0·003). Median overall survival for patients with squamous cell carcinomas was 81·6 months (95% CI 47·2–116·0) in the neoadjuvant chemoradiotherapy plus surgery group and 21·1 months (15·4–26·7) in the surgery alone group (HR 0·48 [95% CI 0·28–0·83]; log-rank p=0·008); for patients with adenocarcinomas, it was 43·2 months (24·9–61·4) in the neoadjuvant chemoradiotherapy plus surgery group and 27·1 months (13·0–41·2) in the surgery alone group (HR 0·73 [95% CI 0·55–0·98]; log-rank p=0·038). Interpretation Long-term follow-up confirms the overall survival benefits for neoadjuvant chemoradiotherapy when added to surgery in patients with resectable oesophageal or oesophagogastric junctional cancer. This improvement is clinically relevant for both squamous cell carcinoma and adenocarcinoma subtypes. Therefore, neoadjuvant chemoradiotherapy according to the CROSS trial followed by surgical resection should be regarded as a standard of care for patients with resectable locally advanced oesophageal or oesophagogastric junctional cancer. Funding Dutch Cancer Foundation (KWF Kankerbestrijding).

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Christophe Mariette, Laetitia Dahan1, F. Mornex2, Emilie Maillard  +11 moreInstitutions (3)
TL;DR: Compared with surgery alone, NCRT with cisplatin plus fluorouracil does not improve R0 resection rate or survival but enhances postoperative mortality in patients with stage I or II EC.
Abstract: Purpose Although often investigated in locally advanced esophageal cancer (EC), the impact of neoadjuvant chemoradiotherapy (NCRT) in early stages is unknown. The aim of this multicenter randomized phase III trial was to assess whether NCRT improves outcomes for patients with stage I or II EC. Methods The primary end point was overall survival. Secondary end points were disease-free survival, postoperative morbidity, in-hospital mortality, R0 resection rate, and prognostic factor identification. From June 2000 to June 2009, 195 patients in 30 centers were randomly assigned to surgery alone (group S; n = 97) or NCRT followed by surgery (group CRT; n = 98). CRT protocol was 45 Gy in 25 fractions over 5 weeks with two courses of concomitant chemotherapy composed of fluorouracil 800 mg/m2 and cisplatin 75 mg/m2. We report the long-term results of the final analysis, after a median follow-up of 93.6 months. Results Pretreatment disease was stage I in 19.0%, IIA in 53.3%, and IIB in 27.7% of patients. For group...

383 citations


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Journal ArticleDOI
Jacques Ferlay1, Hai-Rim Shin1, Freddie Bray1, David Forman1  +2 moreInstitutions (3)
TL;DR: The results for 20 world regions are presented, summarizing the global patterns for the eight most common cancers, and striking differences in the patterns of cancer from region to region are observed.
Abstract: Estimates of the worldwide incidence and mortality from 27 cancers in 2008 have been prepared for 182 countries as part of the GLOBOCAN series published by the International Agency for Research on Cancer. In this article, we present the results for 20 world regions, summarizing the global patterns for the eight most common cancers. Overall, an estimated 12.7 million new cancer cases and 7.6 million cancer deaths occur in 2008, with 56% of new cancer cases and 63% of the cancer deaths occurring in the less developed regions of the world. The most commonly diagnosed cancers worldwide are lung (1.61 million, 12.7% of the total), breast (1.38 million, 10.9%) and colorectal cancers (1.23 million, 9.7%). The most common causes of cancer death are lung cancer (1.38 million, 18.2% of the total), stomach cancer (738,000 deaths, 9.7%) and liver cancer (696,000 deaths, 9.2%). Cancer is neither rare anywhere in the world, nor mainly confined to high-resource countries. Striking differences in the patterns of cancer from region to region are observed.

20,379 citations


BookDOI
01 Jan 1987-
TL;DR: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.' Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumour .
Abstract: Head and Neck Tumours.- Lip and Oral Cavity.- Pharynx.- Larynx.- Maxillary Sinus.- Salivary Glands.- Thyroid Gland.- Digestive System Tumours.- Oesophagus.- Stomach.- Colon and Rectum.- Anal Canal.- Liver.- Gall Bladder.- Extrahepatic Bile Ducts.- Ampulla of Vater.- Pancreas.- Lung Tumours.- Tumours of Bone and Soft Tissues.- Bone.- Soft Tissue.- Skin Tumours.- Carcinoma of Skin.- Melanoma of Skin.- Breast Tumours.- Gynaecological Tumours.- Cervix Uteri.- Corpus Uteri.- Ovary.- Vagina.- Vulva.- Urological Tumours.- Prostate.- Testis.- Penis.- Urinary Bladder.- Kidney.- Renal Pelvis and Ureter.- Urethra.- Ophthalmic Tumours.- Carcinoma of Eyelid.- Malignant Melanoma of Eyelid.- Carcinoma of Conjunctiva.- Malignant Melanoma of Conjunctiva.- Malignant Melanoma of Uvea.- Retinoblastoma.- Sarcoma of Orbit.- Carcinoma of Lacrimal Gland.- Brain Tumours.- Hodgkin's Disease.- Non-Hodgkin's Lymphoma.- Paediatric Tumours.- Nephroblastoma (Wilms' Tumour).- Neuroblastoma.- Soft Tissue Sarcomas - Paediatric.

15,038 citations


Journal ArticleDOI
TL;DR: In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival.
Abstract: Background A regimen of epirubicin, cisplatin, and infused fluorouracil (ECF) improves survival among patients with incurable locally advanced or metastatic gastric adenocarcinoma. We assessed whether the addition of a perioperative regimen of ECF to surgery improves outcomes among patients with potentially curable gastric cancer. Methods We randomly assigned patients with resectable adenocarcinoma of the stomach, esophagogastric junction, or lower esophagus to either perioperative chemotherapy and surgery (250 patients) or surgery alone (253 patients). Chemotherapy consisted of three preoperative and three postoperative cycles of intravenous epirubicin (50 mg per square meter of body-surface area) and cisplatin (60 mg per square meter) on day 1, and a continuous intravenous infusion of fluorouracil (200 mg per square meter per day) for 21 days. The primary end point was overall survival. Results ECF-related adverse effects were similar to those previously reported among patients with advanced gastric cancer. Rates of postoperative complications were similar in the perioperative-chemotherapy group and the surgery group (46 percent and 45 percent, respectively), as were the numbers of deaths within 30 days after surgery. The resected tumors were significantly smaller and less advanced in the perioperative-chemotherapy group. With a median follow-up of four years, 149 patients in the perioperative-chemotherapy group and 170 in the surgery group had died. As compared with the surgery group, the perioperative-chemotherapy group had a higher likelihood of overall survival (hazard ratio for death, 0.75; 95 percent confidence interval, 0.60 to 0.93; P = 0.009; five-year survival rate, 36 percent vs. 23 percent) and of progression-free survival (hazard ratio for progression, 0.66; 95 percent confidence interval, 0.53 to 0.81; P<0.001). Conclusions In patients with operable gastric or lower esophageal adenocarcinomas, a perioperative regimen of ECF decreased tumor size and stage and significantly improved progression-free and overall survival. (Current Controlled Trials number, ISRCTN93793971.)

4,474 citations


Additional excerpts

  • ...Esophagogastric junction 39 (22) 49 (26)...

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  • ...Anastomotic leakage** 36/161 (22) 48/161 (30)...

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Journal ArticleDOI
15 Nov 1998-Cancer
TL;DR: The authors update the incidence trends through 1994 and further consider the trends by age group.
Abstract: BACKGROUND Incidence rates for esophageal adenocarcinoma previously were reported to be increasing rapidly, especially among white males. Rates for gastric cardia adenocarcinoma also were observed to be rising, although less rapidly. In this article, the authors update the incidence trends through 1994 and further consider the trends by age group. METHODS Surveillance, Epidemiology, and End Results (SEER) program data were used to calculate age-adjusted incidence rates for esophageal carcinoma by histologic type and gastric adenocarcinoma by anatomic subsite. RESULTS Among white males, the incidence of adenocarcinoma of the esophagus rose > 350% since the mid-1970s, surpassing squamous cell carcinoma around 1990. Rates also rose among black males, but remained at much lower levels. To a lesser extent, there were continuing increases in gastric cardia adenocarcinoma among white and black males, which nearly equaled the rates for noncardia tumors of the stomach in white men. The upward trend for both tumors was much greater among older than younger men. Although the incidence also rose among females, rates remained much lower than among males. CONCLUSIONS Previously reported increases of esophageal adenocarcinoma are continuing, most notably among white males. Cigarette smoking may contribute to the trend through an early stage carcinogenic effect, along with obesity, which may increase intraabdominal pressure and predispose to gastroesophageal reflux disease. Further research into esophageal and gastric cardia adenocarcinoma is needed to clarify the risk factors and mechanisms responsible for the upward trends as well as the racial and gender disparities in incidence. Cancer 1998;83:2049-2053. © 1998 American Cancer Society.

2,161 citations


Journal ArticleDOI
TL;DR: Three elementary measures of cancer frequency are confined ourselves to: incidence, mortality and prevalence.
Abstract: Although the general idea of ‘burden’ of a disease to a community seems fairly straightforward, there are multiple dimensions in which it may be expressed, either in terms of disease frequency (the ‘need’ for services) or the demand which it places upon them. In this review, we confine ourselves to three elementary measures of cancer frequency: incidence, mortality and prevalence. Incidence is the number of new cases occurring. It can be expressed as an absolute number of cases per year (the volume of new patients presenting for treatment) or as a rate per 100 000 persons per year. The latter provides an approximation to the average risk of developing a cancer, and is necessary if we wish to compare the risk of disease between populations (countries, ethnic groups, or different time periods within a country, for example). When considering the impact of primary prevention strategies, a reduction in incidence (occurrence of new cases) is the appropriate statistic to use. Mortality is the number of deaths occurring, and the mortality rate the number of deaths per 100 000 persons per year. The number of deaths provides one measure (and a rather unambiguous one) of the outcome or impact of cancer. It is the product of the incidence and the fatality of a given cancer. Fatality, the inverse of survival, is the proportion of cancer cases that die and this is generally assumed to be the most severe sequel of the disease. Mortality rates therefore measure the average risk to the population of dying from a specific cancer, while fatality (1-survival) represents the probability that an individual with cancer will die from it. Mortality rates are sometimes used as a convenient proxy measure of the risk of acquiring the disease (incidence) when comparing different groups, since they may be more generally available (as described below). However, when used in this way, an assumption of equal survival/fatality in the populations being compared is introduced. Since this is rarely correct—there are, for example, quite large differences between countries—it is safer to use mortality as a measure of outcome rather than occurrence. Prevalence: There is no agreed definition of ‘prevalence’ of cancer. Strictly speaking, it is the number of persons in a defined population alive at a given time who have had cancer diagnosed at some time in the past. However, the resource requirements for treating newly diagnosed patients are very different from those for supporting long-term survivors. Thus, overall prevalence is not particularly useful for healthcare planning purposes, especially as a large proportion of long-term survivors can be considered cured. Partial prevalence, which limits the number of patients to those diagnosed during a fixed time in the past, is therefore a more useful measure of cancer burden. Prevalence for cases diagnosed within 1, 3 and 5 years are likely to be of relevance to the different stages of cancer therapy, namely, initial treatment (1 year), clinical follow-up (3 years) and cure (5 years). Patients who are still alive 5 years after diagnosis are usually considered cured since the death rates of such patients are similar to those in the general population. There are some exceptions, primarily that of female breast cancer, for which the risk of death remains higher than the general population for many more years. Several other more complex statistics have been used to measure the impact of disease, particularly in health economics. They include person-years of life lost (how many years of normal lifespan are lost due to deaths from cancer). This measurement may be refined by giving different values to life-years at different ages, so that a year saved at, for example, age 20 years, is valued

2,153 citations


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Metrics
No. of citations received by the Paper in previous years
YearCitations
20224
2021466
2020418
2019377
2018379
2017449