Download Extended lymph node dissection for gastric cancer

Στέργιος Β. Μπούσιος
Ογκολόγος - Παθολόγος
Ογκολογική Κλινική
Πανεπιστημιακό Γενικό Νοσοκομείο Ιωαννίνων
Διευθυντής: Καθηγητής Νικόλαος Παυλίδης
Patient
 68 yrs old
 Operated stomach Ca
 Stage: IIIb – TNM staging: T3N2
 D2 excision
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Epidemiology
 5th highest incidence & 4th most common cause of cancer-related
death
 Increasing incidence of EGJ and gastric cardia tumors
 Declining overall incidence
 Peak incidence during the 7th decade
 Twice as common in men compared to women
 USA, 2010: 21,000 new cases – 10,570 deaths
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Risk factors
 Gender: Male
 Smoking
 Helicobacter pylori infection (mainly for adenocarcinoma)
 Atrophic gastritis
 Partial gastrectomy
 Menetrier’s disease
 Obesity (for OGJ/cardia tumors)
 Genetic factors: familial adenomatous polyposis, Peutz-Jeghers
syndrome, hereditary non-polyposis colorectal cancer
 Diet: red meat, smoked foods, spices, foods rich in hydrocarbons
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TNM staging (1)
 Primary tumor (T)
 TX: primary tumor cannot be assessed
 T0: no evidence of primary tumor
 Tis: carcinoma in situ (intraepithelial tumor w/o
invasion of the lamina propria)
 T1: tumor invades lamina propria or submucosa
 T2: tumor invades the muscularis propria (T2a) or the
subserosa (T2b)
 T3: tumor penetrates the serosa w/o invading adjacent
structures
 T4: tumors invades adjacent structures
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TNM staging (2)
 Regional lymph nodes (N)
 NX: regional lymph nodes cannot be assessed
 N0: no regional lymph nodes metastasis
 N1: metastasis in 1-6 regional lymph nodes
 N2: metastasis to 7-15 regional lymph nodes
 N3: metastasis in more than 15 regional lymph nodes
 Distant metastasis (M)
 MX: distant metastasis cannot be assessed
 M0: no distant metastasis
 M1: distant metastasis
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AJCC stage grouping
 Stage 0: TisN0Mo
 Stage IA: T1N0M0
 Stage IB: T1N1M0, T2aN0M0, T2bN0M0
 Stage II: T1N2M0, T2aN1M0, T2bN1M0, T3N0M0
 Stage IIIA: T2aN2M0, T2bN2M0, T3N1M0, T4N0M0
 Stage IIIB: T3N2M0
 Stage IV: T4N1M0, T4N2M0, T4N3M0, T1N3M0, T2N3M0,
T3N3M0, anyTanyNM1
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Preoperative clinical staging
 Endoscopic ultrasound (EUS): tumor invasion depth assessment
 Computed tomography (CT)
 Combined positron emission tomography (PET-CT): lower
sensitivity than CT but improved specificity
 Magnetic resonance imaging (MRI)
 Laparoscopic staging
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Principles of surgery
 Primary treatment for early stage gastric cancer
 Distal gastric cancer => subtotal gastrectomy
 Proximal gastric cancer => proximal and total gastrectomy
 For T1b – T3 => recommended subtotal or total gastrectomy
 For T4 => en bloc resection of involved structures
 Unresectable carcinomas:
 Evidence of peritoneal involvement
 Evidence of distant meatastases
 Evidence of locally advanced disease
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Lymph node dissection
 D0 dissection: incomplete resection of N1 lymph
nodes
 D1 dissection: removal of the involved proximal or
distal part of the stomach or of the entire stomach
 D2 dissection: removal of the omental bursa and the
front leaf of the transverse mesocolon – the
corresponding arteries are cleared
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EMR & laparoscopic resection
 EMR
 For early gastric cancer (Tis or T1a)
 Well-differentiated histology
 Tumors < 30mm
 Ulceration absence
 No evidence of invasive findings
 Laparoscopic resection
 Advantages: reduced blood loss and post-operative pain,
accelerated recovery, early return to normal bowel function
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Radiation
 Adjuvant and neoadjuvant
 BSCG trial:
 No survival benefit due to post-operative RT or chemo
 Reduced locoregional relapse with adjuvant RT
 Review and meta-analysis: 5-year survival benefit with the
addition of RT in patients with resectable gastric cancer
 External-beam RT (45-50.4 Gy) does not improve survival
in unresectable gastric cancer
 EBRT concurrently with 5-fluorouracil improves survival
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Combined modality treatment (1)
 Preoperative chemoRT: 45Gy EBRT + 5-FU
infusion followed by surgery and IORT (10Gy) in
resectable gastric cancer
 83% underwent D2 lymphadenectomy
 63% significant pathologic response
 11% complete pathologic response
 Preoperative induction chemo followed by
chemoRT yields pathologic response resulting in
improved survival
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Combined modality treatment (2)
 Postoperative chemoRT in patients with stomach
adenocarcinoma or GE junction (stage IB – IV M0)
 5 monthly cycles of bolus chemo (5-FU & leucovorin) with
RT (45Gy) concurrent with cycles 2 & 3
 Significant decrease in local failure compared with surgery
only
 Increase in median survival, 3 yrs RFS & OS compared
with surgery only
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Chemotherapy (1)
 MAGIC trial (perioperative ECF chemo):
 improved 5-year survival rates (36% compared to 23% for surgery
only)
 Improved PFS & OS in operable gastric and lower esophageal
adenocarcinoma
 North America trial (postoperative chemo):
 5 cycles of chemo (5-FU & leucovorin) before, during and after RT
resulted in 15% 5-year OS improvement
 Standard therapy in the USA, no standard acceptance in Europe
(late toxicity & quantity of surgery)
 Europeans consider postoperative chemoRT is beneficial after D2
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Chemotherapy (2)
 Japanese phase III study: adjuvant chemo with S-1
(tegafur + oxonic acid) in stage II/III gastric cancer
with LN dissection D2
 3-year OS rate = 80.1% compared to 70.1% for surgery
only
 No data available with Western patients
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Chemo for advanced/metastatic disease (1)
 Provides palliation and improved survival
 Single agents: 5-FU, mitomycin, etoposide, cisplatin –
response rate = 10-20%
 Other agents: irinotecan, paclitaxel, docetaxel, oral
etoposide, oxaliplatin, UFT
 Phase III study: irinotecan-containing regimen can be
alternative when platinum-based therapy cannot be
delivered (patients with advanced adenocarcinoma)
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Chemo for advanced/metastatic disease (2)
 Several randomized studies:
 ECF offers improved median survival and quality of life
compared to FAMTX and MCF regimens
 FLO vs. FLP: FLO offers reduced toxicity, superior response
rates, improved PFS & OS, improved time to treatment
failure (age > 65 yrs)
 Phase III study: DCF vs. CF
 DCF offers longer time to progression
 FDA approved (2006) DCF regimen for advanced gastric
cancer treatment in patients with no prior chemo for
advanced disease
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Chemo for advanced/metastatic disease (3)
 Phase III study: XP vs. FP as first-line treatment in
untreated advanced gastric cancer
 Capecitabine as effective as 5-FU in advanced GE
cancers
 Capecitabine-based combinations offer superior OS and
similar PFS compared to 5-FU-based combinations
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Targeted therapies
 Poor prognosis associated with overexpression of
EGFR/VEGFR/HER2
 Cetuximab/Bevacizumab/Trastuzumab have been
evaluated in combination with chemo in advanced gastric
adenocarcinomas
 Phase III study: Trastuzumab in combination with cisplatin
& fluoropyrimidine
 Trastuzumab + chemo is the new standard of care for the
treatment of HER2-expressing advanced gastric & GE cancers
(improved median OS)
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Workup (1)
 Newly diagnosed patients :
 H&P,
 chest imaging,
 upper GI tract endoscopy,
 CBC,
 chemistry profile,
 abdominal CT with contrast,
 pelvic CT scan or US (for women),
 EUS (for potentially resectable cancer),
 H.pylori testing and appropriate treatment
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Workup (2)
 Optional PET-CT scan:
 Predicting response to preoperative chemo
 Evaluation of recurrent gastric cancer
 Demonstrating occult metastatic disease
 Patient classification:
 Localized cancer (Tis or T1a)
 Locoregional cancer (stages I-III or M0)
 Metastatic cancer (stage IV or M1)
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Workup (3) – PRIMARY TREATMENT
 Localized cancers (Tis/T1a): EMR or surgery
 Potentially resectable locoregional cancer (T1b):
surgery
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Workup (4) – PRIMARY TREATMENT II
 T2 or higher tumors: perioperative chemo with ECF regimen
 Medically fit patients with unresectable locoregional
cancer/medically unfit patients with locoregional cancer: RT
with concurrent fluoropyrimidine-based radiosensitization
 Palliative chemo as an alternative option
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For metastatic or locally advanced cancer
Regimens:
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Primary => DCF, ECF(-modifications), Trastuzumab
Secondary => irinotecan + cisplatin, irinotecan + fluoropyrimidine,
oxalipaltin +fluoropyrimidine, DCF modifications, paclitaxel-based
regimen
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Workup (5) – PRIMARY TREATMENT III
 Medically unfit patients/medically fit patients with
unresectable disease: restaging and observation or
surgery or palliative treatment
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Workup (6) – POSTOPERATIVE TREATMENT
 Based on surgical margins and nodal status
 Patients with T3/T4/any node (+) tumors + R0 resection =>
RT & concurrent fluoropyrimidine-based
radiosensitization + 5-FU (with or w/o leucovorin) or
capecitabine
 Same treatment for R1 resection patients
 Patients with absence of M1 and R2 resection => RT &
concurrent fluoropyrimidine-based radiosensitization or
palliative chemo
 Poor performance status patients => best supportive care
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Follow-up surveillance
 Complete H&P:
 Every 3-6 months for 1-3 yrs
 Every 6 months for 3-5 yrs
 Annually thereafter
 CBC, chemistry profile, imaging studies or endoscopy if
clinically indicated
 After surgical resection: monitoring and indicated
treatment for vitamin B12 and iron deficiency
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Palliative chemo (1)
 Considered for stage IV disease
 Generally used: platinum agent + fluoropyrimidine regimens
 Significant benefit from adding an anthracycline to the doublet
=> ECF among the most active and well-tolerated
 Docetaxel increases the activity of 5-FU/cisplatin – more toxic
in 3-weekly regimen
 Irinotecan combined with 5-FU/LV can be considered in
selected patients
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Palliative chemo (2)
 Substitution of capecitabine for 5-FU & oxaliplatin for
cisplatin (ECF -> ECX/EOF/EOX): EOX offers longer
OS than ECF and reduced thromboembolism rate
 Meta-analysis: capecitabine superior to infused 5-FU
for OS within doublet and triplet regimes for advanced
gastric cancer
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Palliative treatment for
recurrent/metastatic disease (1)
 Chemo + best supportive care vs. best supportive care for
advanced gastric cancer:
 OS: 8 vs. 5 months
 Time to progression: 5 vs. 2 months
 More patients with improved or prolonged high quality of life
with chemo
 Irinotecan vs. best supportive care in the second-line
setting: prolonged OS
 Offering or not chemo with best supportive care depends
on patient’s PS
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Palliative treatment for
recurrent/metastatic disease (2)
 For metastatic/locally advanced gastric cancer:
 DCF(-modifications)
 ECF(-modifications)
 Irinotecan + cisplatin
 Oxaliplatin + 5-FU or capecitabine
 Irinotecan + 5-FU or capecitabine
 Paclitaxel-based regimen
 Trastuzumab
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Best supportive care (1)
 Palliative interventions for the management of
bleeding, obstruction, pain, nausea, vomiting
 Bleeding:
 patients with hematemesis/melena => endoscopic
assessment
 When endoscopy not helpful => angiographic
embolization
 EBRT and/or endoscopy in patients with bleeding
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Best supportive care (2)
 Obstruction:
 Gastrojejunostomy is most commonly used (preferable for patients
with more prolonged prognosis)
 Endoscopic placement of SEMS (relatively short life expectancy)
 EBRT
 Balloon dillation
 Percutaneous endoscopic gastrotomy
 Pain:
 EBRT
 Pain medication
 Endoscopic removal of stent
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
J Clin Oncol. 2004 Jun 1;22(11):2069-77. Epub 2004 Apr 13.

Extended lymph node dissection for gastric cancer: who may benefit? Final results of the
randomized Dutch gastric cancer group trial.

Department of Surgery, Leiden University Medical Centre, PO Box 9600, 2300 RC Leiden, The
Netherlands. [email protected]

PURPOSE: The extent of lymph node dissection appropriate for gastric cancer is still under debate.
We have conducted a randomized trial to compare the results of a limited (D1) and extended (D2)
lymph node dissection in terms of morbidity, mortality, long-term survival and cumulative risk of
relapse. We have reviewed the results of our trial after follow-up of more than 10 years.
PATIENTS AND METHODS: Between August 1989 and June 1993, 1,078 patients with gastric
adenocarcinoma were randomly assigned to undergo a D1 or D2 lymph node dissection. Data were
collected prospectively, and patients were followed for more than 10 years.
RESULTS: A total of 711 patients (380 in the D1 group and 331 in the D2 group) were treated with
curative intent. Morbidity (25% v 43%; P <.001) and mortality (4% v 10%; P =.004) were significantly
higher in the D2 dissection group. After 11 years there is no overall difference in survival (30% v 35%; P
=.53). Of all subgroups analyzed, only patients with N2 disease may benefit of a D2 dissection.
The relative risk ratio for morbidity and mortality is significantly higher than one for D2 dissections,
splenectomy, pancreatectomy, and age older than 70 years.
CONCLUSION: Overall, extended lymph node dissection as defined in this study generated
no long-term survival benefit. The associated higher postoperative mortality offsets its long-term
effect in survival. For patients with N2 disease an extended lymph node dissection may offer
cure, but it remains difficult to identify patients who have N2 disease. Morbidity and mortality are
greatly influenced by the extent of lymph node dissection, pancreatectomy, splenectomy and
age. Extended lymph node dissections may be of benefit if morbidity and mortality can be avoided.
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Radiation and Chemotherapy After Surgery Improves Survival in Stomach Cancer

Postoperative chemotherapy and radiation treatment extended survival by an average of nine months in patients with
operable cancer of the stomach or esophageal junction, according to research from a multicenter clinical trial published in the
September 6, 2001, issue of the New England Journal of Medicine. An initial report of this trial was presented at the May 2000
meeting of the American Society of Clinical Oncology (ASCO).
The trial, conducted by the Southwest Oncology Group, involved 556 patients with cancer of the stomach or esophageal junction
that could be removed by surgery. About 85 percent of patients in each group had cancer that spread to the lymph nodes in the gut,
the first place stomach cancer tends to spread.
Study participants were randomly assigned to receive either surgery alone or surgery followed by chemotherapy with the drugs
fluorouracil and leucovorin plus five weeks of radiation treatment.
After an average of five years of follow-up, average overall survival was 36 months in patients who received the adjuvant
(additional) therapy, compared with 27 months in patients treated with surgery alone. Survival without return of
stomach cancer was 30 months on average in the group receiving adjuvant therapy compared with 19 months in the
surgery-only group.
Forty to 65 percent of patients suffer recurrences of cancer in the gastrointestinal region following surgery for stomach cancer. This
high relapse rate makes it important to consider adjuvant therapy. However, in previous studies, adjuvant postoperative
chemotherapy did not improve survival. Several small studies did suggest that postoperative radiation might extend survival.
In the current trial, the duration of survival in the surgery-only group was similar to that seen in other studies. "The apparent
benefit of adjuvant therapy could not be the result of shorter-than-expected survival in the surgery-only group," principal
investigator John S. Macdonald, M.D., and his colleagues reported.
Although adjuvant therapy extended patients' average overall survival by nine months, long-term survival was still low.
Of the 281 patients who received adjuvant therapy, 169 died during the trial follow-up period, compared with 197 of the 275 patients
who received surgery alone. Over half of the patients in the combination treatment group suffered toxic effects from the
chemotherapy and radiation, and three patients died from those toxicities.
Among patients whose stomach cancer is detected at a very early stage, about 65 percent survive for 10 years, according to data
from the National Cancer Data Base. Among patients with more advanced disease, 10-year survival ranges from 3 to 42 percent,
depending on the extent of disease. Approximately 21,700 new cases of stomach cancer will be diagnosed among Americans in 2001,
with men being at a slightly higher risk than women.
"Adjuvant treatment with fluorouracil plus leucovorin and radiation should be considered for all patients with high-risk
gastric cancer," the researchers conclude. Current clinical trials continue to evaluate further ways of improving treatment for
gastric cancer, including studying newer drugs and giving treatments prior to surgery.
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N Engl J Med. 2006 Jul 6;355(1):11-20.

Perioperative chemotherapy versus surgery alone for resectable gastroesophageal cancer.

Department of Medicine, Royal Marsden Hospital, Sutton , Surrey, United Kingdom.

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
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 Journal of Clinical Oncology, Vol 9, 827-831
 Sequential high-dose methotrexate and fluorouracil combined with
doxorubicin--a step ahead in the treatment of advanced gastric cancer:
a trial of the European Organization for Research and Treatment of
Cancer Gastrointestinal Tract Cooperative Group
 Laurentius Hospital, Roermond, The Netherlands.
 In a prospective phase III multicenter trial, 213 patients with advanced
measurable or nonmeasurable gastric cancer were randomized to
receive methotrexate (MTX), fluorouracil (5-FU), and Adriamycin
(doxorubicin; Farmitalia Carlo Erba, Milan, Italy) (FAMTX) or 5-FU,
Adriamycin, and mitomycin (FAM). The results show a significantly
superior response rate (41% v 9% [P less than .0001]), and survival
(median, 42 weeks v 29 weeks [P = .004]) for FAMTX. There was a cumulative
thrombocytopenia in FAM and not in FAMTX. The FAMTX protocol should be
the reference treatment in future clinical trials that seek to improve the
therapeutic outcome in advanced gastric cancer.
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J Clin Oncol. 2006 Nov 1;24(31):4991-7.

Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and
fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study
Group.

University Hospital Gasthuisberg, Leuven, Belgium.

PURPOSE: In the randomized, multinational phase II/III trial (V325) of untreated advanced gastric
cancer patients, the phase II part selected docetaxel, cisplatin, and fluorouracil (DCF) over
docetaxel and cisplatin for comparison against cisplatin and fluorouracil (CF; reference
regimen) in the phase III part.
PATIENTS AND METHODS: Advanced gastric cancer patients were randomly assigned to docetaxel
75 mg/m2 and cisplatin 75 mg/m2 (day 1) plus fluorouracil 750 mg/m2/d (days 1 to 5) every 3 weeks
or cisplatin 100 mg/m2 (day 1) plus fluorouracil 1,000 mg/m2/d (days 1 to 5) every 4 weeks. The
primary end point was time-to-progression (TTP).
RESULTS: In 445 randomly assigned and treated patients (DCF = 221; CF = 224), TTP was longer
with DCF versus CF (32% risk reduction; log-rank P < .001). Overall survival was longer with
DCF versus CF (23% risk reduction; log-rank P = .02). Two-year survival rate was 18% with DCF
and 9% with CF. Overall response rate was higher with DCF (chi2 P = .01). Grade 3 to 4 treatmentrelated adverse events occurred in 69% (DCF) v 59% (CF) of patients. Frequent grade 3 to 4 toxicities
for DCF v CF were: neutropenia (82% v 57%), stomatitis (21% v 27%), diarrhea (19% v 8%), lethargy
(19% v 14%). Complicated neutropenia was more frequent with DCF than CF (29% v 12%).
CONCLUSION: Adding docetaxel to CF significantly improved TTP, survival, and response
rate in gastric cancer patients, but resulted in some increase in toxicity. Incorporation of
docetaxel, as in DCF or with other active drug(s), is a new therapy option for patients with
untreated advanced gastric cancer.
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Ann Oncol. 2009 Sep;20(9):1529-34. Epub 2009 May 27.

Meta-analysis of the REAL-2 and ML17032 trials: evaluating capecitabine-based
combination chemotherapy and infused 5-fluorouracil-based combination chemotherapy
for the treatment of advanced oesophago-gastric cancer.

The Royal Marsden Hospital NHS Foundation Trust, Sutton, Surrey, UK.

BACKGROUND: The REAL-2 and ML17032 trials demonstrated that the oral fluoropyrimidine,
capecitabine, is noninferior to 5-fluorouracil (5-FU) for overall survival (OS) and progression-free
survival (PFS), respectively, in advanced oesophago-gastric cancer.
METHODS: Individual patient data were collected on all patients randomised within the trials (n =
1318). Kaplan-Meier survival curves were generated and the log-rank test was used to compare OS
and PFS between patients receiving 5-FU combinations and capecitabine combinations.
Stepwise multivariate Cox regression analysis was used to calculate corrected hazard ratios (HRs)
and 95% confidence intervals (CIs) for OS and PFS. Logistic regression was used for objective
response rate. Forest plots with tests of heterogeneity were generated.
RESULTS: OS was superior in the 654 patients treated with capecitabine combinations compared
with the 664 patients treated with 5-FU combinations; HR 0.87 (95% CI 0.77-0.98, P = 0.02). Poor
performance status, age <60 and metastatic disease were independent predictors of poor survival.
There was no significant difference in PFS between treatment groups on multivariate analysis.
Assessable patients treated with capecitabine combinations were significantly more likely to have
an objective response to treatment than those treated with 5-FU combinations; odds ratio 1.38 (95%
CI 1.10-1.73, P = 0.006).
CONCLUSION: OS is superior in patients treated with capecitabine combinations
compared with 5-FU combinations in advanced oesophago-gastric cancer.
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Cancer Res Treat. 2010 Mar;42(1):24-9. Epub 2010 Mar 31.

Oxaliplatin, 5-fluorouracil and Leucovorin (FOLFOX-4) Combination Chemotherapy as a
Salvage Treatment in Advanced Gastric Cancer.

Division of Hematology/Oncology, Department of Internal Medicine, Gachon University Gil
Hospital, Incheon, Korea.

PURPOSE: This study was designed to determine the efficacy and safety of FOLFOX-4
chemotherapy as a salvage treatment for patients with advanced gastric cancer (AGC).
MATERIALS AND METHODS: The AGC patients with an ECOG performance status of 0~1 and
progressive disease after prior treatments were registered onto this phase II trial. The patients
received oxaliplatin (85 mg/m(2) on day 1), leucovorin (200 mg/m(2) on days 1 and 2) and 5fluorouracil (400 mg/m(2) as a bolus and 600 mg/m(2) as a 22-hour infusion on days 1 and 2) every
2 weeks.
RESULTS: For the 42 treated patients, a total of 228 chemotherapy cycles (median: 5, range: 1~12)
were administered. Twenty-nine patients (69%) received FOLFOX-4 chemotherapy as a third-(50%)
or fourth-line (19%) treatment. On the intent-to-treat analysis, 9 patients (21%) achieved a partial
response, which was maintained for 4.6 months. The median progression-free survival and
overall survival were 3.0 months and 6.2 months, respectively. The frequently encountered
toxicities were neutropenia and gastrointestinal side effects, including anorexia. Although there
was one possible treatment-related death, the toxicity profiles were generally predictable and
manageable.
CONCLUSION: Salvage chemotherapy with FOLFOX-4 is an effective and tolerable regimen
for those heavily pretreated AGC patients who have a good performance status.
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Journal of Clinical Oncology, Vol 17, Issue 12 (December), 1999: 3810-3815
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Randomized Clinical Trial of Adjuvant Mitomycin Plus Tegafur in Patients With Resected
Stage III Gastric Cancer
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Medical Oncology Unit, Hospital Mútua de Terrassa-Universitat de Barcelona, Plaça Dr Robert 5,
08221 Terrassa, Barcelona, Spain
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PURPOSE: The efficacy of adjuvant chemotherapy in gastric cancer is controversial. We conducted a
phase III, randomized, multicentric clinical trial with the goal of assessing the efficacy of the
combination of mitomycin plus tegafur in prolonging the disease-free survival and overall
survival of patients with resected stage III gastric cancer.
PATIENTS AND METHODS: Patients with resected stage III gastric adenocarcinoma were randomly
assigned, using sealed envelopes, to receive either chemotherapy or no further treatment.
Chemotherapy was started within 28 days after surgery according to the following schedule:
mitomycin 20 mg/m2 intravenously (bolus) at day 1 of chemotherapy; 30 days later, oral tegafur at 400
mg bid daily for 3 months. Disease-free survival and overall survival were estimated using the KaplanMeier analysis and the Cox proportional hazards model.
RESULTS: Between January 1988 and September 1994, 148 patients from 10 hospitals in Catalonia,
Spain, were included in the study. The median follow-up period was 37 months. The tolerability of
the treatment was excellent. The overall survival and disease-free survival were higher in the
group of patients treated with chemotherapy (P = .04 for survival and P = .01 for disease-free
survival in the log-rank test). The overall 5-year survival rate and the 5-year disease-free survival
rate were, respectively, 56% and 51% in the treatment group and 36% and 31% in the control
group.
CONCLUSION: Our positive results are consistent with the results of recent studies; which conclude
that there is a potential benefit from adjuvant chemotherapy in resected gastric cancer.
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Journal of Clinical Oncology, Vol 12, 2687-2693
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Fluorouracil, doxorubicin, and mitomycin combination versus PELF chemotherapy in
advanced gastric cancer: a prospective randomized trial of the Italian Oncology Group for
Clinical Research
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Medical Oncology Institution of Parma, Italy.
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PURPOSE: The combination of cisplatin, epirubicin, and leucovorin preceding
fluorouracil (PELF) includes three novel agents compared with the standard combination
of fluorouracil, doxorubicin, and mitomycin (FAM) in the treatment of advanced gastric
carcinoma. We report the results of a prospective randomized comparison of the two
combinations in previously untreated patients.
PATIENTS AND METHODS: One hundred thirty assessable patients were entered onto the trial;
52 received FAM and 85 PELF. A 1:2 unbalanced randomization in favor of the experimental
treatment was chosen. Approximately 90% of patients had measurable tumor masses.
RESULTS: The overall response rates (complete responses [CRs] and partial responses
[PRs]) were 15% and 43% for the FAM and the PELF regimens, respectively, with a
statistically significant advantage for the experimental treatment (P = .001). Time to
progression (median, 2.6 and 4.7 months), duration of response (median, 10.7 and 10.2
months), and survival durations (median, 5.6 and 8.1 months) were not significantly
different between the FAM and PELF regimens, respectively. The PELF combination was more
toxic compared with FAM, but generally tolerable.
CONCLUSION: This study showed that the PELF combination is about three times more
effective than the FAM combination in inducing objective responses. Due to tolerability, it
is not recommended for routine clinical use. However, it should be considered, among other
second-generation chemotherapy combinations, in future randomized studies aimed to improve
the therapeutic outcome in gastric carcinoma.
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Thank you
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